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Cited by 824Bone Metabolism and DiseasesBone health and osteoporosis researchRheumatoid Arthritis Research and Therapies

Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease

Open access
Kearns, Ann E., Khosla, Sundeep, Kostenuik, Paul J.·2008·Endocrine Reviews
DOI 10.1210/er.2007-0014PMC PMC2528846
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Abstract

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone.Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts.The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle.Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture.Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor B ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling.The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK.Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG.Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength.RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis.Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.(Endocrine Reviews 29: 155-192, 2008) I. Introduction II.Discovery and Validation of the OPG/RANKL/RANK Pathway A. Description of proteins and methods of discovery B. Expression patterns and hormone/cytokine regulation of expression C. Role of OPG, RANK, and RANKL in normal bone turnover D. Non-osseous roles for OPG, RANK, and RANKL III.Pharmacological Effects of RANKL Inhibition in Preclinical Models of Bone Disease A. RANKL and RANKL inhibition in normal healthy animals B. RANKL and RANKL inhibition in ovariectomy models of bone loss C. RANKL and RANKL inhibition in orchiectomy models of bone loss D. RANKL and RANKL inhibition in rheumatoid arthritis models E. RANKL and RANKL inhibition in glucocorticoidinduced bone loss models F. RANKL and RANKL inhibition in disuse osteopenia models G. RANKL and RANKL inhibition in bone metastasis and multiple myeloma models H. RANKL and RANKL inhibition in animal models of breast cancer metastasis to bone I. RANKL and RANKL inhibition in animal models of prostate cancer metastasis to bone J. RANKL and RANKL inhibition in animal models of multiple myeloma K. RANKL and RANKL inhibition in fracture and fracture repair IV.Role and Regulation of OPG/RANKL in the Human Skeleton A. Postmenopausal osteoporosis B. Men C. Glucocorticoid treatment D. Paget's disease of bone E. Rheumatoid arthritis V. Clinical Therapeutics Targeting the RANK/RANKL/OPG System A. Mechanism of action of denosumab B. Clinical studies of denosumab in postmenopausal women with osteoporosis

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Crossref · 10.1210/er.2007-0014

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Claims the paper makes

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  • Findingnone given

    RANKL inhibitors prevent focal bone loss in animal models of rheumatoid arthritis and bone metastasis.

    “RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis.”
    Quote in the paperSubstantial claim
  • Findingnone given

    In numerous animal models of bone disease, RANKL inhibition markedly suppresses bone resorption and increases cortical and cancellous bone volume, density, and strength.

    “Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the MDA-231 treatment model, there was no radiographic or histological progression in mice treated for 7 days with OPG.

    “there was no radiographic or histological progression in mice treated for 7 d with OPG.”
    Quote in the paperSubstantial claim
  • Findingown data

    OPG treatment was associated with nearly complete elimination of tumor-associated osteoclasts in the MDA-231 treatment model.

    “OPG treatment was also associated with a nearly complete elimination of tumor-associated osteoclasts (Fig. 8).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the MDA-231 treatment model, during the final 7 days, radiographic lesion area and histological tumor burden increased by 3-fold in vehicle-treated animals.

    “During those final 7 d, radiographic lesion area and histological tumor burden increased by 3-fold in vehicle-treated animals”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 214
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims.

    Findingown data

    OPG treatment prevented prednisolone-induced bone loss and increased osteoclast surface in rats.

    “OPG treatment prevented these changes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In rats, 45 days of prednisolone was associated with significant bone loss and increased osteoclast surface.

    “In this study, 45 d of prednisolone were associated with significant bone loss and increased osteoclast surface”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In young gonad-intact female mice treated for 3 weeks with human OPG-Fc (5 mg/kg twice weekly), trabecular number was 70% higher in the distal femur and 28% higher in the lumbar vertebra than in vehicle-treated controls.

    “Trabecular no. | ϩ70 a | ϩ28 a”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In young gonad-intact female mice treated for 3 weeks with human OPG-Fc (5 mg/kg twice weekly), trabecular thickness was 13% higher in the distal femur and 22% higher in the lumbar vertebra than in vehicle-treated controls.

    “Trabecular thickness | ϩ13 | ϩ22 a”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In young gonad-intact female mice treated for 3 weeks with human OPG-Fc (5 mg/kg twice weekly), trabecular volumetric BMD was 54% higher in the distal femur and 36% higher in the lumbar vertebra than in vehicle-treated controls.

    “Trabecular volumetric BMD (mg/cm 3 ) | ϩ54 a | ϩ36 a”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In young gonad-intact female mice treated for 3 weeks with human OPG-Fc (5 mg/kg twice weekly), trabecular connectivity in the distal femur was 108% higher than in vehicle-treated controls.

    “Trabecular connectivity | ϩ108 |”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In young gonad-intact female mice treated for 3 weeks with human OPG-Fc (5 mg/kg twice weekly), trabecular bone matrix mineral density was 14% higher in the distal femur and 5% higher in the lumbar vertebra than in vehicle-treated controls.

    “Trabecular bone matrix mineral density | ϩ14 a | ϩ5 a”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In young gonad-intact female mice treated for 3 weeks with human OPG-Fc (5 mg/kg twice weekly), trabecular spacing was 40% lower in the distal femur and 42% lower in the lumbar vertebra than in vehicle-treated controls.

    “Trabecular spacing | Ϫ40 a | Ϫ42”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In young gonad-intact female mice treated for 3 weeks with human OPG-Fc (5 mg/kg twice weekly), trabecular bone volume/total volume was 162% higher in the distal femur and 56% higher in the lumbar vertebra than in vehicle-treated controls.

    “MicroCT data from young gonad-intact female mice treated for 3 wk with either human OPG-Fc (5 mg/kg, twice weekly) or vehicle”
    • Also stated in: § VI. Summary · plain
      “Trabecular bone volume/total volume | ϩ162 a | ϩ56 a”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OPG overexpression in transgenic mice causes high bone mass that progresses with age and is associated with reduced osteoclast numbers and activity.

    “These OPG transgenic mice were born with high bone mass, and this phenotype progressed as animals aged with no evidence of resolution.High bone mass in these animals was associated with marked reductions in osteoclast numbers and activity (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Simonet, 1997, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG is a secreted TNF receptor family member that lacks a transmembrane domain and has no direct signaling properties.

    “OPG is an atypical member of the TNF receptor family in that it is a secreted protein with no transmembrane domain and no direct signaling properties (4,6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Simonet, 1997, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density., Cell source

      Not checked in the free run.

    • cites [6] Yasuda, 1998, Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro., Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG contains four cysteine-rich TNF receptor domains that are necessary and sufficient for binding RANKL and for inhibiting osteoclasts in culture.

    “to its target RANKL (17) and for osteoclast inhibition in cell culture studies (4,16).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Schneeweis, 2005, Functional dissociation of osteoprotegerin and its interaction with receptor activator of NF-κB ligand., J Biol Chem source

      Not checked in the free run.

    • cites [4] Simonet, 1997, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density., Cell source

      Not checked in the free run.

    • cites [16] Yamaguchi, 1998, Characterization and structural domains of human osteoclastogenesis inhibitory factor., J Biol Chem source

      Not checked in the free run.

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    Premisecitation

    OPG/OCIF suppresses osteoclastogenesis in vitro and also suppresses osteoclast activity, survival, and adhesion to bone surfaces.

    “This molecule was referred to as osteoclastogenesis inhibitory factor (OCIF) based on its ability to suppress osteoclastogenesis in vitro (5).OPG/OCIF was shown soon thereafter to also suppress osteoclast activity (7)(8)(9), survival (10,11), and adhesion to bone surfaces (12,13).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [5] Tsuda, 1997, Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis., Biochem Biophys Res Comm source

      Not checked in the free run.

    • cites [7] Akatsu, 1998, Osteoclastogenesis inhibitory factor exhibits hypocalcemic effects in normal mice and in hypercalcemic nude mice carrying tumors associated with humoral hypercalcemia of malignancy., Bone source

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    • cites [8] Hakeda, 1998, Osteoclastogenesis inhibitory factor (OCIF) directly inhibits bone-resorbing activity of isolated mature osteoclasts., Biochem Biophys Res Comm source

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    • cites [9] Burgess, 1999, The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts., J Cell Biol source

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    • cites [10] Akatsu, 1998, Osteoclastogenesis inhibitory factor suppresses osteoclast survival by interfering in the interaction of stromal cells with osteoclast., Biochem Biophys Res Comm source

      Not checked in the free run.

    • cites [11] Lacey, 2000, Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo., Am J Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG, a TNF receptor family member, binds RANKL and prevents activation of RANK, thereby blocking RANKL's catabolic effects.

    “The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Schneeweis, 2005, Functional dissociation of osteoprotegerin and its interaction with receptor activator of NF-κB ligand., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG overexpression increases cortical and cancellous bone mass with reduced osteoclast numbers.

    “OPG overexpression was shown to result in increased cor-tical and cancellous bone mass in association with reduced osteoclast numbers (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Simonet, 1997, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density., Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    RANK tends to be minimally regulated, and modulation of OPG and/or RANKL levels is probably sufficient to control RANK signaling output.

    “RANK tends to be minimally regulated, which is not unexpected because the modulation of OPG and/or RANKL levels is probably sufficient to control the signaling output of RANK.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Reciprocal regulation of RANKL and OPG is often observed and might amplify proresorptive signals.

    “Reciprocal regulation of RANKL and OPG is often observed, a phenomenon that might serve to amplify proresorptive signals (82)(83)(84).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [82] Nagai, 1999, Reciprocal gene expression of osteoclastogenesis inhibitory factor and osteoclast differentiation factor regulates osteoclast formation., Biochem Biophys Res Comm source

      Not checked in the free run.

    • cites [83] Nakagawa, 1999, Basic fibroblast growth factor induces osteoclast formation by reciprocally regulating the production of osteoclast differentiation factor and osteoclastogenesis inhibitory factor in mouse osteoblastic cells., Biochem Biophys Res Comm source

      Not checked in the free run.

    • cites [84] Bord, 2004, Synthesis of osteoprotegerin and RANKL by megakaryocytes is modulated by estrogen., Brit J Haematol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG deficiency is associated with poor bone quality; cortical bone collagen in OPG knockout mice has a woven rather than lamellar orientation, linked to elevated bone turnover.

    “In addition to a deficit in bone quantity, OPG deficiency is associated with poor bone quality as well.Collagen within the cortical bone of OPG knockout mice has a woven rather than lamellar orientation, a phenomenon that is associated with pathologically elevated bone turnover (127).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Min, 2000, Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis., J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PTH infusion into parathyroidectomized rats causes a dose-dependent increase in RANKL mRNA and a dose-dependent decrease in OPG mRNA in bone.

    “PTH infusion led to a dose-dependent increase in RANKL mRNA and a dose-dependent decrease in OPG mRNA (Fig. 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Ma, 2001, Catabolic effects of continuous human PTH (1-38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation., Endocrinology source

      Not checked in the free run.

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    Premisecitation

    β-catenin ablation reduces OPG mRNA in osteoblasts, while gain-of-function β-catenin increases bone mass and OPG mRNA in cultured osteoblasts.

    “OPG mRNA expression was significantly reduced in osteoblasts isolated from these ␤-catenin-ablated mice.In contrast, mice with a gain-of-function mutation in ␤-catenin had high bone mass, and their cultured osteoblasts had increased expression of OPG mRNA.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [119] Glass, 2005, Canonical wnt signaling in differentiated osteoblasts controls osteoclast differentiation., Dev Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    RANK and RANKL knockout mice are virtual phenocopies, indicating that RANK and RANKL have few if any roles beyond their mutual interactions.

    “RANK and RANKL knockout mice were virtual phenocopies of each other (62)(63)(64), which indicated that RANK and RANKL had few if any roles beyond their mutual interactions.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Dougall, 1999, RANK is essential for osteoclast and lymph node development., Genes Dev source

      Not checked in the free run.

    • cites [63] Li, 2000, RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism., Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [64] Kong, 1999, OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis., Nature source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Wnt/β-catenin signaling in osteoblasts may regulate bone mass by coordinating osteoblast and osteoclast activity, with osteoclast regulation occurring through changes in OPG and RANKL.

    “These observations raised the interesting possibility that wnt/␤-catenin signaling in osteoblasts regulates bone mass by coordinating the activity of both osteoblasts and osteoclasts, with osteoclast regulation occurring via changes in OPG and RANKL.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the absence of RANK or RANKL, osteoclasts cannot form, function, or survive.

    “In the absence of RANK or RANKL, osteoclasts cannot form, function, or survive (62-64, 110, 111).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [62] Dougall, 1999, RANK is essential for osteoclast and lymph node development., Genes Dev source

      Not checked in the free run.

    • cites [63] Li, 2000, RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism., Proc Natl Acad Sci USA source

      Not checked in the free run.

    • cites [64] Kong, 1999, OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis., Nature source

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    • cites [110] Pettit, 2001, TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis., Am J Pathol source

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    • cites [111] Li, 2004, RANK signaling is not required for TNFα-mediated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation in TNF α-mediated inflammatory arthritis., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG knockout mice have severe osteopenia with increased bone turnover, cortical porosity, reduced cortical and cancellous bone volume and density, and spontaneous fragility fractures in early life.

    “The essential physiological role of OPG in maintaining bone mass was shown by the severe osteopenic phenotype of OPG knockout mice (124 -126).These mice exhibit increased bone turnover, cortical porosity, and reductions in cortical and cancellous bone volume and density.These deleterious changes are accompanied by spontaneous fragility fractures in the first weeks of life (124).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [124] Bucay, 1998, Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification., Genes Dev source

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    • cites [125] Mizuno, 1998, Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin., Biochem Biophys Res Comm source

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    • cites [126] Nakamura, 2003, Osteoprotegerin regulates bone formation through a coupling mechanism with bone resorption., Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANKL has at least three forms, two of which possess a transmembrane domain and can be cleaved into soluble forms with osteoclast-stimulating activity.

    “There are at least three forms of RANKL, two of which possess a transmembrane domain that positions the biologically active carboxy-terminus to the extracellular domain (i.e., a type II transmembrane protein) (Fig. 2).One of these forms, RANKL2, is a shorter alternative splicing variant of RANKL1 (44).Both of these variants can remain on cell surfaces or can be proteolytically cleaved into soluble”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Ikeda, 2001, Determination of three isoforms of the receptor activator of nuclear factor-κB ligand and their differential expression in bone and thymus., Endocrinology source

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    • cites [45] Hikita, 2006, Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-κB ligand., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANK knockout mice have high bone mass and are virtually devoid of osteoclasts, demonstrating an essential role for RANK in bone resorption.

    “The essential role for RANK in bone resorption was demonstrated soon therafter by the high bone mass phenotype of RANK knockout mice, which were virtually devoid of osteoclasts (62,63).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Dougall, 1999, RANK is essential for osteoclast and lymph node development., Genes Dev source

      Not checked in the free run.

    • cites [63] Li, 2000, RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism., Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Direct injection of IL-1 and/or TNF-α into RANK knockout mice induces few if any osteoclasts, with no bone resorption or hypercalcemia that is seen in similarly challenged wild-type mice.

    “Yet the direct injection of IL-1 and/or TNF-␣ into RANK knockout mice induced the appearance of few if any osteoclasts, with no evidence of bone resorption (115) or hypercalcemia that was apparent in similarly challenged wild-type mice (63).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] Li, 2001, Combination of TNF-α and IL-1β induced osteoclast formation and bone resorption is dependent on RANK signal transduction, J Bone Miner Res

      Not checked in the free run.

    • cites [63] Li, 2000, RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism., Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conditional knockout of β-catenin in osteoblasts increases RANKL and decreases OPG, while increased β-catenin activity reduces RANKL and increases OPG.

    “Other studies showed that the conditional knockout of ␤-catenin in osteoblasts resulted in increased expression of RANKL and decreased expression of OPG.Conversely, increased ␤-catenin activity in osteoblasts was shown to reduce RANKL and increase OPG expression (120).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Holmen, 2005, Essential role of β-catenin in postnatal bone acquisition., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    RANKL plays a dominant role in regulating bone resorption, and no factor or combination has been shown to restore bone resorption when RANKL is absent.

    “These results suggest that RANKL plays a dominant role in the regulation of bone resorption, and no factor or combination of factors have been shown to be capable of restoring bone resorption when RANKL is absent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    RANKL is involved in osteoclast precursor fusion, differentiation into mature osteoclasts, attachment to bone, activation to resorb bone, and survival by avoiding apoptosis.

    “RANKL was implicated in the fusion of osteoclast precursors into multinucleated cells (39), their differentiation into mature osteoclasts (39), their attachment to bone surfaces (12), their activation to resorb bone (9,39), and their continued survival by avoiding apoptosis (11).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Lacey, 1998, Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation., Cell source

      Not checked in the free run.

    • cites [12] O’Brien, 2000, Osteoprotegerin ligand regulates osteoclast adherence to the bone surface in mouse calvaria., Biochem Biophys Res Comm source

      Not checked in the free run.

    • cites [9] Burgess, 1999, The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts., J Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intermittent PTH treatment in humans increases serum RANKL and reduces serum OPG, suggesting that OPG and RANKL might mediate the resorptive response to PTH independent of administration mode.

    “Intermittent PTH treatment in humans was also shown to increase serum RANKL and to reduce serum OPG (93), suggesting that OPG and RANKL might mediate the resorptive response to PTH independent of the mode of PTH administration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Buxton, 2004, Changes in serum receptor activator of nuclear factor-κB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1-34)., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG prevents the ability of proresorptive agents (IL-1, TNF-α, PTH, PTHrP, vitamin D) to increase bone resorption in mice, consistent with those agents increasing resorption by raising the RANKL:OPG ratio.

    “OPG prevents the ability of proresorptive agents (IL-1, TNF-␣, PTH, PTHrP, vitamin D) to increase bone resorption in mice (21), which is consistent with the interpretation that those agents increase bone resorption by increasing the RANKL:OPG ratio.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Morony, 1999, A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1β, TNF-α, PTH, PTHrP, and 1,25(OH)2D3., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANKL injections into adult rats and mice produce rapid skeletal changes resembling lifelong OPG absence: increased bone turnover, cortical porosity, weakened cancellous microarchitecture, and reduced bone volume, density, and strength.

    “RANKL injections led to rapid skeletal changes that closely resembled those associated with the lifelong absence of OPG: increased bone turnover, increased cortical porosity, weakened cancellous microarchitecture, and reductions in bone volume, density, and strength (54 -56).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [54] Yuan, 2005, Soluble RANKL has detrimental effects on cortical and trabecular bone volume, mineralization and bone strength in mice, J Bone Miner Res

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    • cites [55]

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    • cites [56] Yuan, 2006, RANKL infusion as a disease model: implications for bone and vascular systems, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conditional ablation of osteocytes in mice causes rapid bone loss with increased bone resorption, increased skeletal RANKL mRNA, and an increased RANKL:OPG ratio.

    “The conditional ablation of osteoctyes in mice was associated with rapid bone loss in association with increased bone resorption, increased skeletal expression of RANKL mRNA, and an increased RANKL:OPG ratio (123).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Tatsumi, 2007, Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction., Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bisphosphonates have a different mechanism of action and can be associated with normal or increased osteoclast numbers despite clear antiresorptive effects.

    “In contrast, bisphosphonates have a different mechanism of action that can be associated with normal or even increased osteoclast numbers despite clear antiresorptive effects (129 -138).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [129] Sato, 1990, Effects of visphosphonates on isolated rat osteoclasts as examined by reflected light microscopy., J Bone Miner Res source

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    • cites [130] Marshall, 1990, Effects of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate on mouse osteoclasts., J Bone Miner Res source

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    • cites [131] Evans, 1982, The effect of long-term low-dose diphosphonate treatment on rat bone., Clin Orthop source

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    • cites [132] Evans, 1979, The effects of two diphosphonates on bone metabolism in the rat., Metab Bone Dis Relat Res source

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    • cites [133] Marshall, 1993, Osteoclast recruitment in mice is stimulated by (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate., Calcif Tissue Int source

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    • cites [134] Balena, 1993, The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates., J Clin Invest source

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    • cites [135] Herrak, 2004, Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis., Arthritis Rheum source

      Not checked in the free run.

    • cites [136] Redlich, 2002, Tumor necrosis factor α-mediated joint destruction is inhibited by targeting osteoclasts with osteoprotegerin., Arthritis Rheum source

      Not checked in the free run.

    • cites [137] Morony, 2005, The inhibition of RANKL causes greater suppression of bone resorption and hypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy., Endocrinology source

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    • cites [138] Yang Li, 2005, High-dose risedronate treatment partially preserves cancellous bone mass and microarchitecture during long-term disuse., Bone source

      Not checked in the free run.

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    Premisecitation

    Bisphosphonate treatment suppresses vascular calcification in the rat warfarin model, associated with bone turnover suppression.

    “Bisphosphonate treatment of rats also suppressed vascular calcification in this warfarin model, in association with bone turnover suppression (145).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] Price, 2001, Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption., Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recombinant OPG and RANKL are notable for rapid effects on bone resorption and for regulating osteoclast numbers.

    “Two interesting hallmarks of recombinant OPG and RANKL are the rapidity of their effects on bone resorption and their ability to regulate osteoclast numbers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Prolonged osteoclast suppression with OPG-Fc is probably due to the drug's long circulating half-life and the time needed to regenerate osteoclasts from precursors after clearance.

    “The prolonged duration of osteoclast suppression with OPG-Fc treatment was probably related to the long circulating half-life of the drug (24), as well as the time required to regenerate new osteoclasts from their precursor population once the drug is cleared (11).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Capparelli, 2003, Sustained antiresorptive effects after a single treatment with human recombinant osteoprotegerin (OPG): a pharmacodynamic and pharmacokinetic analysis in rats., J Bone Miner Res source

      Not checked in the free run.

    • cites [11] Lacey, 2000, Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo., Am J Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bone turnover and RANKL levels are systemically elevated in OPG knockout mice.

    “Bone turnover and RANKL levels are both systemically elevated in OPG knockout mice (143)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Bennett, 2006, Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice., Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Observational studies frequently show positive correlations between serum OPG levels and vascular disease, while correlations between serum OPG and fractures or BMD are inconsistent.

    “observational studies frequently show positive correlations between serum OPG levels and vascular disease, although the correlation between serum OPG levels and fractures or BMD is inconsistent as discussed in Section IV.A (151,(153)(154)(155)(156)(157)(158)(159)(160).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites (151,(153)(154)(155)(156)(157)(158)(159)(160)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In postmenopausal women, aortic calcifications are inversely related to bone density and positively associated with fractures.

    “Observational studies in postmenopausal women showed that aortic calcifications were inversely related to bone density and positively associated with fractures (152).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Schulz, 2004, Aortic calcification and the risk of osteoporosis and fractures., J Clin Endorinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although OPG and bisphosphonates have opposite effects on endothelial cell survival, both suppress bone turnover and prevent vascular calcification in a similar animal model.

    “Thus, although OPG and bisphosphonates can have opposite effects on the survival of endothelial cells, both agents suppress bone turnover and prevent vascular calcification when tested in a similar animal model (144, 145).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [144] Price, 2001, Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D., Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

    • cites [145] Price, 2001, Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption., Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An LDL receptor knockout mouse on a high-fat diet recapitulates progressive atherosclerosis and vascular calcification with elevated endogenous OPG.

    “Those very conditions were recently described in an animal model involving LDL receptor knockout mice on a high-fat diet (167).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Shao, 2004, Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice., J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG transgenic mice show an osteopetrotic phenotype with high bone mass but without major changes in long-bone external shape or defective tooth eruption.

    “OPG transgenic mice exhibited an osteopetrotic phenotype, with high bone mass but without significant changes in the external shape of their long bones or defective tooth eruption (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Simonet, 1997, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bisphosphonates suppress proliferation, adhesion, migration, and survival of endothelial cells in vitro and induce endothelial apoptosis in vivo.

    “these agents have also been shown to suppress the proliferation, adhesion, migration, and survival of endothelial cells in vitro (147, 148) while inducing endothelial cell apoptosis in vivo (149).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [147] Wood, 2002, Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid., J Pharm Exp Ther source

      Not checked in the free run.

    • cites [148] Bezzi, 2003, Zoledronate sensitizes endothelial cells to tumor necrosis factor-induced programmed cell death: evidence for the suppression of sustained activation of focal adhesion kinase and protein kinase B/Akt., J Biol Chem source

      Not checked in the free run.

    • cites [149] Giraudo, 2004, An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vascular calcification in OPG knockout animals can be prevented by transgenic overexpression of soluble OPG, indicating systemic RANKL inhibition can prevent vascular consequences of endogenous OPG deficiency.

    “This vascular calcification could be prevented via transgenic overexpression of soluble OPG, indicating that systemic RANKL inhibition could prevent the vascular consequences of endogenous OPG deficiency (127).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Min, 2000, Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis., J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG treatment had no effect on aortic inflammatory cytokine concentrations or plasma cholesterol levels in these mice.

    “OPG had no effect on concentrations of inflammatory cytokines in the aorta or on plasma cholesterol levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Morony, 2008, Osteoprotegrin (OPG) inhibits vascular calcification without affecting atherosclerosis in ldlr(−/−) mice., Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In LDL receptor knockout mice on a high-fat diet, 5 months of OPG treatment significantly reduced calcified lesion area in the aorta without affecting atherosclerotic lesion size or number.

    “OPG treatment significantly reduced calcified lesion area in the aorta of these mice, without affecting atherosclerotic lesion size or number (166).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Morony, 2008, Osteoprotegrin (OPG) inhibits vascular calcification without affecting atherosclerosis in ldlr(−/−) mice., Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG therapy consistently suppresses vascular calcification in animal models, but data on its effects on atherogenesis or other vascular disease aspects are minimal.

    “Although OPG therapy consistently suppresses vascular calcification in animal models (127, 144, 166), there are minimal data on the effects of OPG therapy on atherogenesis or other aspects of vascular disease.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [127] Min, 2000, Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis., J Exp Med source

      Not checked in the free run.

    • cites [144] Price, 2001, Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D., Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

    • cites [166] Morony, 2008, Osteoprotegrin (OPG) inhibits vascular calcification without affecting atherosclerosis in ldlr(−/−) mice., Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG knockout animals develop medial calcification of the aorta and renal arteries along with elevated bone turnover.

    “OPG knockout animals developed medial calcification of the aorta and renal arteries, in association with elevated bone turnover (124).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Bucay, 1998, Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification., Genes Dev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANK-Fc transgenic animals resemble OPG transgenics in having high bone mass, normal bone shape, and normal tooth eruption.

    “Similar to OPG transgenic animals, RANK-Fc transgenic animals had high bone mass, normal bone shape, and normal tooth eruption.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Hsu, 1999, Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand., Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Short-term (up to 2 weeks) RANKL inhibition by OPG in mice did not impair cell-mediated reactions, innate immunity, humoral responses, or influenza infection.

    “Short-term (up to 2-wk) mouse studies have show that RANKL inhibition by OPG did not impair cell-mediated reactions such as contact hypersensitivity or granuloma formation, innate immunity, humoral responses to defined immune challenges (175), or influenza infection (173).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [175] Stolina, 2003, Regulatory effects of osteoprotegerin on cellular and humoral immune responses., Clin Immunol source

      Not checked in the free run.

    • cites [173] Miller, 2005, The RANKL inhibitor RANK-Fc has potent antiresorptive efficacy but does not affect host immune responses to influenza infection, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANKL knockout mice have no lymph nodes but no apparent intrinsic immune cell defect, as their T and B cells can populate lymph nodes of wild-type mice.

    “Although RANKL knockout mice had no lymph nodes, there was no apparent intrinsic defect in immune cells from those animals, because T and B cells from RANKL knockout mice were able to populate the lymph nodes of normal wild-type mice (64).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Kong, 1999, OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph node organogenesis., Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANK and RANKL knockout mice have normal Peyer's patches and intact splenic architecture, indicating lymph node and secondary lymphoid organ development can be differentially regulated.

    “However, RANK and RANKL knockout mice had normal Peyer's patches and intact splenic architecture (49,62), indicating that the development of lymph nodes and secondary lymphoid organs can be differentially regulated.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [49] Kong, 1999, Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand., Nature source

      Not checked in the free run.

    • cites [62] Dougall, 1999, RANK is essential for osteoclast and lymph node development., Genes Dev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pregnant RANK knockout mice fail to lactate and their litters do not survive.

    “whereas pregnant RANK knockout mice failed to lactate and their litters did not survive.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Fata, 2000, The osteoclast differentiation factor osteoprotegerin ligand is essential for mammary gland development., Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG transgenic rat and mouse pups are viable, show normal suckling, and survive to weaning without supplemental feeding.

    “OPG transgenic rat and mouse pups are viable, show normal suckling behaviors, and survive to weaning without supplemental feeding (Ref.4, and P. J. Kostenuik, unpublished observations).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (Ref.4, and P. J. Kostenuik, unpublished observations)

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These results support the hypothesis that OPG reduces vascular calcification via suppression of bone turnover, with a neutral effect on atherosclerotic changes.

    “These results support the hypothesis that OPG might reduce vascular calcification via suppression of bone turnover, with a neutral effect on atherosclerotic changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    There is no evidence that suppression of bone remodeling in mice or rats reduces whole bone strength, and abundant evidence that it increases bone strength in those species and nonhuman primates.

    “There is no evidence that suppression of bone remodeling in mice or rats results in reduced whole bone strength and abundant evidence (described in Sections III.A, B, and F) that suppression of bone remodeling increases bone strength in those species and in nonhuman primates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These changes were associated with progressive increase in cancellous bone volume and significant BMD increase at day 30 versus vehicle controls.

    “These changes were associated with a progressive increase in cancellous bone volume and a significant increase in bone mineral density (BMD) at d 30 compared with vehicle-treated controls (24).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Capparelli, 2003, Sustained antiresorptive effects after a single treatment with human recombinant osteoprotegerin (OPG): a pharmacodynamic and pharmacokinetic analysis in rats., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    OPG and RANKL play important ongoing roles in maintaining bone mass and regulating normal bone remodeling in healthy animals.

    “Studies in normal healthy animals have revealed that OPG and RANKL play important ongoing roles in the maintenance of bone mass and in the regulation of normal bone remodeling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In animal models of inflammatory bone loss, RANKL inhibition preserved bone without significant effects on the inflammatory component.

    “Similar findings have been noted in animal models of inflammatory bone loss, wherein RANKL inhibition effectively preserved bone while having no significant effects on the inflammatory component of disease (26,110,136,(177)(178)(179)(180)(181).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (26,110,136,(177)(178)(179)(180)(181)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANKL is expressed by T cells, RANK by dendritic cells, and OPG by B lymphocytes and dendritic cells.

    “Within the developed immune system, RANKL is expressed by T cells (42), RANK is expressed by dendritic cells (49), and OPG is expressed by B lymphocytes and dendritic cells (4,70).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [42] Wong, 1997, TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor., J Exp Med source

      Not checked in the free run.

    • cites [49] Kong, 1999, Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand., Nature source

      Not checked in the free run.

    • cites [4] Simonet, 1997, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density., Cell source

      Not checked in the free run.

    • cites [70] Yun, 1998, OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40., J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG is overexpressed 100-fold during gestation and throughout life in these animals, associated with marked bone turnover suppression.

    “OPG is overexpressed in these animals by 100-fold during gestation and throughout life, and this level of OPG was associated with marked suppression of bone turnover (169, 182).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [169] Stolina, 2006, Rats overexpressing soluble OPG from a prenatal stage have high bone mass but no alterations in the development of lymphoid organs or innate immune response, J Bone Miner Res

      Not checked in the free run.

    • cites [182] Stolina, 2007, Continuous RANKL inhibition in OPG transgenic mice and rats suppresses bone resorption without impairing lymphorganogenesis or functional immune responses., J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    OPG transgenic rats had marked bone turnover suppression and increased BMD, demonstrating RANKL inhibition can suppress turnover without measurable changes in integrated immune response.

    “OPG transgenic rats in these studies had marked suppression of bone turnover and increased BMD, thereby demonstrating that RANKL inhibition can cause turnover suppression in the absence of measurable changes in the integrated response of the immune system (169).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [169] Stolina, 2006, Rats overexpressing soluble OPG from a prenatal stage have high bone mass but no alterations in the development of lymphoid organs or innate immune response, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG treatment significantly increased lumbar and leg BMD and biomechanical strength at lumbar vertebrae and femoral shaft.

    “OPG treatment also significantly increased lumbar and leg BMD, while increasing biomechanical strength parameters at the lumbar vertebrae and femoral shaft.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Kostenuik, 2001, OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats., Endocrinology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Ovariectomy is a model of surgical menopause with a more precipitous estrogen drop than natural menopause.

    “Ovariectomy (OVX) represents a model of surgical menopause, wherein estrogen levels drop more precipitously compared with the slower decline seen in natural menopause.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    OVX is associated with increased bone turnover and reductions in BMD, volume, and strength in mice, rats, and cynomolgus monkeys.

    “OVX is associated with increased bone turnover and reductions in BMD, volume, and strength in numerous species, including mice, rats, and cynomolgus monkeys.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OPG showed significantly greater changes in femur BMD, vertebral bone volume, and osteoclast numbers compared with alendronate.

    “OPG also showed significantly greater changes in fe-mur BMD, vertebral bone volume, and osteoclast numbers when compared with alendronate (203).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Samadfam, 2007, Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, estrogen deficiency is associated with increased RANKL expression by bone marrow osteoblastic, T, and B cells, and estrogen treatment reverses this increase.

    “In humans, estrogen deficiency is associated with increased RANKL expression by bone marrow osteoblastic, T and B cells, whereas estrogen treatment reversed this increase ( 76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Eghbali-Fatourechi, 2003, Role of RANK ligand in mediating increased bone resorption in early postmenopausal women., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normal healthy rats, 4 weeks of RANKL infusion reduced matrix mineralization, decreased trabecular and cortical bone volume, reduced trabecular connectivity, and reduced bone strength.

    “In normal healthy rats, 4 wk of RANKL infusion led to reduced matrix mineralization, decreased trabecular and cortical bone volume, reduced trabecular connectivity, and reduced bone strength (56).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Yuan, 2006, RANKL infusion as a disease model: implications for bone and vascular systems, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this study, OPG but not alendronate increased mechanical strength of the femoral shaft.

    “In this study OPG, but not alendronate, increased the mechanical strength of the femoral shaft.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Samadfam, 2007, Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a separate study, OPG preserved bone density in OVX rats and fully prevented OVX-related cancellous microarchitecture changes.

    “In a separate study, OPG was shown to preserve bone density in OVX rats while fully preventing the deleterious OVX-related changes in cancellous microarchitecture (200).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Li, 2006, RANKL inhibition with OPG preserves bone density and trabecular architecture in ovariectomized rats, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In normal healthy mice, 10 days of recombinant RANKL injections reduced matrix mineralization, reduced trabecular bone volume by 85%, caused deleterious cortical geometry changes, and reduced bone strength.

    “In normal healthy mice, 10 d of recombinant RANKL injections led to reduced matrix mineralization, an 85% reduction in trabecular bone volume, deleterious changes in cortical geometry, and significantly reduced bone strength (54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Yuan, 2005, Soluble RANKL has detrimental effects on cortical and trabecular bone volume, mineralization and bone strength in mice, J Bone Miner Res

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Denosumab is a fully human monoclonal antibody that inhibits RANKL.

    “Denosumab (previously known as AMG 162) is a fully human monoclonal antibody that inhibits RANKL.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    OPG treatment of normal rats increases matrix mineralization and improves bone strength.

    “OPG treatment of normal rats was shown to increase matrix mineralization and improve bone strength (185).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Ross, 2001, The effects of osteoprotegerin on the mechanical properties of rat bone., J Mater Sci Mater Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both OPG and alendronate significantly suppressed osteoclast and osteoblast numbers and biochemical markers of bone turnover.

    “Both agents also caused significant suppression of osteoclast and osteoblast numbers, as well as biochemical markers of bone turnover.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Samadfam, 2007, Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    No clinical signs of hypocalcemia were noted in this toxicology study, perhaps due to OPG-related PTH increase maintaining serum calcium asymptomatically.

    “No clinical signs of hypocalcemia were noted in this toxicology study, perhaps due to an observed OPG-related increase in serum PTH that maintained serum calcium at an asymptomatic level.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Smith, 2003, A toxicity profile of osteoprotegerin in the cynomolgus monkey., Int J Toxicol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANKL causes deleterious effects on trabecular microarchitecture in normal rats and reduces matrix mineralization in normal mice, while OPG treatment has opposite effects in normal mice.

    “While RANKL caused deleterious effects on trabecular microarchitecture in normal rats (56) and reduced matrix mineralization in normal mice (56), OPG treatment was recently shown to have the opposite effects in normal mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Yuan, 2006, RANKL infusion as a disease model: implications for bone and vascular systems, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG treatment in these old OVX rats reduced osteoclast surfaces and increased cancellous bone volume in vertebrae and tibiae.

    “OPG treatment was associated with marked reductions in osteoclast surfaces and increased cancellous bone volume in the vertebrae and tibiae.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Kostenuik, 2001, OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats., Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In 2- to 3-month-old Black Swiss/129 gonad-intact mice, 3 weeks of OPG-Fc treatment was associated with significantly greater bone volume, volumetric BMD, bone matrix mineral density, trabecular thickness, number, and connectivity.

    “OPG treatment was associated with significantly greater bone volume, volumetric BMD, bone matrix mineral density, trabecular thickness, number, and connectivity (Table 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (Table 3)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG levels have been reported to increase or decrease after OVX, possibly due to animal model or tissue source differences.

    “OPG levels have been reported to increase (199) or decrease (198,201) in association with OVX, and this difference in response could relate to variations in the animal model and/or the tissue source analyzed.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [199] Miyazaki, 2004, Changes in receptor activator of nuclear factor-κB, and its ligand, osteoprotegerin, bone-type alkaline phosphatase, and tartrate-resistant acid phosphatase in ovariectomized rats., J Cell Biochem source

      Not checked in the free run.

    • cites [198] Yoneda, 2004, Estrogen deficiency accelerates murine autoimmune arthritis asociated with receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis., Endocrinology source

      Not checked in the free run.

    • cites [201] Wang, 2007, Knocking down dickkopf-1 alleviates estrogen deficiency induction of bone loss. A histomorphological study in ovariectomized rats., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In young adult OVX mice, both OPG and alendronate prevented OVX-related decreases in spine and femur BMD and increased vertebral cancellous bone volume.

    “Both agents prevented OVX-related decreases in spine and femur BMD, while increasing vertebral cancellous bone volume.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Samadfam, 2007, Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Long-term RANKL inhibition improves bone strength in normal animals primarily by increasing bone mass while preserving bone matrix quality.

    “These data suggest that long-term RANKL inhibition improves bone strength in normal animals primarily by increasing bone mass, while preserving the quality of bone matrix.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Total genetic ablation of RANKL in knockout mice rendered animals resistant to arthritis-related joint destruction, with osteoclasts essentially absent in joints.

    “Total genetic ablation of RANKL in knockout mice rendered the animals resistant to arthritis-related joint destruction, and osteoclasts were essentially absent in their joints (110).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Pettit, 2001, TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis., Am J Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    A key difference between standard ORX rat models and human androgen deprivation therapy is the presence of prostate cancer in humans and its absence in ORX rats.

    “An important distinction between standard ORX rat models and androgen deprivation therapy in humans is the existence of prostate cancer in the latter population and the lack thereof in ORX rats.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    OPG stimulates proliferation and differentiation of cultured osteoblasts.

    “OPG was recently shown to stimulate the proliferation and differentiation of cultured osteoblasts (203)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [203] Samadfam, 2007, Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG, RANK, and RANKL are expressed at the protein level in human articular cartilage, but their functional roles in cartilage are not clearly demonstrated.

    “OPG, RANK, and RANKL are all expressed at the protein level in human articular cartilage, but their functional roles in cartilage have not been clearly demonstrated (238).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [238] Komuro, 2001, The osteoprotegerin/receptor activator of nuclear factor κB/receptor activator of nuclear factor κB ligand system in cartilage., Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Denosumab improved bone strength primarily by increasing bone mass, and bone formed during denosumab therapy has normal material properties.

    “These results suggest that denosumab improved bone strength primarily by increasing bone mass, and that bone formed during denosumab therapy has normal material properties.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    In those arthritic rat models, RANKL protein levels increased in inflamed joints, leading to marked increases in the RANKL:OPG ratio.

    “RANKL protein levels were concomitantly increased in inflamed joints, leading to marked increases in the RANKL:OPG ratio.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Rheumatoid arthritis is characterized by multiple forms of osteoclast-mediated bone loss, including focal bone erosions at the bone-pannus junction, subchondral bone loss adjacent to inflamed joints, and generalized systemic bone loss.

    “multiple forms of osteoclast-mediated bone loss that are characteristic of the disease, including focal bone erosions at the bone-pannus junction of inflamed joints, subchondral (periarticular) bone loss adjacent to inflamed joints, and generalized systemic bone loss (223-227).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [223] Goldring, 2002, Pathogenesis of bone lesions in rheumatoid arthritis., Curr Rheumatol Rep source

      Not checked in the free run.

    • cites [224] Gough, 1994, Generalised bone loss in patients with early rheumatoid arthritis., Lancet source

      Not checked in the free run.

    • cites [225] Romas, 2000, Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis., Arthritis Rheum source

      Not checked in the free run.

    • cites [226] Shimizu, 1985, Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis., Arthritis Rheum source

      Not checked in the free run.

    • cites [227] Kapur, 2004, Malignant autosomal recessive osteopetrosis caused by spontaneous mutation of murine RANK., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In orchiectomized rats, histomorphometry showed significant reductions in periosteal bone formation rate and cancellous bone volume.

    “histomorphometry showed significant ORX-related reductions in periosteal bone formation rate and cancellous bone volume.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [222] Li, 2005, RANKL inhibition improves cortical bone geometry by stimulating periosteal bone formation in orchiectomized rats, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG treatment fully prevented the ORX-related reductions in BMD, periosteal bone formation rate, and cancellous bone volume.

    “OPG treatment fully prevented each of these changes (222).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [222] Li, 2005, RANKL inhibition improves cortical bone geometry by stimulating periosteal bone formation in orchiectomized rats, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DEX prolongs osteoclast lifespan while decreasing their individual capacity to degrade bone.

    “DEX was recently shown to prolong the lifespan of osteoclasts, while decreasing their individual capacity to degrade bone (257).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [257] Kim, 2006, Glucocorticoids suppress bone formation via the osteoclast., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A more likely mechanism for chondroprotection is OPG preservation of subchondral bone, which preserves joint geometry and prevents osteoclasts from undermining epiphyses.

    “A more likely mechanism for chondroprotection is related to the well-established ability of OPG to preserve subchondral bone, which helps to preserve the geometry of the joint while preventing osteoclasts from undermining the epiphyses from within.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The skeletal response to prednisolone in these rats shared similarities to humans, including decreased BMD, histological evidence of increased bone resorption, and biochemical evidence of suppressed bone formation.

    “the skeletal response to prednisolone in these rats shared several similarities to changes observed in humans, including significantly decreased BMD (243), histological evidence of increased bone resorption (194), and biochemical evidence of suppressed bone formation (244, 267, 268).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [243] Israel, 2001, Effects of inhaled glucocorticoids on bone density in premenopausal women., N Engl J Med source

      Not checked in the free run.

    • cites [194] Dalle Carbonare, 2001, Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis., J Bone Miner Res source

      Not checked in the free run.

    • cites [244] Tirpitz, 2003, Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn’s disease., Eur J Gastroenterol Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glucocorticoids have complex effects on bone, virtually all detrimental.

    “Glucocorticoids also have remarkably complex effects on bone, virtually all of which are detrimental, and these influences have been summarized in recent reviews (241,242).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [241] Canalis, 2003, Mechanisms of glucocorticoid-induced osteoporosis., Curr Opin Rheumatol source

      Not checked in the free run.

    • cites [242] Patschan, 2001, Molecular mechanisms of glucocorticoid-induced osteoporosis., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spinal cord injury is associated with decreased BMD, increased fracture risk, and deterioration of cortical geometry.

    “Spinal cord injury is associated with decreased BMD, increased fracture risk, and deterioration of cortical geometry (270, 271).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [270] Modlesky, 2005, Deteriorated geometric structure and strength of the midfemur in men with complete spinal cord injury., Bone source

      Not checked in the free run.

    • cites [271] Jiang, 2006, Osteoporosis after spinal cord injury., Osteoporos Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous RANKL did not appear to activate signaling in cultured chondrocytes, suggesting RANK might be functionally inactive in those cells.

    “exogenous RANKL did not appear to activate signaling in cultured chondrocytes, suggesting that RANK might be functionally inactive in those cells (238).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [238] Komuro, 2001, The osteoprotegerin/receptor activator of nuclear factor κB/receptor activator of nuclear factor κB ligand system in cartilage., Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biochemical markers of bone resorption and osteoclast numbers are significantly elevated in spaceflight and bed rest.

    “Biochemical markers of bone resorption and osteoclast numbers are significantly elevated in spaceflight and bed rest (275, 276)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [275] Smith, 1998, Collagen cross-link excretion during space flight and bed rest., J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [276] Chappard, 1991, Cortical osteoclasts are less sensitive to etidronate than trabecular osteoclasts., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glucocorticoids can inhibit osteoblast differentiation, attachment to bone matrix, and production of IGF-I.

    “Glucocorticoids can also inhibit osteoblast differentiation (249 -251), osteoblast attachment to bone matrix (252), and osteoblast production of IGF-I (253).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [249] Ishida, 1998, Glucocorticoid-induced osteoporosis: both in vivo and in vitro concentrations of glucocorticoids higher than physiological levels attenuate osteoblast differentiation., J Bone Miner Res source

      Not checked in the free run.

    • cites [250] Lian, 1997, Species-specific glucocorticoid and 1,25-dihydroxyvitamin D responsiveness in mouse MC3T3–E1 osteoblasts: dexamethasone inhibits osteoblast differentiation and vitamin D down-regulates osteocalcin gene expression., Endocrinology source

      Not checked in the free run.

    • cites [251] Weinstein, 1998, Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone., J Clin Invest source

      Not checked in the free run.

    • cites [252] Gronowicz, 1995, Glucocorticoids inhibit the attachment of osteoblasts to bone extracellular matrix proteins and decrease β1 integrin levels., Endocrinology source

      Not checked in the free run.

    • cites [253] McCarthy, 1990, Cortisol inhibits the synthesis of insulin-like growth factor-I in skeletal cells., Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In another rat study, prednisolone infusion reduced biochemical markers of bone resorption and formation and paradoxically increased cancellous bone volume.

    “In another rat study, prednisolone infusion led to reductions in biochemical markers of bone resorption and bone formation and a paradoxical increase in cancellous bone volume (265).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [265] King, 1996, Effects of continuous glucocorticoid infusion on bone metabolism in the rat., Calcif Tissue Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The prednisolone-related increase in bone volume in rats is not consistent with histological data from patients with glucocorticoid-induced osteoporosis and is a recognized limitation of the model.

    “The prednisolonerelated increase in bone volume in rats, confirmed in a study described immediately below (262), is not consistent with histological data from patients with glucocorticoid-induced osteoporosis (194) and is a recognized limitation of the model (251).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [262] Morony, 2001, Osteoprotegerin (OPG) prevents bone loss in a rat model of glucocorticoid-induced osteopenia, J Bone Miner Res

      Not checked in the free run.

    • cites [194] Dalle Carbonare, 2001, Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis., J Bone Miner Res source

      Not checked in the free run.

    • cites [251] Weinstein, 1998, Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    OPG's ability to markedly reduce osteoclasts and prevent prednisolone-related BMD loss suggests RANKL inhibition is a potential new strategy for treatment and prevention of glucocorticoid-induced bone loss.

    “The ability of OPG to markedly reduce osteoclasts and to prevent the prednisolone-related loss of BMD suggests that RANKL inhibition represents a potential new strategy for the treatment and prevention of glucocorticoid-induced bone loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Glucocorticoids suppress OPG mRNA expression in primary human osteoblasts and osteoblast cell lines while up-regulating RANKL expression.

    “Glucocorticoids have been shown to suppress OPG mRNA expression in primary human osteoblasts and in osteoblast cell lines (254, 258), while up-regulating RANKL expression (254).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [254] Hofbauer, 1999, Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis., Endocrinology source

      Not checked in the free run.

    • cites [258] Vidal, 1998, Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: down-regulation by glucocorticoids., J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The most universally described skeletal consequence of glucocorticoid therapy is reduction in BMD, which can lead to increased fracture risk.

    “The most universally described skeletal consequence of glucocorticoid therapy is a reduction in BMD, which can lead to increased fracture risk (243-245).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [243] Israel, 2001, Effects of inhaled glucocorticoids on bone density in premenopausal women., N Engl J Med source

      Not checked in the free run.

    • cites [244] Tirpitz, 2003, Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn’s disease., Eur J Gastroenterol Hepatol source

      Not checked in the free run.

    • cites [245] Kanis, 2004, A meta-analysis of prior corticosteroid use and fracture risk., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prednisolone infusion in rats suppresses bone growth and decreases cortical area and cortical strength.

    “Prednisolone infusion in rats resulted in suppressed bone growth and decreases in cortical area and cortical strength (263).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [263] Ortoft, 1995, Growth hormone is not able to counteract osteopenia of rat cortical bone induced by glucocorticoid with protracted effect., Bone source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Animal studies account for in vivo RANKL:OPG ratio and might have greater relevance than cell culture models.

    “Regardless of net effects of glucocortoids on the RANKL: OPG ratio in vivo, animal studies account for this variable and might therefore have greater relevance than cell culture models.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DEX and prednisolone inhibit OPG production and increase RANKL production by human osteoblasts, leading to increased RANKL:OPG ratio.

    “DEX and prednisolone were shown to inhibit OPG production and increase RANKL production by human osteoblasts, leading to increased RANKL:OPG ratio (259).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Humphrey, 2006, Effects of dissociated glucocorticoids on OPG and RANKL in osteoblastic cells., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In minipigs, prednisolone decreases biochemical parameters of bone resorption and formation while decreasing bone growth and strength.

    “In minipigs, prednisolone decreased biochemical parameters of bone resorption and bone formation while decreasing bone growth and bone strength (264).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [264] Ikeda, 2003, Reductions in bone turnover, mineral, and structure associated with mechanical properties of lumbar vertebra and femur in glucocorticoid-treated growing minipigs., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glucocorticoids stimulate osteoblasts to produce M-CSF, an important cofactor for osteoclastogenesis.

    “Glucocorticoids also stimulate osteoblasts to produce M-CSF (260), which is an important cofactor for osteoclastogenesis (261).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [260] Rubin, 1998, Dexamethasone promotes expression of membrane-bound macrophage colony-stimulating factor in murine osteoblast-like cells., Endocrinology source

      Not checked in the free run.

    • cites [261] Arai, 1999, Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor κB (RANK) receptors., J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, prednisolone-induced BMD loss is associated with decreased osteocalcin and decreased bone formation, with no histological or biochemical evidence for increased bone resorption.

    “In mice, BMD loss with prednisolone was associated with decreased osteocalcin and decreased bone formation, with no histological or biochemical evidence for increased bone resorption (251).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [251] Weinstein, 1998, Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a bone xenograft model, glucocorticoids inhibited osteoclast recruitment and bone resorption, whereas delayed glucocorticoid treatment stimulated osteoclast activity and bone resorption.

    “A bone xenograft model showed that glucocorticoids inhibited osteoclast recruitment and bone resorption, whereas delayed treatment with glucocorticoids resulted in stimulation of osteoclast activity and bone resorption (256).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Defranco, 1992, Differential effects of glucocorticoid on recruitment and activity of osteoclasts induced by normal and osteocalcin-deficient bone implanted in rats., Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bisphosphonates are frequently ineffective at improving cortical bone strength in rat unloading models, even when cancellous bone strength is significantly improved.

    “bisphosphonates are frequently ineffective at improving cortical bone strength in rat unloading models (284 -286), even when cancellous bone strength was significantly improved (286).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [284] Kodama, 1997, Inhibition of bone resorption by pamidronate cannot restore normal gain in cortical bone mass and strength in tail-suspended rapidly growing rats., J Bone Miner Res source

      Not checked in the free run.

    • cites [285] Apseloff, 1993, Effects of aminohydroxybutane bisphosphonate on bone growth when administered after hind limb bone loss in tail-suspended rats., J Pharmacol Exp Ther

      Not checked in the free run.

    • cites [286] Mosekilde, 2000, Treatment with risedronate or alendronate prevents hind-limb immobilization-induced loss of bone density and strength in adult female rats., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In unloaded dogs treated with bisphosphonates, there was no evidence of suppression of cortical bone resorption, and cortical bone strength remained significantly lower than normally loaded controls.

    “There was no evidence of suppression of cortical bone resorption in unloaded dogs treated with bisphosphonates, and cortical bone strength in treated animals remained significantly lower than the strength of normally loaded control bones (282).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [282] Li, 2005, Long-term disuse osteoporosis seems less sensitive to bisphosphonate treatment than other osteoporosis., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bisphosphonates act by binding directly to mineralized bone matrix and directly inhibiting activity of osteoclasts that attempt to degrade bisphosphonate-laden bone.

    “These agents act by binding directly to mineralized bone matrix and directly inhibiting the activity of osteoclasts that attempt to degrade bisphosphonate-laden bone (140).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Sato, 1991, Bisphosphonate action: alendronate localization in rat bone and effects on osteoclast ultrastructure., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a botulism toxin mouse model of disuse osteopenia, OPG treatment prevented deficits in cancellous bone volume and unloading-related decreases in cortical thickness, volume, and strength.

    “In this model, OPG treatment was shown to prevent deficits in cancellous bone volume as well as the unloadingrelated decreases in cortical thickness, volume, and strength (297).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [297] Warner, 2006, RANKL inhibition prevents the loss of bone volume and bone strength caused by Botox induced muscle paralysis., Trans Orthoped Res Soc

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single injection of OPG before a 12-day spaceflight caused significant increases in BMD and improved strength of the femoral diaphysis of mice.

    “a single injection of OPG before a 12-d spaceflight caused significant increases in BMD and improved the strength of the femoral diaphysis of mice (294,295).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [294] Bateman, 2002, Osteoprotegerin mitigates spaceflight-induced changes in mouse bone mass, density and mineral composition, J Bone Miner Res

      Not checked in the free run.

    • cites [295] Kostenuik, 2002, OPG prevents relative osteopenia and deficits in skeletal strength in mice during a 12 day spaceflight, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Paget observed that certain cancer cells had a predilection to metastasize to bone and proposed that the bone microenvironment provided fertile soil for localization and growth of particular cancer cells.

    “British surgeon Stephen Paget observed that certain cancer cells had a predilection to metastasize to bone, and he proposed that the bone microenvironment provided a fertile”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [299] Paget, 1889, The distribution of secondary growths in cancer of the breast., Lancet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The vicious cycle model posits that bone resorption attracts tumor cells and stimulates their growth, while tumor cells promote osteoclast formation and activity, resulting in more bone resorption.

    “This rationale is predicated on the interruption of a”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OPG preserved bone mass and increased cortical bone strength in tail-suspended mice.

    “OPG preserved bone mass and increased cortical bone strength in tail-suspended mice (186).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Bateman, 2000, Osteoprotegerin mitigates tail suspension-induced osteopenia., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prostate cancer cells and multiple myeloma cells express RANKL directly.

    “prostate cancer cells (CaP) (314 -316) and MM cells (317-322) have been shown to express RANKL directly.”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [314] Zhang, 2003, Soluble receptor activator of nuclear factor κB Fc diminishes prostate cancer progression to bone., Cancer Res

      Not checked in the free run.

    • cites [315] Brown, 2001, Osteoprotegerin and RANK ligand expression in prostate cancer., Urology source

      Not checked in the free run.

    • cites [316] Zhang, 2001, Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone., J Clin Invest source

      Not checked in the free run.

    • cites [317] Farrugia, 2003, Receptor activator of nuclear factor-κB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo., Cancer Res

      Not checked in the free run.

    • cites [318] Lai, 2004, Myeloma cells can directly contribute to the pool of RANKL in bone bypassing the classic stromal and osteoblast pathway of osteoclast stimulation., Brit J Haematol source

      Not checked in the free run.

    • cites [319] Roux, 2002, RANK (receptor activator of nuclear factor-κB) and RANKL expression in multiple myeloma., Brit J Haematol source

      Not checked in the free run.

    • cites [320] Sezer, 2002, Immunohistochemistry reveals RANKL expression of myeloma cells., Blood source

      Not checked in the free run.

    • cites [321] Sezer, 2002, Human bone marrow myeloma cells express RANKL., J Clin Oncol source

      Not checked in the free run.

    • cites [322] Sezer, 2003, RANK ligand and osteoprotegerin in myeloma bone disease., Blood source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG reduced cortical bone resorption and increased bone density in mouse nerve crush models.

    “OPG reduced cortical bone resorption and increased bone density in mouse nerve crush models (290,291).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [290] Bateman, 2001, Osteoprotegerin ameliorates sciatic nerve crush induced bone loss., J Orthop Res source

      Not checked in the free run.

    • cites [291] Simske, 1999, Effect of osteoprotegerin, pamidronate and ibandronate on the sciatic nerve crush model for disuse osteopenia, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple myeloma has deleterious effects on bone by increasing bone resorption while suppressing bone formation.

    “Multiple myeloma also has deletrious effects on bone by virtue of increasing bone resorption while suppressing bone formation (305).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [305] Berenson, 2002, Advances in the biology and treatment of myeloma bone disease., Semin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Skeletal unloading suppresses bone formation and increases osteocyte apoptosis.

    “Skeletal unloading also suppresses bone formation (277, 278) and increases osteocyte apoptosis (121).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [277] Grano, 2002, Rat hindlimb unloading by tail suspension reduces osteoblast differentiation, induces IL-6 secretion, and increases bone resorption in ex vivo cultures., Calcif Tissue Int source

      Not checked in the free run.

    • cites [278] Globus, 1986, The temporal response of bone to unloading., Endocrinology source

      Not checked in the free run.

    • cites [121] Aguirre, 2006, Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Seed-and-soil and vicious cycle theories have gained abundant experimental support, such that adjuvant therapies used today to control bone metastases target bone turnover rather than tumor cells.

    “These seed-and-soil and vicious cycle theories have gained abundant experimental support, such that adjuvant therapies used today to control bone metastases target bone turnover rather than tumor cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In that rat sciatic neurectomy study, femur BMD strongly correlated with femoral neck strength, consistent with preservation of bone quality and improvements in bone mass.

    “This study showed strong correlations between femur BMD and femoral neck strength, consistent with the preservation of bone quality and improvements in bone mass (292).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [292] Mochizuki, 2002, Osteoclastogenesis inhibitory factor/osteoprotegerin ameliorates the decrease in both bone mineral density and bone strength in immobilized rats., J Bone Miner Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG is capable of inhibiting osteoclastogenic responses associated with direct RANKL production by cancer cells and in coculture systems where cancer cells induce other cells to express RANKL.

    “OPG is capable of inhibiting the osteoclastogenic responses associated with direct RANKL production by cancer cells (317, 332) as well as in coculture systems where cancer cells induce other cells to express RANKL (316,324,329,333).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [317] Farrugia, 2003, Receptor activator of nuclear factor-κB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo., Cancer Res

      Not checked in the free run.

    • cites [332] Atkins, 2001, Osteoprotegerin inhibits osteoclast formation and bone resorbing activity in giant cell tumors of bone., Bone source

      Not checked in the free run.

    • cites [316] Zhang, 2001, Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that C4-2B intratibial model, OPG also significantly reduced skeletal tumor burden and prevented radiographic bone destruction.

    “This therapeutic effect was accompanied by significant reductions in skeletal tumor burden and the prevention of radiographic bone destruction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [316] Zhang, 2001, Osteoprotegerin inhibits prostate cancer-induced osteoclastogenesis and prevents prostate tumor growth in the bone., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANKL stimulates directed migration of human breast cancer cells, and this migration is inhibited by OPG.

    “RANKL was recently shown to stimulate the directed migration of human breast cancer cells in a manner that was inhibited by OPG (337).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [337] Hwang, 2002, Effects of RANKL on breast cancer cell lines, J Bone Miner Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both OPG and ibandronate caused significant reductions in tumor-associated osteoclasts, histological tumor area, and tumor cell apoptosis.

    “Both drugs caused significant reductions in tumor-associated osteoclasts, histological tumor area, and tumor cell apopotosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [340] Zheng, 2007, Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumor actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prostate cancer bone metastases usually look osteoblastic, yet bone resorption is often raised in these lesions.

    “While bone metastasis lesions in prostate cancer patients typically have an osteoblastic (osteosclerotic) appearance, there is evidence that bone resorption is also frequently increased in these lesions (346,347).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [346] Clarke, 1992, Disodium pamidronate identifies differential osteoclastic bone resorption in metastatic prostate cancer., Br J Urol source

      Not checked in the free run.

    • cites [347] Keller, 2002, The role of osteoclastic activity in prostate cancer skeletal metastases., Drugs Today source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    OPG functions systemically as a soluble osteoclast inhibitor and, unlike bisphosphonates, does not require binding to bone surfaces for efficacy.

    “OPG functions systemically as a soluble osteoclast inhibitor, and unlike bisphosphonates OPG does not require binding to bone surfaces for efficacy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Combination of OPG plus ibandronate showed no greater effects on tumor cell proliferation and apoptosis compared with OPG alone, arguing against a direct bisphosphonate-mediated antitumor effect.

    “The combination of OPG ϩ IBA showed no greater effects on tumor cell proliferation and apoptosis compared with OPG alone, which argues against a direct bisphosphonate-mediated antitumor effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [340] Zheng, 2007, Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumor actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ibandronate caused significant reduction in tumor-associated osteoclasts, whereas OPG caused their total elimination.

    “Although IBA caused a significant reduction in tumor-associated osteoclasts, OPG treatment caused their total elimination.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [340] Zheng, 2007, Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumor actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice with LN-CaP tumors producing an osteoblastic response, OPG significantly decreased bone tumor development and reduced progression of established tumors.

    “In this study, OPG significantly decreased the development of bone tumors and also reduced the progression of established tumors (348).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [348] Yonou, 2003, Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe immunodeficient mice., Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The mechanism for reduction in tumor burden was probably related to OPG inhibition of bone destruction because tumor burden in numerous soft tissue organs was unaffected by treatment.

    “The mechanism for this reduction in tumor burden was probably related to OPG inhibition of bone destruction because tumor burden in numerous soft tissue organs was unaffected by treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [338] Morony, 2001, Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis., Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG did not inhibit LNCaP cells grown subcutaneously or in culture.

    “whereas OPG did not inhibit LNCaP cells grown sc or in culture.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [348] Yonou, 2003, Osteoprotegerin/osteoclastogenesis inhibitory factor decreases human prostate cancer burden in human adult bone implanted into nonobese diabetic/severe immunodeficient mice., Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANK-Fc treatment significantly reduced serum prostate-specific antigen and skeletal tumor burden in mice injected with human LuCaP prostate cancer cells.

    “RANK-Fc treatment was associated with a significant reduction in serum prostate-specific antigen and decreased skeletal tumor burden”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [314] Zhang, 2003, Soluble receptor activator of nuclear factor κB Fc diminishes prostate cancer progression to bone., Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As monotherapies, OPG and ibandronate each were associated with significant and similar suppression of tumor cell proliferation and induction of tumor cell apoptosis in bone.

    “As monotherapies, OPG and IBA were each associated with significant and similar suppression of tumor cell proliferation and induction of tumor cell apoptosis in bone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [340] Zheng, 2007, Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumor actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis., Bone source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Interventional studies with different RANKL inhibitory strategies suggest that RANKL plays a role in callus remodeling but not callus formation.

    “interventional studies with different RANKL inhibitory strategies suggest that RANKL plays a role in callus remodeling but not callus formation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The tissue source of circulating OPG and RANKL cannot be determined, which may complicate interpretation of their levels in different situations.

    “these proteins are expressed in a wide range of tissues, and therefore, the tissue source of circulating OPG and RANKL cannot be determined and may complicate the interpretation of levels in different situations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    RANK-Fc treatment started after skeletal lesions were established prevented radiographic progression and significantly reduced osteoclast and tumor cell numbers in human bone xenografts.

    “RANK-Fc treatment, initiated after the establishment of skeletal lesions, prevented radiographic progression of disease and significantly reduced osteoclast numbers and tumor cell numbers in the xenografts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [328] Pearse, 2001, Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression., Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Osteoclast numbers in fracture calluses returned to normal within 15 days after stopping RANK-Fc, and those animals also achieved union.

    “Osteoclast numbers in fracture calluses were shown to return to normal levels within 15 d of stopping RANK-Fc treatment, and animals from this experimental group also achieved union.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [369] Flick, 2003, Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing., J Orthop Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This finding highlights the potent yet reversible nature of osteoclast suppression with RANKL inhibitors.

    “This finding highlights the potent yet reversible nature of osteoclast suppression with RANKL inhibitors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The murine myeloma line 5T33MM directly expresses RANKL and caused extensive skeletal tumor burden, with 85% of bone marrow cells being myeloma-derived.

    “Another murine myeloma cell line (5T33MM), which also directly expresses RANKL, caused extensive skeletal tumor burden in mice such that 85% of bone marrow cells were of myeloma origin (353).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [353] Vanderkerken, 2003, Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma., Cancer Res

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Serum RANKL measurements ignore the membrane-bound form, which could be an important source of RANKL in normal or disease states.

    “Serum RANKL measurements also ignore the membrane-bound form, which could be an important source of RANKL in normal and/or disease states.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    At week 8, fracture calluses from OPG-treated rats were about 20% larger and had 30% greater bone mineral content than vehicle controls.

    “At wk 8, fracture calluses from OPGtreated rats were about 20% larger and had 30% greater BMC compared with vehicle controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [363] Ulrich-Vinther, 2005, Osteoprotegerin treatment impairs remodeling and apparent material properties of callus tissue without influencing structural fracture strength., Calcif Tissue Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANK-Fc prevented osteolysis and hind limb paralysis in mice injected with ARH-77 plasma cell leukemia cells, but did not change skeletal tumor burden.

    “RANK-Fc prevented osteolysis in these mice and prevented hind limb paralysis, but without evidence of changes in skeletal tumor burden (328).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [328] Pearse, 2001, Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression., Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG and zoledronic acid both suppressed tumor-associated osteolysis and decreased osteoclast surfaces in tumor-bearing bones.

    “OPG and ZOL both suppressed tumor-associated osteolysis and decreased osteoclast surfaces in tumor-bearing bones (344).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [344] Quinn, 2005, Comparison of Fc-osteoprotegerin and zoledronic acid activities suggest that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms., Prostate Cancer Prostatic Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple myeloma cells originate in bone marrow, clonally expand, and spread to cause widespread osteolysis.

    “Unlike bone metastasis, MM cells originate in bone marrow where they clonally expand and spread to cause widespread osteolysis (350).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [350] Kyle, 2003, Review of 1027 patients with newly diagnosed multiple myeloma., Mayo Clin Proc source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG can bind membrane RANKL in a manner displaceable by soluble RANKL, and OPG might bind cell membrane glycosaminoglycans in a manner displaceable by heparin.

    “OPG can bind to membrane RANKL in a manner that is displaceable by soluble RANKL (370), and OPG might also bind to cell membrane glycosaminoglycans in a manner that is displaceable by heparin (19).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [370] Tat, 2006, OPG/membranous-RANKL complex is internalized via the clathrin pathway before a lysosomal and a proteosomal degradation., Bone source

      Not checked in the free run.

    • cites [19] Irie, 2007, Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANK-Fc treatment in normal mice eliminated osteoclasts in long bone fracture calluses, but union occurred in all animals within 28 days.

    “In this study, RANK-Fc treatment was associated with the elimination of osteoclasts in long bone fracture calluses, but union occurred in all animals within 28 d (369).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [369] Flick, 2003, Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing., J Orthop Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDA-231 cells are TRAIL-sensitive, as recombinant TRAIL injection into MDA-231 tumor-bearing mice produced significant antitumor effects and increased survival.

    “MDA-231 cells have been shown to be TRAIL-sensitive because the injection of recombinant TRAIL into MDA-231 tumor-bearing mice led to significant antitumor effects and increased mouse survival (360).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [360] Walczak, 1999, Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo., Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The larger calluses at week 8 are consistent with delayed callus remodeling, a phenomenon typically associated with bisphosphonates and other antiresorptive therapies.

    “These findings are consistent with a delay in callus remodeling, a phenomenon that is typically associated with bisphosphonates and other antiresorptive therapies in similar models (364 -366).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [364] Cao, 2002, Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats., J Bone Miner Res source

      Not checked in the free run.

    • cites [365] Li, 1999, Effect of bisphosphonate (Incadronate) on fracture healing of long bones in rats., J Bone Miner Res source

      Not checked in the free run.

    • cites [366] Madsen, 1998, No adverse effects of clodronate on fracture healing in rats., Acta Orthop Scand source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG and zoledronic acid both significantly decreased skeletal tumor burden when given preventatively, but only OPG did so when treatment was delayed until lytic tumors were established.

    “OPG and ZOL both significantly decreased skeletal tumor burden when delivered in a preventative manner, whereas only OPG caused significant suppression of skeletal tumor burden when treatment was delayed until lytic tumors were established (344).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [344] Quinn, 2005, Comparison of Fc-osteoprotegerin and zoledronic acid activities suggest that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms., Prostate Cancer Prostatic Dis source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many factors influencing circulating levels of OPG and RANKL have been identified.

    “Many factors influencing the circulating levels of these cytokines have been identified (371).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [371] Rogers, 2005, Circulating osteoprotegerin ligand and receptor activator for nuclear factor κB ligand: clinical utility in metabolic bone disease assessment., J Clin Endorinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Heparin binding by native OPG likely limits its distribution and half-life, so serum OPG may have limited ability to influence osteoclasts within bone.

    “Heparin binding by native OPG is likely to limit its distribution and half-life ( 18) such that OPG measured in serum might have limited potential to influence osteoclasts within bone.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Tomoyasu, 1998, Characterization of monomeric and homodimeric forms of osteoclastogenesis inhibitory factor., Biochem Biophys Res Comm source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationreasoning

    The relative expression of OPG and RANKL is critical for regulating osteoclast activity and bone turnover in health and disease.

    “From nonhuman studies, it is apparent that the relative expression of OPG and RANKL is critical to regulation of osteoclast activity and, in turn, bone turnover in health and disease.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Human reference ranges for OPG and RANKL have not been clearly established.

    “Additionally, human reference ranges for OPG and RANKL have not been clearly established.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    RANK-Fc had no direct effects on cultured myeloma cells, suggesting that bone turnover suppression was the main mechanism by which tumor burden was inhibited.

    “RANK-Fc had no direct effects on cultured myeloma cells, which suggests that bone turnover suppression was the primary mechanism by which tumor burden was inhibited.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OPG treatment of 5T33MM tumor-bearing mice significantly reduced tumor burden, lowered serum paraprotein, and prolonged survival compared with untreated mice.

    “OPG treatment of tumor-bearing mice led to significant reductions in tumor burden, including a reduction in serum paraprotein levels, and OPG-treated animals showed significantly longer survival than untreated mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [353] Vanderkerken, 2003, Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma., Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a murine model with primary human myeloma cells in human bone xenografts, RANK-Fc or bisphosphonates reduced bone resorption and skeletal tumor burden.

    “Treatment of mice with RANK-Fc or with bisphosphonates resulted in decreased bone resorption and reduced skeletal tumor burden (345).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [345] Yaccoby, 2002, Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is depenendent on osteoclast activity., Brit J Haematol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG did not significantly affect proliferation of cultured C4-2 cells, whereas high doses of zoledronic acid (10-100 μM) significantly suppressed C4-2 growth.

    “Although OPG had no significant effects on the proliferation of cultured C4 -2 cells, high doses of ZOL (10 -100 m) were associated with significant C4 -2 growth suppression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [344] Quinn, 2005, Comparison of Fc-osteoprotegerin and zoledronic acid activities suggest that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms., Prostate Cancer Prostatic Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TRAIL-deficient knockout mice had no skeletal abnormalities, and TRAIL had no cytotoxic effects in OPG-deficient knockout mice.

    “However, TRAIL-deficient knockout mice had no skeletal abnormalities, and TRAIL had no cytotoxic effects in OPGdeficient knockout mice (358).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [358] Sedger, 2002, Characterization of the in vivo function of TNF-α-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice., Eur J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG did not significantly affect survival or proliferation of cultured 5T33MM cells.

    “OPG had no significant effects on the survival or proliferation of cultured 5T33MM cells”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [353] Vanderkerken, 2003, Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma., Cancer Res

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lentiviral transfer of the human OPG gene into human myeloma cells caused secretion of therapeutic OPG levels and prevented bone destruction in immunodeficient mice without altering in vitro growth.

    “Direct lentiviral transfer of the human OPG gene into human myeloma cells led to their secretion of therapeutic levels of OPG, which was shown to prevent bone destruction in immunodeficient mice without altering their in vitro growth properties (359).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [359] Doran, 2004, Native osteoprotegerin gene transfer inhibits the development of murine osteolytic bone disease induced by tumor xenografts., Exp Hematol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At week 3, callus dimensions, bone mineral content, and biomechanical strength did not differ between OPG-treated and vehicle-treated rats.

    “At wk 3, there were no reported differences in callus dimensions, BMC, or biomechanical strength of the callus between OPGand vehicle-treated controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [363] Ulrich-Vinther, 2005, Osteoprotegerin treatment impairs remodeling and apparent material properties of callus tissue without influencing structural fracture strength., Calcif Tissue Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some human prostate cancer cell lines express RANK and respond directly to RANKL stimulation with signal transduction activation and increased migration in culture.

    “Other human prostate cancer cell lines have been shown to express RANK and to respond directly to RANKL stimulation via activation of signal transduction and increased migration in culture (349).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [349] Mori, 2007, DU145 human prostate cancer cells express functional receptor activator of NFκB: new insights in the prostate cancer bone metastasis process., Bone source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ARH-77 cells are less dependent on the bone marrow microenvironment than multiple myeloma cells, which may explain why RANK-Fc did not reduce tumor burden.

    “ARH-77 cells are less dependent on the bone marrow microenvironment compared with MM cells, which may explain the lack of reduced tumor burden with RANK-Fc.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The antitumor effect of RANK-Fc in the myeloma xenograft model was probably due to osteoclast suppression, because RANK-Fc had no direct cytotoxic effect on cultured myeloma cells.

    “The antitumor effect of RANK-Fc was probably related to osteoclast suppression because RANK-Fc did not show direct cytotoxic effects on cultured myeloma cells (328).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [328] Pearse, 2001, Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression., Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with human PTH in women receiving chronic glucocorticoid and hormone replacement therapy rapidly increased serum RANKL by 1 month and decreased serum OPG at 6 and 12 months.

    “Treatment with human PTH in women receiving chronic glucocorticoid and hormone replacement therapy resulted in rapid increase in serum RANKL by 1 month and a decrease in serum OPG levels at 6 and 12 months of therapy (93).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Buxton, 2004, Changes in serum receptor activator of nuclear factor-κB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoid-induced osteoporosis treated with human parathyroid hormone (1-34)., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Residual estrogen levels after menopause correlate with bone density and fracture risk, but the relationship between estrogen levels and serum OPG in postmenopausal women has been inconsistent.

    “Residual estrogen levels after the menopause correlate with bone density and fracture risk, yet the relationship of estrogen levels with serum OPG levels in postmenopausal women has been inconsistent across studies, with some supporting a weak relationship (375) and others no relationship (373, 379) or a negative correlation (381).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [375] Rogers, 2002, Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [373] Khosla, 2002, Correlates of osteoprotegerin levels in women and men., Osteoporos Int source

      Not checked in the free run.

    • cites [379] Mezquita-Raya, 2005, The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women., Osteoporos Int source

      Not checked in the free run.

    • cites [381] Trofimov, 2004, Circulating levels of receptor activator of nuclear factor-κB ligand/osteoprotegerin/macrophage-colony stimulating factor in a presumably healthy human population., Eur J Endocrinol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The effects of bisphosphonates on serum OPG may reflect changes in the osteoblast cell pool or OPG production.

    “The effects of bisphosphonates on serum OPG may reflect changes in osteoblast cell pool or OPG production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    OPG levels generally increase after menopause and with GnRH agonist therapy, both low-estrogen conditions.

    “There is general agreement that OPG levels increase after the menopause (373, 379 -381) and with GnRH agonist therapy (382), both conditions of low estrogen levels.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [373] Khosla, 2002, Correlates of osteoprotegerin levels in women and men., Osteoporos Int source

      Not checked in the free run.

    • cites [379] Mezquita-Raya, 2005, The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women., Osteoporos Int source

      Not checked in the free run.

    • cites [380] Oh, 2005, Circulating osteoprotegerin levels are associated with age, waist-to-hip ratio, serum total cholesterol, and low-density lipoprotein cholesterol levels in healthy Korean women., Metabolism source

      Not checked in the free run.

    • cites [381] Trofimov, 2004, Circulating levels of receptor activator of nuclear factor-κB ligand/osteoprotegerin/macrophage-colony stimulating factor in a presumably healthy human population., Eur J Endocrinol source

      Not checked in the free run.

    • cites [382] Uemura, 2003, Circulating osteoprotegerin in women during GnRH-agonist treatment and their relationship with mineral components and biomarkers of bone turnover., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Estrogen deficiency increases bone resorption over bone formation and causes net bone loss.

    “Estrogen deficiency results in increased bone resorption over bone formation and net bone loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    OPG levels in men have been inversely correlated with BMD, borderline positively correlated with BMD, or not correlated with BMD.

    “OPG levels in men have been correlated inversely with BMD (373, 392), borderline positively with BMD (372), or not at all (376).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [373] Khosla, 2002, Correlates of osteoprotegerin levels in women and men., Osteoporos Int source

      Not checked in the free run.

    • cites [392] Oh, 2005, Circulating osteoprotegerin and receptor activator of NF-κB ligand system are associated with bone metabolism in middle-aged males., Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [372] Indridason, 2005, Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover., Osteoporos Int source

      Not checked in the free run.

    • cites [376] Szulc, 2001, Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status., J Clin Endocrinol Metab

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RANKL expression per cell correlated with bone resorption markers and inversely with serum estradiol levels.

    “RANKL expression per cell correlated with bone resorption markers and inversely with serum estradiol levels (76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Eghbali-Fatourechi, 2003, Role of RANK ligand in mediating increased bone resorption in early postmenopausal women., J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These studies suggest that a relative increase in molecular promoters of osteoclast formation and activity in the bone microenvironment may underlie susceptibility to fracture, but prospective studies are needed to prove this conclusively.

    “These studies suggest that a relative increase in the expression of molecular promoters of osteoclast formation and activity in the bone microenvironment may underlie the susceptibility to fracture, but more detailed prospective studies are needed to prove this conclusively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The data on serum OPG levels in postmenopausal women are conflicting, and their potential clinical applicability as a marker of bone disease is not proven.

    “Collectively, the data regarding serum OPG levels in postmenopausal women have been conflicting, and their potential clinical applicability as a marker of bone disease is not yet proven.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In one study over half of postmenopausal women had undetectable RANKL concentrations, and in another 40% of samples were below the assay detection limit.

    “However, in one of the studies over half of the women (54.9%) had concentrations of RANKL that were undetectable (379), and in the other study 40% of samples were below the detection limit of the assay (385).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [379] Mezquita-Raya, 2005, The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women., Osteoporos Int source

      Not checked in the free run.

    • cites [385] Schett, 2004, Soluble RANKL and risk of nontraumatic fracture., JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum OPG levels in postmenopausal women have been positively related to BMD, negatively related to BMD, or unrelated to BMD.

    “Serum OPG levels have been found to be positively related to BMD (375, 379), negatively related to BMD (374, 383), or unrelated to BMD (372, 373) in postmenopausal women.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [375] Rogers, 2002, Circulating estradiol and osteoprotegerin as determinants of bone turnover and bone density in postmenopausal women., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [379] Mezquita-Raya, 2005, The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women., Osteoporos Int source

      Not checked in the free run.

    • cites [374] Kudlacek, 2003, Serum levels of osteoprotegerin increase with age in a healthy adult population., Bone source

      Not checked in the free run.

    • cites [383] Jorgensen, 2004, Serum osteoprotegerin (OPG) and the A163G polymorphism in the OPG promoter region are related to peripheral measures of bone mass and fracture odds ratios., J Bone Miner Metab source

      Not checked in the free run.

    • cites [372] Indridason, 2005, Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover., Osteoporos Int source

      Not checked in the free run.

    • cites [373] Khosla, 2002, Correlates of osteoprotegerin levels in women and men., Osteoporos Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum RANKL levels in postmenopausal women have been reported not to be associated with menopausal status or BMD, but to be associated with nontraumatic fracture.

    “Serum RANKL levels have also been investigated in postmenopausal women and reported not to be associated with menopausal status or BMD (379, 385) but to be associated with nontraumatic fracture (385).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [379] Mezquita-Raya, 2005, The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women., Osteoporos Int source

      Not checked in the free run.

    • cites [385] Schett, 2004, Soluble RANKL and risk of nontraumatic fracture., JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In postmenopausal women receiving hormone replacement therapy, OPG levels declined by 3 months and positively correlated with changes in bone turnover markers at 3 months.

    “In postmenopausal women receiving hormone replacement therapy, OPG levels declined by 3 months and positively correlated with changes in bone turnover markers at 3 months (389).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [389] Han, 2005, The changes in circulating osteoprotegerin after hormone therapy in postmenopausal women and their relationship with estrogen responsiveness on bone., Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Glucocorticoid therapy suppresses bone formation by increasing osteoblast apoptosis and, to a lesser extent and perhaps indirectly, increases bone resorption.

    “The detrimental skeletal effects of glucocorticoid therapy include suppression of bone formation by increasing osteoblast apoptosis and, to a lesser extent, and perhaps indirectly, increase in bone resorption.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    There appears to be some consistency in the effect of glucocorticoids to lower serum OPG levels in vivo, which may partially explain their adverse skeletal effects.

    “Although it is difficult to draw firm conclusions from the few human studies to date, there does appear to be some consistency in the effect of glucocorticoids to lower serum OPG levels in vivo that may partially explain the adverse skeletal effects of these drugs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the same transplant study, serum OPG levels fell after transplant, and bone loss based on BMD was positively associated with the decrease in OPG level.

    “In the same study, serum OPG levels fell after transplant, and bone loss based on BMD measurement was positively associated with the decrease in OPG level (393).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [393] Fahrleitner, 2003, Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In Paget's disease, osteoclast-mediated bone resorption is increased with a compensatory increase in new bone formation.

    “Osteoclast-mediated bone resorption is increased with a compensatory increase in new bone formation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Glucocorticoids reduce intestinal calcium absorption, increase renal calcium excretion, and disturb vitamin D metabolism.

    “However, glucocorticoids also reduce intestinal calcium absorption, increase renal calcium excretion, and disturb vitamin D metabolism.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Paget's disease of bone is a focal disorder of accelerated and disordered bone remodeling.

    “PDB is a focal disorder of accelerated and disordered bone remodeling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inflammatory cytokines in an inflamed joint probably increase RANKL and RANK, which drives osteoclast development and bone destruction.

    “The production of inflammatory cytokines in the inflamed joint is likely to up-regulate RANKL and RANK (90, 412), which promotes osteoclast development and bone destruction.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90] Haynes, 2001, Osteoprotegerin and receptor activator of nuclear factor κB ligand (RANKL) regulate osteoclast formation by cells in the human rheumatoid arthritic joint., Rheumatology source

      Not checked in the free run.

    • cites [412] Gravellese, 2000, Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor., Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The increased circulating OPG in conditions of elevated turnover may act as a protective mechanism, although the relationship between OPG levels and bone turnover in unaffected individuals is less clear.

    “This lends support to the concept of increased OPG circulating in conditions of elevated turnover potentially as a protective mechanism, although the relationship between OPG levels and bone turnover in unaffected individuals is less clear as discussed earlier.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Deficient OPG production or an altered RANKL:OPG ratio in the joint may underlie the development of erosions.

    “These results suggest that the deficient production of OPG or the ratio of RANKL:OPG in the joint may underlie the development of erosions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    These differing results may be due to differences in the mechanism of action of amino bisphosphonates compared with non-amino bisphosphonates on osteoclasts and osteoblasts, or to differences in study populations.

    “These differing results may be due to differences in the mechanism of action of amino bisphosphonates compared with non-amino bisphosphonates on osteoclasts and osteoblasts, or due to differences in study populations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A cross-sectional study of cardiac transplant recipients found a positive correlation between serum OPG levels and BMD, and lower average serum OPG levels in those with prevalent vertebral fractures.

    “A cross-sectional study of cardiac transplant recipients found a positive correlation between serum OPG levels and BMD, and a lower average serum OPG level was seen in those with prevalent vertebral fractures (393).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [393] Fahrleitner, 2003, Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation., Bone source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG levels in Paget's disease have been reported to increase modestly after pamidronate and risedronate and to decrease after tiludronate.

    “OPG levels in PDB have been reported to increase modestly after treatment with pamidronate (406) and risedronate (407) and to decrease after treatment with tiludronate (405).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [406] Martini, 2007, Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget’s disease of bone., Bone source

      Not checked in the free run.

    • cites [407] Mossetti, 2005, Interleukin-6 and osteoprotegerin systems in Paget’s disease of bone: relationship to risedronate treatment., Bone source

      Not checked in the free run.

    • cites [405] Alvarez, 2003, Serum osteoprotegerin and its ligand in Paget’s disease of bone: relationship to disease activity and effect of treatment with bisphosphonates., Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with Crohn's disease, serum OPG levels decreased and RANKL tended to increase with glucocorticoid therapy compared with baseline.

    “In a study of patients with Crohn's disease, serum OPG levels decreased, whereas RANKL tended to increase with glucocorticoid therapy compared with baseline (244).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [244] Tirpitz, 2003, Effect of systemic glucocorticoid therapy on bone metabolism and the osteoprotegerin system in patients with active Crohn’s disease., Eur J Gastroenterol Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Osteoblasts in pagetic bone are numerous and active, rapidly synthesizing new bone.

    “Osteoblasts in pagetic bone are also numerous and active, rapidly synthesizing new bone.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Constitutive activation of RANK has been demonstrated in familial expansile osteolysis and familial early onset Paget's disease.

    “Constitutive activation of RANK has been demonstrated in familial expansile osteolysis, another disorder with abnormal bone remodeling, and in familial early onset PDB (398).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [398] Whyte, 2006, Paget’s disease of bone and genetic disorders of RANKL/OPG/RANK/NF-κB signaling., Ann NY Acad Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In synovial tissue from active RA, RANKL expression is present but OPG expression is absent.

    “Also, in synovial tissue from active RA, RANKL expression was seen but OPG was not (33)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Haynes, 2003, Osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathies and osteoarthritis and normal controls., Rheumatology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although the exact etiology of Paget's disease remains undetermined, there is abundant evidence for involvement of the OPG/RANKL/RANK system and NF-κB signaling in its pathogenesis.

    “Although the exact etiology of Paget's disease remains to be determined, there is abundant evidence of the involvement of the OPG/RANKL/RANK system and the NF-B signaling pathway in the pathogenesis of the disorder.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The OPG/RANKL ratio is similar between RA patients and controls.

    “the ratio of OPG/RANKL was similar between the two groups”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Ziolkowska, 2002, High levels of osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor α treatment., Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Osteoclasts in pagetic bone are increased in number and size and have abnormal appearance with more nuclei and nuclear and cytoplasmic inclusions.

    “Osteoclasts in pagetic bone are increased in number and size and have abnormal appearance with substantially more nuclei than normal and with nuclear and cytoplasmic inclusions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A fully human anti-RANKL antibody has low potential for immune responses, an attribute borne out in clinical trials with denosumab.

    “Another potential advantage of a fully human anti-RANKL antibody is the low potential for immune responses (431), a theoretical attribute that has been borne out in clinical trials with denosumab.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [431] Weiner, 2006, Fully human therapeutic monoclonal antibodies., J Immunother source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The long dosing interval of denosumab holds potential to facilitate treatment compliance.

    “This long dosing interval holds the potential to facilitate treatment compliance, which is increasingly being recognized as a major obstacle in therapy for these conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Systemic bone loss and increased fracture risk are important components of RA.

    “In addition to focal bone erosions and periarticular bone loss, systemic bone loss and increased fracture risk are important components of RA (224, 239, 420 -422).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [224] Gough, 1994, Generalised bone loss in patients with early rheumatoid arthritis., Lancet source

      Not checked in the free run.

    • cites [239] Geusens, 2002, Receptor activator of the nuclear factor κ-Β ligand (RANKL) in serum is related to bone density, cartilage breakdown and inflammation in early active rheumatoid arthritis, J Bone Miner Res

      Not checked in the free run.

    • cites [420] Haugeberg, 2002, Bone loss in patients with rheumatoid arthritis: results from a population-based cohort of 366 patients followed for two years., Arthritis Rheum source

      Not checked in the free run.

    • cites [421] Lodder, 2004, Bone mineral density in patients with rheumatoid arthritis: relation between disease and low bone mineral density., Ann Rheum Dis source

      Not checked in the free run.

    • cites [422] Van Staa, 2006, Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis., Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Systemic stimulation of bone resorption in RA patients is suggested by increases in circulating biochemical markers of bone resorption and increased osteoclastogenic potential of their bone marrow.

    “Systemic stimulation of bone resorption in RA patients is suggested by increases in circulating biochemical markers of bone resorption (426) and increased osteoclastogenic potential of their bone marrow (426, 427).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [426] Garnero, 1999, Uncoupling of bone metabolism in rheumatoid arthritis patients with or without joint destruction: assessment with serum type I collagen breakdown products., Bone source

      Not checked in the free run.

    • cites [427] Toritsuka, 1997, Osteoclastogenesis in iliac bone marrow of patients with rheumatoid arthritis., J Rheumatol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infliximab treatment is associated with stabilization of BMD at the hip and spine but continued bone loss in the hand.

    “Infliximab treatment was also associated with stabilization of BMD at the hip and spine but continued bone loss in the hand (428).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [428] Vis, 2006, Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFκB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis., Ann Rheum Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Across dose groups, women treated with denosumab for 2 years had significantly greater improvements in BMD compared with placebo at the lumbar spine, total hip, and distal radius; these improvements were similar to or greater than those with alendronate.

    “Across dose groups, women treated with denosumab for 2 yr had significantly greater improvements in BMD compared with placebo (P Ͻ 0.001) at the lumbar spine, total hip, and distal radius; these improvements were similar to or greater than those observed in the open-label alendronate group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [435] Lewiecki, 2007, Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density., J Bone Miner Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Denosumab and many other fully human therapeutic antibodies are produced in transgenic mice in which murine Ig genes have been deleted and replaced with human orthologs.

    “Denosumab and numerous other fully human therapeutic antibodies have been made in transgenic mice, wherein their murine Ig genes have been deleted and replaced with human orthologs (431, 432).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [431] Weiner, 2006, Fully human therapeutic monoclonal antibodies., J Immunother source

      Not checked in the free run.

    • cites [432] Lonberg, 2005, Human antibodies from transgenic animals., Nat Biotechnol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Denosumab treatment resulted in a mean increase in total hip BMD of 1.9 to 3.6%, compared with an increase of 2% with alendronate and a loss of 0.6% with placebo.

    “at the total hip of 1.9 to 3.6% (vs.an increase of 2% with alendronate and a loss of 0.6% with placebo)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [230] McClung, 2006, Denosumab in postmenopausal women with low bone mineral density., N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infliximab treatment in RA causes a decline in serum RANKL and the OPG/RANKL ratio but no change in serum OPG.

    “Vis et al. (428) found that infliximab treatment in RA caused a decline in serum RANKL and the OPG/RANKL ratio but no change in serum OPG.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [428] Vis, 2006, Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFκB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis., Ann Rheum Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OPG-Fc dose-dependently reduced uNTX within 1 day, with a nadir of approximately −60% in multiple myeloma and −84% in breast cancer at 1.0 and 3.0 mg/kg.

    “A dose-dependent reduction in uNTX occurred within 1 d of dosing with OPG-Fc, and uNTX reached a nadir of approximately Ϫ60 and Ϫ84% in the MM and breast cancer strata, respectively, at the higher doses (1.0 and 3.0 mg/kg).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Body, 2003, A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases, Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Denosumab treatment resulted in a mean increase in lumbar spine BMD of 3.0 to 6.7%, compared with an increase of 4.6% with alendronate and a loss of 0.8% with placebo.

    “Treatment with denosumab resulted in a mean increase in BMD at the lumbar spine of 3.0 to 6.7% (vs.an increase of 4.6% with alendronate and a loss of 0.8% with placebo)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [230] McClung, 2006, Denosumab in postmenopausal women with low bone mineral density., N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because OPG and denosumab have similar mechanisms of action, OPG has been used as a surrogate for denosumab in mouse and rat models of bone disease.

    “However, because OPG and denosumab have similar mechanisms of action, OPG has been used as a surrogate for denosumab to examine the effects of RANKL inhibition in numerous mouse and rat models of bone disease.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Denosumab is a fully human monoclonal antibody with high affinity and specificity for RANKL, and it binds and neutralizes human RANKL similarly to OPG.

  • May combine two claims.

    Premisecitation

    Denosumab has a significantly longer circulating half-life than OPG-Fc, which allows reduced dosing frequency.

    “An important practical consideration was that denosumab had a significantly longer circulating half-life compared with OPG-Fc (430), which would allow for reduced dosing frequency.”
    • Also stated in: § A. Mechanism of action of denosumab · hedged
      “One potential advantage of denosumab is that it has a significantly longer half-life compared with human OPG-Fc (430), which promotes more sustained suppression of bone resorption and thereby permits infrequent dosing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [430] Kostenuik, 2005, Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength., Curr Opin Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a 2-year extension, denosumab treatment resulted in persistent reductions in bone resorption and continued significant increases in BMD from baseline in 337 women who completed 2 years.

    “In a planned extension of this study, denosumab treatment for 2 yr resulted in persistent reductions in bone resorption and continued, significant increases in BMD from baseline in the 337 women (82%) who completed 2 yr of study (38 placebo, 259 denosumab, 40 alendronate) (435).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [435] Lewiecki, 2007, Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, infliximab decreases RANK expression in peripheral blood mononuclear cells; infliximab, methotrexate, sulfasalazine, or hydroxychloroquine inhibit RANKL expression and increase OPG secretion in cultured synovial cells.

    “This agrees with in vitro cell culture studies showing a decrease in RANK expression in peripheral blood mononuclear cells treated with infliximab and inhibition of RANKL expression and increase in OPG secretion in cultured synovial cells treated with infliximab, methotrexate, sulfasalazine, or hydroxychloroquine (429).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [429] Lee, 2004, Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor κB, osteoprotegerin, and receptor activator of nuclear factor κB ligand., Arthritis Rheum source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Suppression of uNTX by Fc-OPG occurred within 12 hours, reached a maximum of 80% below baseline at 3.0 mg/kg, and was maintained for up to 45 days.

    “Suppression of uNTX occurred within 12 h after dose, reached a maximum of 80% below baseline at the highest dose tested (3.0 mg/kg), and was maintained for up to 45 d (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Bekker, 2001, The effect of a single dose of osteoprotegerin in postmenopausal women., J Bone Miner Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Infliximab therapy normalizes serum OPG and RANKL by 14-22 weeks in RA, but the RANKL:OPG ratio does not change during therapy.

    “Ziolkowska et al. (53) reported normalization of serum OPG and RANKL by 14 -22 wk of therapy with infliximab, although the RANKL:OPG ratio did not change during therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Ziolkowska, 2002, High levels of osteoprotegerin and soluble receptor activator of nuclear factor κB ligand in serum of rheumatoid arthritis patients and their normalization after anti-tumor necrosis factor α treatment., Arthritis Rheum source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Approximately 40% of patients in each treatment group had baseline CTx-II levels below quantifiable limits.

    “Of particular note, approximately 40% of patients in each treatment group had baseline CTx-II levels below quantifiable limits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [438] Lane, 2006, RANKL inhibition with denosumab decreases markers of bone and cartilage turnover in patients with rheumatoid arthritis, Arthritis Rheum

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with denosumab (n=212) resulted in rapid and sustained suppression of bone turnover and was similar to IV bisphosphonates at reducing the risk of skeletal-related events.

    “Treatment with denosumab (n ϭ 212) resulted in rapid and sustained suppression of bone turnover and was similar to IV BP at reducing the risk of skeletal-related events (439).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [439] Lipton, 2007, Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases., J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At 3.0 mg/kg, denosumab had mean half-lives of 46.3 days in breast cancer patients and 33.3 days in multiple myeloma patients.

    “At the 3.0 mg/kg dose, denosumab demonstrated mean halflives of 46.3 and 33.3 d in patients with breast cancer and MM, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [442] Body, 2006, A study of the biological receptor activator of nuclear factor-κB ligant inhibitor, Denosumab, in patients with multiple myeloma or bone metastases from breast cancer., Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The decreases in uNTX and serum NTX were similar in magnitude but numerically longer in duration compared with intravenous pamidronate 90 mg.

    “These decreases were similar in magnitude, but of numerically longer duration, vs. those observed in a comparator group receiving an iv dose of pamidronate 90 mg.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [442] Body, 2006, A study of the biological receptor activator of nuclear factor-κB ligant inhibitor, Denosumab, in patients with multiple myeloma or bone metastases from breast cancer., Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a phase 1 study, denosumab was well tolerated with an adverse event profile not significantly different from placebo in patients with bone metastases from breast cancer and multiple myeloma.

    “A recent double-blind phase 1 study of denosumab published by Body et al. (442) in patients with bone metastases from breast cancer (n ϭ 29 women) and patients with MM (n ϭ 25; 14 men and 11 women) showed that denosumab was well tolerated, with an adverse event profile that was not significantly different from placebo patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [442] Body, 2006, A study of the biological receptor activator of nuclear factor-κB ligant inhibitor, Denosumab, in patients with multiple myeloma or bone metastases from breast cancer., Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Human data are generally supportive of the importance of OPG and RANKL in normal bone physiology and in metabolic bone disease.

    “The data in humans are generally supportive of the importance of OPG and RANKL in normal bone physiology as well as in metabolic bone disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    At 3 months, the percentage of patients with CTx-II below quantifiable limits increased to 81% and 89% in the 60- and 180-mg denosumab groups, then returned to approximately 40% at 6 months.

    “However, at 3 months, this percentage increased to 81 and 89% in the 60-and 180-mg denosumab groups, respectively, and then returned to approximately 40% in all groups at 6 months, before the next denosumab dose (438).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [438] Lane, 2006, RANKL inhibition with denosumab decreases markers of bone and cartilage turnover in patients with rheumatoid arthritis, Arthritis Rheum

      Not checked in the free run.

226 of 226

  • The paper relies on this without support.

    Findings from animal models of bone disease can be extrapolated to human skeletal disease and therapy.

    “Nonhuman primates represent the most appropriate preclinical species for examining the skeletal response to therapeutic intervention.”

  • The paper relies on this without support.

    Ovariectomy in animals is a valid model for human postmenopausal bone loss.

    “Ovariectomy (OVX) represents a model of surgical menopause, wherein estrogen levels drop more precipitously compared with the slower decline seen in natural menopause.”

  • The paper relies on this without support.

    The ORX rat is a valid model for the skeletal effects of androgen deprivation in men.

    “Normal ORX rat models are appropriate to examine the isolated effects of androgen ablation on bone.”

  • The paper relies on this without support.

    Osteoblasts are an important source of both OPG and RANKL.

    “Osteoblasts are an important source of both OPG and RANKL”

  • The paper relies on this without support.

    Animal models of prostate cancer bone metastasis and multiple myeloma reproduce the key biology of human skeletal metastasis and myeloma sufficiently to inform human disease.

    “In animal models of prostate cancer metastasis, skeletal lesions frequently exhibit increased osteoclast activation and osteolysis (316,348).”
    “Systemic bone loss was a feature of a murine MM model, wherein RANKL-expressing 5T2MM myeloma cells were shown to cause extensive bone lesions in mice with increased osteoclasts, decreased BMD, and cortical thinning of long bones.”

  • The paper relies on this without support.

    Biomechanical strength in rodent fracture calluses is a relevant preclinical endpoint for human fracture repair.

    “Biomechanical strength is perhaps the most relevant preclinical endpoint for fracture repair.”

  • The paper relies on this without support.

    RA is characterized by chronic inflammation of the synovium, a predominance of proerosive mediators, and subsequent destruction of bone and cartilage.

    “RA is characterized by chronic inflammation of the synovium, the predominance of proerosive mediators, and subsequent destruction of bone and cartilage.”

  • The paper relies on this without support.

    Inflammatory cytokines (IL-1α, IL-1β, IL-6, IL-11, TNF-α) are important mediators stimulating bone lysis in RA.

    “Many investigations have implicated inflammatory cytokines (IL-1␣, IL-1␤, IL-6, IL-11, TNF-␣) as important mediators stimulating bone lysis in RA.”

  • The paper relies on this without support.

    Denosumab is a fully human monoclonal antibody with high affinity and specificity for RANKL, and it binds and neutralizes human RANKL similarly to OPG.

    “Denosumab is a fully human monoclonal antibody with a high affinity (K d 3 ϫ 10 Ϫ12 m) and specificity for RANKL and can thus bind and neutralize the activity of human RANKL in a similar fashion to the action of OPG.”

  • The paper relies on this without support.

    Denosumab activity is primate specific, so it cannot be tested in mouse or rat models of bone disease.

    “Because the activity of denosumab is primate specific, it cannot be tested in mouse or rat models of bone disease.”
10 of 10

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • OPG-Fc is assigned opposite fusion orientations

    Major

    The figure description places Fc at the carboxy terminus of the OPG fragment, whereas the clinical-therapeutics section places it at the amino terminus for the construct called OPG-Fc.

  • Figure 5 reverses the anatomical positions of its image panels

    Minor

    One part of the caption places the lumbar vertebra at the bottom and distal femur at the top; another assigns them to the opposite panels.

  • The reported direction of the tumor-cell apoptosis effect reverses

    Minor

    The account of the OPG and ibandronate comparison first says both drugs reduced tumor-cell apoptosis, then says both induced it.

3 of 3

The citation lists haven’t been fetched yet

References 418 · Cited by 824

Research works printed but not linked: 35

  1. Nakamichi, 2007, M-CSF independent mechanisms for osteoclastogenesis, J Bone Miner Res, 22, S380
  2. Yuan, 2005, Soluble RANKL has detrimental effects on cortical and trabecular bone volume, mineralization and bone strength in mice, J Bone Miner Res, 20, S161
  3. Yuan, 2006, RANKL infusion as a disease model: implications for bone and vascular systems, J Bone Miner Res, 21, S163
  4. Khosla, 2000, Estrogen and testosterone have opposite effects on circulating OPG levels following induction of hypogonadism and aromatase inhibition in normal elderly men: potential mechanism for differential effects of estrogen versus testosterone on bone resorption, J Bone Miner Res, 16, S146
  5. Li, 2001, Combination of TNF-α and IL-1β induced osteoclast formation and bone resorption is dependent on RANK signal transduction, J Bone Miner Res, 16, S379
  6. Stolina, 2006, Rats overexpressing soluble OPG from a prenatal stage have high bone mass but no alterations in the development of lymphoid organs or innate immune response, J Bone Miner Res, 21, S153
  7. Miller, 2005, The RANKL inhibitor RANK-Fc has potent antiresorptive efficacy but does not affect host immune responses to influenza infection, J Bone Miner Res, 20, S293
  8. Stolina, 2005, RANKL inhibition with osteoprotegerin (OPG) prevents bone loss but does not affect immune status in arthritic rats, J Bone Miner Res, 20, S257
  9. Stolina, 2005, Rats and mice overexpressing soluble OPG have high bone mass but no alteration in immunological parameters or lymphocyte function, Arthritis Rheum, 20, S708
  10. Ominsky, 2005, RANKL inhibition increases extrinsic bone strength and maintains intrinsic bone strength in transgenic rats that continously overexpress a secreted osteoprotegerin transgene, J Bone Miner Res, 20, S294
  11. Ominsky, 2007, Transgenic overexpression of OPG results in increased bone mass and strength and decreased bone turnover in one-year-old female rats, J Bone Miner Res, 22, S25
  12. Ominsky, 2005, RANKL inhibition improves trabecular architecture in female mice, J Bone Miner Res, 20, S294
  13. Atkinson, 2005, AMG 162, a fully human RANKL antibody, increases bone mass and bone strength in cynomolgus monkeys, J Bone Miner Res, 20, S294
  14. Li, 2006, RANKL inhibition with OPG preserves bone density and trabecular architecture in ovariectomized rats, J Bone Miner Res, 21, S304
  15. Ominsky, 2006, Denosumab (AMG 162, a fully human RANKL antibody) increases cortical and cancellous bone mass in aged ovariectomized cynomolgus monkeys, J Bone Miner Res, 21, S72
  16. Ominsky, 2007, Denosumab (AMG 162), a fully human RANKL antibody, improves cortical and cancellous bone mass and bone strength in ovariectomized cynomolgus monkeys, J Bone Miner Res, 22, S23
  17. Li, 2006, RANKL inhibition by OPG prevents bone loss and preserves trabecular architecture in orchiectomized rats, Calcif Tissue Int, 78, S144
  18. Li, 2005, RANKL inhibition improves cortical bone geometry by stimulating periosteal bone formation in orchiectomized rats, J Bone Miner Res, 20, S57
  19. Stolina, 2006, Progression of inflammatory arthritis is associated with decreased OPG protein, increased RANKL protein and a greater RANKL:OPG ratio., Ann Rheum Dis, 65, 139
  20. Geusens, 2002, Receptor activator of the nuclear factor κ-Β ligand (RANKL) in serum is related to bone density, cartilage breakdown and inflammation in early active rheumatoid arthritis, J Bone Miner Res, 17, S386
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  24. Bateman, 2002, Osteoprotegerin mitigates spaceflight-induced changes in mouse bone mass, density and mineral composition, J Bone Miner Res, 17, S136
  25. Kostenuik, 2002, OPG prevents relative osteopenia and deficits in skeletal strength in mice during a 12 day spaceflight, J Bone Miner Res, 17, S209
  26. Warner, 2006, RANKL inhibition prevents the loss of bone volume and bone strength caused by Botox induced muscle paralysis., Trans Orthoped Res Soc, 31, 0189
  27. Manishen, 1986, Resorbing bone stimulates tumor cell growth., Am J Pathol, 123, 39
  28. Hwang, 2002, Effects of RANKL on breast cancer cell lines, J Bone Miner Res, 17, S310
  29. Tometsko, 2006, RANKL inhibition causes a greater suppression of tumor-induced osteoclastogenesis than zoledronate treatment in vivo and RANKL rescues osteoclasts from zoledronate killing in vitro, J Bone Miner Res, 21, S346
  30. Morony, 2002, OPG inhibits the progression of bone destruction and skeletal tumor burden in mice with established osteolytic MDA-231 breast cancer metastases, J Bone Miner Res, 17, S147
  31. Garrett, 1995, Evidence for bidirectional interactions between osteoclasts and myeloma cells, J Bone Miner Res, 10, S195
  32. Kostenuik, 2005, RANKL inhibition with AMG 162, a fully human MAb, causes sustained suppression of bone resorption and increased BMD in knockin mice expressing humanized RANKL, J Bone Miner Res, 20, S259
  33. Cohen, 2006, RANKL inhibition with denosumab reduces progression of bone erosions in patients with rheumatoid arthritis: month 6 MRI results, Arthritis Rheum, 54, S831
  34. Dore, 2006, Denosumab increases bone mineral density in patients with rheumatoid arthritis, Arthritis Rheum, 54, S240
  35. Lane, 2006, RANKL inhibition with denosumab decreases markers of bone and cartilage turnover in patients with rheumatoid arthritis, Arthritis Rheum, 54, S225

Authors
Kearns, A. E., Khosla, S., & Kostenuik, P. J.
Affiliations
  • Mayo Clinic (US)
  • Amgen (United States) (US)
Corresponding author
Kostenuik, Paul J.
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2007-12-05
Volume
29
Issue
2
Pages
155-192
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/er.2007-0014
PMC
PMC2528846
OpenAlex
W2035416199
Cited by
824
References
418
Citations by year
2026: 21 · 2025: 36 · 2024: 35 · 2023: 30 · 2022: 46 · 2021: 51 · 2020: 42 · 2019: 41 · 2018: 46 · 2017: 41 · 2016: 39 · 2015: 41 · 2014: 46 · 2013: 42 · 2012: 65
FWCI
3.63
Type
journal article
Language
en
Open access
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Amgen
  • National Institutes of Health (AG004875)
  • National Institute on Aging (P01AG004875, AG004875)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Keywords
RANKL, osteoprotegerin, RANK, bone remodeling, bone resorption, osteoclasts, osteoblasts, RANKL inhibition, denosumab, postmenopausal osteoporosis, bone metastasis, rheumatoid arthritis, multiple myeloma, bone loss, TNF family cytokines, ovariectomy, orchiectomy
MeSH terms
Animals, Bone Diseases, Humans, Bone Remodeling, Osteoprotegerin, RANK Ligand

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