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Cited by 1,779Bone health and osteoporosis researchBone Metabolism and DiseasesAlkaline Phosphatase Research Studies

Pathogenesis of osteoporosis: concepts, conflicts, and prospects

Open access
Raisz, L. G.·2005·Journal of Clinical Investigation
DOI 10.1172/jci27071PMC PMC1297264
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Abstract

Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.

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Crossref · 10.1172/jci27071

Cites

133 of 133 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

16 of 80 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In men, estrogen inhibits bone resorption more than androgen does.

    “estrogen has a greater effect than androgen in inhibiting bone resorption in men”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] 15. Falahati-Nini, A., et al. 2000. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J. Clin. Invest. 106:1553-1560. source
  • Premisecitation

    The largest study, in Icelandic and Danish cohorts, links BMP2 polymorphisms to low BMD and fracture risk.

    “the largest study to date, in Icelandic and Danish cohorts, suggests that polymorphisms of the BMP2 gene are linked to low BMD and fracture risk”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [79] 79. Styrkarsdottir, U., et al. 2003. Linkage of osteo- porosis to chromosome 20p12 and association to BMP2. PLoS Biol. 1:E69. source

      The Abstract and Results (Haplotype Confirmation in Danish Cohort; page numbers unavailable) report BMP2-variant associations with low BMD and osteoporotic fractures in Icelandic patients, with supporting results in a Danish cohort. The copy describes a large Icelandic study but does not establish that it was the largest study to date. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    RANKL is elevated on bone marrow cell surfaces in early postmenopausal estrogen-deficient women.

    “RANKL levels were increased on the surface of bone marrow cells from early postmenopausal women who are estrogen deficient”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] 48. Eghbali-Fatourechi, G., et al. 2003. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Invest. 111:1221-1230. doi:10.1172/JCI200317215. source
  • Premisecitation

    An LRP5 mutation causing constitutive activation can raise bone density.

    “A mutation of LRP5 that leads to constitutive activation can result in an increase in bone density”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [58] 58. Little, R.D., et al. 2002. A mutation in the LDL receptor-related protein 5 gene results in the auto- somal dominant high-bone-mass trait. Am. J. Hum. Genet. 70:11-19. source

      Section 6 says the LRP5 gain-of-function mutation described by the authors produces increased bone mass. It does not establish that the mutation causes constitutive activation; its discussion of how the mutation affects protein interactions is tentative. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [59] 59. Boyden, L.M., et al. 2002. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346:1513-1521. source
  • Premisecitation

    Cytokines such as IL-1 and prostaglandins such as PGE2 can affect bone.

    “locally produced cytokines such as IL-1 and prostaglandins such as prostaglandin E 2 (PGE 2 ) can affect bone”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [81] 81. Klein, D.C., and Raisz, L.G. 1970. Prostaglandins: stimulation of bone resorption in tissue culture. Endocrinology. 86:1436-1440. source
    • cites [82] 82. Raisz, L.G., et al. 1975. Effect of osteoclast activat- ing factor from human leukocytes on bone metab- olism. J. Clin. Invest. 56:408-413. source

      The Discussion reports that osteoclast-activating factor (OAF) secreted by human leukocytes stimulates bone resorption in fetal rat bone cultures, and that PGE2 can also affect resorption. It does not identify OAF as IL-1 or establish that PGE2 is locally produced. The claim's specific IL-1 and local-production details are therefore unsupported by this copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Premisecitation

    Wnt signaling is crucial for osteoblast function and for setting bone mass and strength.

    “the critical role for the Wnt signaling pathway in regulating osteoblast function is of particular interest, since it has been shown to play an important role in determining bone mass and strength”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [58] 58. Little, R.D., et al. 2002. A mutation in the LDL receptor-related protein 5 gene results in the auto- somal dominant high-bone-mass trait. Am. J. Hum. Genet. 70:11-19. source

      The discussion (section 6) reports that LRP5 participates in Wnt signaling and that an LRP5 mutation increases bone mass; it also reports enhanced skeletal strength in transgenic mice. It describes Wnt as important in skeletal differentiation, but does not directly establish that Wnt signaling regulates osteoblast function or itself determines bone mass and strength. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [59] 59. Boyden, L.M., et al. 2002. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346:1513-1521. source
    • cites [60] 60. Van Wesenbeeck, L., et al. 2003. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am. J. Hum. Genet. 72:763-771. source
    • cites [61] 61. Gong, Y., et al. 2001. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 107:513-523. source

  • May combine two claims.

    Premisecitation

    Sclerostin, encoded by SOST, blocks both BMP2 and Wnt signaling.

    “sclerostin, the product of the SOST gene, has been shown to inhibit both BMP2 and Wnt signaling”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [70] 70. Li, X., et al. 2005. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280:19883-19887. source

      The paper identifies sclerostin as the SOST gene product and demonstrates that it inhibits canonical Wnt signaling. In Results and Discussion (page not specified), it discusses earlier reports of BMP antagonism but questions whether sclerostin functionally inhibits BMP signaling; it does not establish inhibition of BMP2 specifically. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [71] 71. Winkler, D.G., et al. 2004. Sclerostin inhibition of Wnt-3a-induced C3H10T1/2 cell differentiation is indirect and mediated by BMP proteins. J. Biol. Chem. 280:2498-2502. source

      The Results section reports that sclerostin reduced BMP-6- and Wnt-3A-induced alkaline phosphatase activity in C3H10T1/2 cells; it does not establish inhibition of BMP-2 specifically. The Discussion says the Wnt-related effect was indirect, through BMP inhibition, and that sclerostin did not block early Wnt signaling measured by β-catenin accumulation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mice overexpressing OPG get osteopetrosis, while OPG-knockout mice get severe osteoporosis and frequent fractures.

    “overexpression of OPG produced osteopetrosis, while OPG-knockout mice had a phenotype of severe osteoporosis with a high incidence of fractures”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [46] 46. Bucay, N., et al. 1998. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12:1260-1268. source

  • May combine two claims.

    Premisecitation

    Vitamin D deficiency and secondary hyperparathyroidism can speed bone loss, increase fragility, and impair neuromuscular function, raising fall risk.

    “Vitamin D deficiency and secondary hyperparathyroidism can contribute not only to accelerated bone loss and increasing fragility, but also to neuromuscular impairment that can increase the risk of falls”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [33] 33. Bischoff-Ferrari, H.A., et al. 2004. Effect of vitamin D on falls: a meta-analysis. JAMA. 291:1999-2006. source
    • cites [34] 34. Sambrook, P.N., et al. 2004. Serum parathyroid hormone predicts time to fall independent of vita- min D status in a frail elderly population. J. Clin. Endocrinol. Metab. 89:1572-1576. source

      The Introduction (page unavailable) says vitamin D deficiency may increase fall risk through neuromuscular effects and that secondary hyperparathyroidism occurs with vitamin D deficiency. The Discussion (page unavailable) reports associations between PTH, diminished muscle function, and falls. The paper does not address accelerated bone loss or increasing bone fragility, so those parts of the claim are unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    SOST inactivating mutations cause Van Buchem disease or sclerosteosis, both high-bone-mass disorders.

    “Inactivating mutations of this gene can produce the high-bone-mass disorder Van Buchem disease or sclerosteosis”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [72] 72. Loots, G.G., et al. 2005. Genomic deletion of a long- range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res. 15:928-935. source

      The Abstract states that sclerosteosis patients carry SOST-null mutations, but Van Buchem patients have no SOST coding mutations; instead, they carry a noncoding deletion downstream of SOST. The Discussion explains that this deletion removes a SOST regulatory element and reduces its expression in adult bone. Thus, the paper supports SOST inactivation in both disorders, but not an inactivating mutation of the gene itself in Van Buchem disease. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [73] 73. Balemans, W., et al. 2001. Increased bone den- sity in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10:537-543. source

      The Introduction and Discussion identify loss-of-function SOST mutations as causative for sclerosteosis, a disorder of increased bone formation. The Mutation analysis section found no SOST mutation in the Dutch van Buchem family; the Discussion proposes a regulatory explanation but does not establish that SOST-inactivating mutations cause van Buchem disease. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisenone given

    Bone remodeling is controlled by many mechanisms involving osteoblast and osteoclast lineages, other marrow cells, hormones, cytokines, growth factors, and transcription factors.

    “There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Bone remodeling starts when hematopoietic precursors become osteoclasts, normally needing contact with osteoblastic cells.

    “the process begins with the activation of hematopoietic precursors to become osteoclasts, which normally requires an interaction with cells of the osteoblastic lineage”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Low calcium, low vitamin D, and secondary hyperparathyroidism also contribute to osteoporosis.

    “calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Too much bone resorption lowers bone mass and damages microarchitecture, contributing to fragility.

    “excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration of the skeleton”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because osteoporosis is complex and polygenic, individual gene polymorphisms likely have small effects but may still matter clinically.

    “Since osteoporosis is a complex, polygenic disorder, the contributions of specific gene polymorphisms are likely to be relatively small, but may still be clinically important.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Osteoporosis is a complex polygenic disorder.

  • May combine two claims.

    Premisecitation

    Bone cells make NO, which supports the anabolic response to mechanical loading.

    “NO is produced by bone cells and is a cofactor for the anabolic response to mechanical loading”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] 91. Bakker, A.D., et al. 2004. Additive effects of estro- gen and mechanical stress on nitric oxide and prostaglandin E(2) production by bone cells from osteoporotic donors. Osteoporos. Int. 16:983-989. source
    • cites [94] 94. Chow, J.W., Fox, S.W., Lean, J.M., and Chambers, T.J. 1998. Role of nitric oxide and prostaglandins in mechanically induced bone formation. J. Bone Miner. Res. 13:1039-1044. source

  • May combine two claims.

    Premisecitation

    Deleting Runx2 or osterix blocks osteoblast differentiation.

    “Gene deletion studies have shown that absence of runt-related transcription factor 2 (Runx2) or a downstream factor, osterix, are critical for osteoblast differentiation”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] 55. Ducy, P., Zhang, R., Geoffroy, V., Ridall, A.L., and Karsenty, G. 1997. Osf2/Cbfa1: a transcrip- tional activator of osteoblast differentiation. Cell. 89:747-754. source
    • cites [56] 56. Nakashima, K., et al. 2002. The novel zinc finger- containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 108:17-29. source

  • May combine two claims.

    Premisecitation

    IGF-1 and TGF-β gene polymorphisms are associated with BMD and osteoporotic fractures.

    “There is some association between BMD and the incidence of osteoporotic fractures and polymorphisms in the genes encoding IGF-1 and TGF-β”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [76] 76. Lau, E.M., et al. 2004. Osteoporosis and trans- forming growth factor-beta-1 gene polymorphism in Chinese men and women. J. Bone Miner. Metab. 22:148-152. source
    • cites [77] 77. Langdahl, B.L., Carstens, M., Stenkjaer, L., and Erik- sen, E.F. 2003. Polymorphisms in the transforming growth factor beta 1 gene and osteoporosis. Bone. 32:297-310. source
    • cites [78] 78. Kim, J.G., Roh, K.R., and Lee, J.Y. 2002. The relation- ship among serum insulin-like growth factor-I, insu- lin-like growth factor-I gene polymorphism, and bone mineral density in postmenopausal women in Korea. Am. J. Obstet. Gynecol. 186:345-350. source

  • May combine two claims.

    Premisecitation

    Estrogen signals through ERα and ERβ, with ERα the main mediator in bone.

    “Estrogen acts through 2 receptors: estrogen receptor α (ERα) and ERβ.ERα appears to be the primary mediator of estrogen's actions on the skeleton”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] 10. Lee, K., Jessop, H., Suswillo, R., Zaman, G., and Lanyon, L. 2003. Endocrinology: bone adapta- tion requires oestrogen receptor-alpha. Nature. 424:389.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    LRP5 deletion produces severe osteoporotic syndrome with abnormal eye development.

    “Deletion of LRP5 results in a severe osteoporotic syndrome”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] 61. Gong, Y., et al. 2001. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 107:513-523. source

  • May combine two claims.

    Premisecitation

    Low calcium intake, poor intestinal calcium absorption from aging or disease, and vitamin D deficiency can cause secondary hyperparathyroidism.

    “Decreased calcium intake, impaired intestinal absorption of calcium due to aging or disease, as well as vitamin D deficiency can result in secondary hyperparathyroidism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] 32. Lips, P. 2001. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic impli- cations. Endocr. Rev. 22:477-501.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Fracture risk rises as estrogen falls in postmenopausal women, and a quarter of the breast/uterus dose can lower resorption and raise bone mass in older women.

    “Fracture risk is inversely related to estrogen levels in postmenopausal women, and as little as one-quarter of the dose of estrogen that stimulates the breast and uterus is sufficient to decrease bone resorption and increase bone mass in older women”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] 13. Prestwood, K.M., Kenny, A.M., Kleppinger, A., and Kulldorff, M. 2003. Ultralow-dose micron- ized 17beta-estradiol and bone density and bone metabolism in older women: a randomized con- trolled trial. JAMA. 290:1042-1048. source

  • May combine two claims.

    Interpretationreasoning

    RANKL/RANK signaling is essential for osteoclast differentiation and maintenance and is a final common pathway for osteoporosis factors that increase resorption.

    “The RANKL/RANK interaction is critical for both differentiation and maintenance of osteoclast activity and hence represents a final common pathway for any pathogenetic factor in osteoporosis that acts by increasing bone resorption.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Resorption stimulators raise RANKL expression in osteoblasts, and some lower OPG expression.

    “Stimulators of bone resorption have been found to increase RANKL expression in osteoblasts, and some also decrease OPG expression”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] 43. Suda, T., et al. 1999. Modulation of osteoclast dif- ferentiation and function by the new members of the tumor necrosis factor receptor and ligand fami- lies. Endocr. Rev. 20:345-357.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Since resorption and reversal are brief while osteoblastic replacement is long, faster remodeling causes bone loss.

    “Because the resorption and reversal phases of bone remodeling are short and the period required for osteoblastic replacement of the bone is long, any increase in the rate of bone remodeling will result in a loss of bone mass.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Trials in older people at high risk of calcium and vitamin D deficiency show supplementation can reverse secondary hyperparathyroidism, reduce resorption, raise bone mass, cut fractures, and reduce falls.

    “Clinical trials involving older individuals at high risk for calcium and vitamin D deficiency indicate that supplementation of both can reverse secondary hyperparathyroidism, decrease bone resorption, increase bone mass, decrease fracture rates, and even decrease the frequency of falling”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] 32. Lips, P. 2001. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic impli- cations. Endocr. Rev. 22:477-501.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    Estrogen is both anti-catabolic and anabolic because mechanical loading-induced bone formation is reduced when estrogen is deficient.

    “the increased bone formation that normally occurs in response to mechanical loading is diminished in estrogen deficiency, suggesting estrogen is both anti-catabolic and anabolic”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] 10. Lee, K., Jessop, H., Suswillo, R., Zaman, G., and Lanyon, L. 2003. Endocrinology: bone adapta- tion requires oestrogen receptor-alpha. Nature. 424:389.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In rodents, blocking IL-1 or TNF-α prevents ovariectomy bone loss, and mice lacking IL-1 receptor or TNF-α do not lose bone after ovariectomy.

    “Bone loss after ovariectomy in rodent models can be prevented by inhibiting IL-1 or TNF-α and does not occur in mice deficient in the IL-1 receptor or TNF-α”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] 26. Kimble, R.B., et al. 1995. Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early post- ovariectomy period. Endocrinology. 136:3054-3061. source
    • cites [27] 27. Lorenzo, J.A., et al. 1998. Mice lacking the type I interleukin-1 receptor do not lose bone mass after ovariectomy. Endocrinology. 139:3022-3025. source

  • May combine two claims.

    Premisecitation

    At menopause bone remodeling speeds up, with rises in both resorption and formation markers.

    “bone remodeling is accelerated at the menopause, as both markers of resorption and formation are increased”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] 8. Parfitt, A.M., Villanueva, A.R., Foldes, J., and Rao, D.S. 1995. Relations between histologic indices of bone formation: implications for the patho- genesis of spinal osteoporosis. J. Bone Miner. Res. 10:466-473. source
    • cites [9] 9. Ebeling, P.R., et al. 1996. Bone turnover markers and bone density across the menopausal transi- tion. J. Clin. Endocrinol. Metab. 81:3366-3371.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    COX inhibitors reduce responses to impact loading and fluid shear, showing prostaglandins matter for mechanical responses.

    “Treatment with COX inhibitors blunts the response to impact loading and fluid shear stress, indicating that prostaglandins play an important role in the response mechanical forces”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [90] 90. Forwood, M.R. 1996. Inducible cyclo-oxygenase (COX-2) mediates the induction of bone forma- tion by mechanical loading in vivo. J. Bone Miner. Res. 11:1688-1693. source
    • cites [91] 91. Bakker, A.D., et al. 2004. Additive effects of estro- gen and mechanical stress on nitric oxide and prostaglandin E(2) production by bone cells from osteoporotic donors. Osteoporos. Int. 16:983-989. source

  • May combine two claims.

    Premisecitation

    Raloxifene lowers vertebral fracture risk and does not appear to raise breast cancer risk.

    “One of these, raloxifene, has been shown to decrease the risk of vertebral fracture and does not appear to increase the risk of breast cancer (114).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    This may reflect altered collagen helix formation or cross-linking, challenging the idea that mineral and matrix are normal in osteoporosis and only structure causes fragility.

    “This may be due to differences in helix formation or cross-linking of collagen, challenging the concept that mineral and matrix composition are normal in osteoporosis and that only structural abnormalities account for skeletal fragility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Women's Health Initiative data indicated that estrogen, especially with progestins, raised breast cancer and cardiovascular disease risk, outweighing skeletal benefits.

    “Data from the Women's Health Initiative indicated that the estrogen, particularly when combined with progestins, increased the risk of breast cancer and cardiovascular disease, which outweighed the benefits to the skeleton.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Leukotrienes can stimulate resorption and inhibit formation.

    “Leukotrienes, the products of lipoxygenase, can affect bone by stimulating resorption and inhibiting formation”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] 97. Traianedes, K., Dallas, M.R., Garrett, I.R., Mundy, G.R., and Bonewald, L.F. 1998. 5-Lipoxygenase metabolites inhibit bone formation in vitro. Endo- crinology. 139:3178-3184.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Bisphosphonates provide effective and relatively safe antiresorptive therapy.

    “The clinical trials showing that bisphosphonates could provide effective and relatively safe antiresorptive therapy have had an enormous impact on the management of osteoporosis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [112]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [114]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    Current tools are sufficient to assess fracture risk and to prevent or treat osteoporosis so as to reduce that risk.

    “While improvements in diagnosis and therapy are important, it is equally true that we have sufficient tools today to assess fracture risk and prevent or treat osteoporosis to reduce that risk.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The rate of bone remodeling is a key predictor of fracture risk.
    • Rests on an assumption: Increased bone resorption and formation markers are associated with higher risk of bone loss and fragility fractures.
    • Rests on an assumption: Genetic factors largely determine whether an individual reaches optimal peak bone mass.
    • Rests on an assumption: Nutrition and lifestyle can affect peak bone mass during growth and development.
    • Rests on an assumption: Calcium and vitamin D sufficiency and regular physical activity may raise peak bone mass, slow bone loss, and lower fracture risk over life.

  • May combine two claims.

    Premisecitation

    Some but not all epidemiologic studies suggest that β-adrenergic blockers can lower fracture risk and raise bone mineral density.

    “Some, but not all, epidemiologic studies suggest that β-adrenergic blockers can decrease fracture risk and increase BMD (106, 107).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] 106. Rodan, G.A., and Martin, T.J. 2000. Therapeutic approaches to bone diseases. Science. 289:1508-1514. source
    • cites [107]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Osteoporosis and fractures are projected to increase as the population ages.

    “Moreover, it is critical that we meet both these challenges in the coming decades if we are to deal effectively with the increase in osteoporosis and fractures that is projected as our population ages (111).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

33 of 33

  • The authors state this as an assumption.

    The stromal/osteoblastic lineage is the main source of RANKL in normal bone remodeling.

    “While it is assumed that cells of the stromal/osteoblastic lineage are the major source of RANKL in physiologic bone remodeling”

  • The paper relies on this without support.

    Osteoporosis is a complex polygenic disorder.

    “Since osteoporosis is a complex, polygenic disorder”

  • The paper relies on this without support.

    Current knowledge about osteoporosis is not applied broadly in the community.

    “The latter is far from being met.”

  • The paper relies on this without support.

    The rate of bone remodeling is a key predictor of fracture risk.

    “Another key predictor is the rate of bone remodeling.”

  • The paper relies on this without support.

    Increased bone resorption and formation markers are associated with higher risk of bone loss and fragility fractures.

    “Increased rates of osteoclastic bone resorption, measured by the level of collagen breakdown products, as well as increased bone formation, measured by bonespecific alkaline phosphatase, osteocalcin, or procollagen peptide levels, are associated with an increase in risk for bone loss and fragility fractures.”

  • The paper relies on this without support.

    Genetic factors largely determine whether an individual reaches optimal peak bone mass.

    “While the first major pathogenetic mechanism, failure to achieve optimal peak bone mass, is determined largely by our genes, nutrition and lifestyle can have an effect during growth and development.”

  • The paper relies on this without support.

    Nutrition and lifestyle can affect peak bone mass during growth and development.

    “While the first major pathogenetic mechanism, failure to achieve optimal peak bone mass, is determined largely by our genes, nutrition and lifestyle can have an effect during growth and development.”

  • The paper relies on this without support.

    Calcium and vitamin D sufficiency and regular physical activity may raise peak bone mass, slow bone loss, and lower fracture risk over life.

    “Moreover, adequate calcium and vitamin D intake and appropriate physical activity may not only increase peak bone mass but also slow bone loss and reduce fracture risk throughout life.”
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Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1359/jbmr.040716

    Info

    The cited work was retracted; the date of the notice is not on record.

    Cited work 10.1359/jbmr.040716 · retraction date not known · this paper published 2005-12-01

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Authors
Raisz, L. G.
Affiliations
UConn Health (US)
Corresponding author
Raisz, L. G.
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2005-12-01
Volume
115
Issue
12
Pages
3318-3325
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci27071
PMC
PMC1297264
OpenAlex
W2069811152
Cited by
1,779
References
145
Citations by year
2026: 49 · 2025: 69 · 2024: 80 · 2023: 70 · 2022: 79 · 2021: 94 · 2020: 79 · 2019: 80 · 2018: 93 · 2017: 108 · 2016: 101 · 2015: 92 · 2014: 103 · 2013: 110 · 2012: 108
FWCI
11.33
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
Keywords
osteoporosis pathogenesis, bone fragility, bone resorption, bone formation, estrogen deficiency, calcium deficiency, vitamin D deficiency, secondary hyperparathyroidism, bone remodeling, osteoblasts, osteoclasts, bone marrow cells, cytokines, growth factors, transcription factors, genetic polymorphism, bone mass, fracture risk, antiresorptive therapy
MeSH terms
Animals, Bone and Bones, Calcium, Cell Differentiation, Collagen, Estrogens, Glycoproteins, Hematopoietic Stem Cells, Hormones, Humans, Ligands, Models, Biological, Neurons, Nitric Oxide, Osteoblasts, Osteoporosis, Parathyroid Hormone, Prostaglandins, Vitamin D, Vitamin D Deficiency, Bone Density, Osteoporosis, Postmenopausal, NF-kappa B, Bone Remodeling, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Leptin, Fractures, Bone, Mice, Osteoprotegerin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-30.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-30.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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