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

The DOI matches its Crossref record; 133 of the 145 references it cites were found in a registry or an index; 16 of the 80 sources its claims cite were checked for support.

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

Every source the paper cites for this claim was checked and supports it.
In the paper
“estrogen has a greater effect than androgen in inhibiting bone resorption in men”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Central role of estrogen
What the sources say
- Supported
  The paper reports that estrogen played the major role in preventing an increase in bone-resorption markers, while testosterone had no statistically significant effect (p. 1). It concludes that estrogen is the dominant sex steroid regulating bone resorption in normal elderly men (p. 7). (LLM, conf=0.93)
  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
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Local and systemic growth factors
What the sources say
- Partly supported
  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)
  cites [79] 79. Styrkarsdottir, U., et al. 2003. Linkage of osteo- porosis to chromosome 20p12 and association to BMP2. PLoS Biol. 1:E69. sourceExperimental — accuracy not yet measured
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
Every source the paper cites for this claim was checked and supports it.
In the paper
“RANKL levels were increased on the surface of bone marrow cells from early postmenopausal women who are estrogen deficient”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Receptor activator of NF-κB, its ligand, and osteoprotegerin
What the sources say
- Supported
  The Introduction (p. 2) reports increased surface expression of RANKL on bone marrow cells from untreated early postmenopausal women compared with estrogen-replete women. The Discussion (p. 8) identifies the untreated group as estrogen deficient and reports a two- to threefold increase in the measure of cell-surface RANKL. (LLM, conf=0.95)
  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
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A mutation of LRP5 that leads to constitutive activation can result in an increase in bone density”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Genes determining osteoblast differentiation and function
What the sources say
- Partly supported
  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)
  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. sourceExperimental — accuracy not yet measured
- Not checked — no full text of the sourcecites [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
Load-bearingStrength:plain· not yet calibratedCausal:conditional· not yet calibrated
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“locally produced cytokines such as IL-1 and prostaglandins such as prostaglandin E 2 (PGE 2 ) can affect bone”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Cytokines, prostaglandins, NO, and leukotrienes
What the sources say
- Not checked — no full text of the sourcecites [81] 81. Klein, D.C., and Raisz, L.G. 1970. Prostaglandins: stimulation of bone resorption in tissue culture. Endocrinology. 86:1436-1440. source
- Partly supported
  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)
  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. sourceExperimental — accuracy not yet measured
Load-bearingStrength:plain· not yet calibratedCausal:conditional· not yet calibrated
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A polymorphism of the first intron of the gene coding for the type I collagen α1 chain and increased levels of homocysteine can influence fracture risk independent of BMD”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Collagen abnormalities
What the sources say
- Partly supported
  The results passage (indexed under “covariables”; page unavailable) associates higher homocysteine levels with greater hip-fracture risk in older men and women. The discussion says baseline BMD data were unavailable, so the study could not determine whether that association was independent of BMD. The paper does not address the claimed type I collagen α1 first-intron polymorphism. (LLM, conf=0.91)
  cites [100] 100. McLean, R.R., et al. 2004. Homocysteine as a pre- dictive factor for hip fracture in older persons. N. Engl. J. Med. 350:2042-2049. 102. van Meurs, J.B., et al. 2004. Homocysteine levels and the risk of osteoporotic fracture. N. Engl. J. Med. 350:2033-2041. 103. Ducy, P., et al. 2000. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 100:197-207. 104. sourceExperimental — accuracy not yet measured
- Not checked — no full text of the sourcecites [101] 101. Elefteriou, F., et al. 2005. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 434:514-520. 105. Takeda, S. 2005. Central control of bone remodel- ing. Biochem. Biophys. Res. Commun. 328:697-699. 106. source
- Not checked — no full text of the sourcecites [102] 102. Pasco, J.A., et al. 2004. Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study. J. Bone Miner. Res. 19:19-24. 107. source
Load-bearingStrength:plain· not yet calibratedCausal:conditional· not yet calibrated
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The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Increased β-adrenergic activity can decrease bone mass, but other neural pathways may be involved (104, 105).”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Leptin and neural pathways
What the sources say
- Could not verify
  The Introduction (page unavailable) says neuroendocrine pathways and neurotransmitters regulate bone remodelling, but does not identify β-adrenergic activity. The Results and Discussion (pages unavailable) address cannabinoid receptors and bone mass; searches for β-adrenergic activity and sympathetic signalling found no passage supporting the specific claim. (LLM, conf=0.74)
  cites [104] 104. Idris, A.I., et al. 2005. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat. Med. 11:774-799. 109. Raisz, L.G. 2005. Clinical practice. Screening for osteoporosis. N. Engl. J. Med. 353:164-171. 110. Benito, M., et al. 2003. Deterioration of trabecular architecture in hypogonadal men. J. Clin. Endocri- nol. Metab. 88:1497-1502. 111. Office of the Surgeon General. 2004. Bone health and osteoporosis: a report of the Surgeon General. US Department of Health and Human Services. Rockville, Maryland, USA. 404 pp. 112. Rosen, C.J. 2005. Clinical practice. Po sourceExperimental — accuracy not yet measured
- Not checked — no full text of the sourcecites [105] 105. Neer, R.M., et al. 2001. Effect of parathyroid hor- mone (1-34) on fractures and bone mineral den- sity in postmenopausal women with osteoporosis. N. Engl. J. Med. 344:1434-1441. 117. Meunier, P.J., et al. 2004. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N. Engl. J. Med. 350:459-468. 118. source
Load-bearingStrength:plain· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Leptin deficiency or resistance is associated with high BMD in mice despite the fact that gonadal function is diminished (103).”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Leptin and neural pathways
What the sources say
- Could not verify
  The Introduction (page unavailable) says leptin affects bone formation and bone mass in mice, but does not discuss leptin deficiency or resistance, high BMD in those mice, or diminished gonadal function. Searches for the claimed combination and for gonadal function found no passage addressing it. (LLM, conf=0.72)
  cites [103] 103. Reid, I.R., et al. 2005. beta-Blocker use, BMD, and fractures in the study of osteoporotic fractures. J. Bone Miner. Res. 20:613-618. 108. sourceExperimental — accuracy not yet measured
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes

Show all 44 claims

It may state two separate claims as one. 32
Probably not a substantial claim. 1

The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Genes determining osteoblast differentiation and function
What the sources say
- Partly supported
  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)
  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. sourceExperimental — accuracy not yet measured
- Not checked — no full text of the sourcecites [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
- Supported
  The Figure 3 passage describes LRP5 as a Wnt coreceptor required for osteoblast proliferation and function, and says its signaling pathway is important in regulating bone mass. The same section reports that children with inactivating LRP5 mutations have very low bone mass and are highly susceptible to fractures, supporting the claim about bone strength. Page numbers are unavailable in our copy. (LLM, conf=0.86)
  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
- Not checked — no full text of the sourcecites [61] 61. Gong, Y., et al. 2001. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 107:513-523. source
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“sclerostin, the product of the SOST gene, has been shown to inhibit both BMP2 and Wnt signaling”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Genes determining osteoblast differentiation and function
What the sources say
- Partly supported
  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)
  cites [70] 70. Li, X., et al. 2005. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280:19883-19887. sourceExperimental — accuracy not yet measured
- Partly supported
  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)
  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. sourceExperimental — accuracy not yet measured
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“overexpression of OPG produced osteopetrosis, while OPG-knockout mice had a phenotype of severe osteoporosis with a high incidence of fractures”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Receptor activator of NF-κB, its ligand, and osteoprotegerin
What the sources say
- Supported
  The Discussion reports increased bone density in OPG-overexpressing mice and severe bone loss in OPG-knockout mice. The Results report an increased incidence of fractures in the knockout mice, supporting the claimed phenotype. (LLM, conf=0.92)
  cites [46] 46. Bucay, N., et al. 1998. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12:1260-1268. source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Calcium, vitamin D, and parathyroid hormone
What the sources say
- Not checked — no full text of the sourcecites [33] 33. Bischoff-Ferrari, H.A., et al. 2004. Effect of vitamin D on falls: a meta-analysis. JAMA. 291:1999-2006. source
- Partly supported
  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)
  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. sourceExperimental — accuracy not yet measured
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Inactivating mutations of this gene can produce the high-bone-mass disorder Van Buchem disease or sclerosteosis”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Genes determining osteoblast differentiation and function
What the sources say
- Partly supported
  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)
  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. sourceExperimental — accuracy not yet measured
- Partly supported
  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)
  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. sourceExperimental — accuracy not yet measured
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Abstract
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Osteoporosis is a complex polygenic disorder.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“NO is produced by bone cells and is a cofactor for the anabolic response to mechanical loading”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Cytokines, prostaglandins, NO, and leukotrienes
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Gene deletion studies have shown that absence of runt-related transcription factor 2 (Runx2) or a downstream factor, osterix, are critical for osteoblast differentiation”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Genes determining osteoblast differentiation and function
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“There is some association between BMD and the incidence of osteoporotic fractures and polymorphisms in the genes encoding IGF-1 and TGF-β”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Local and systemic growth factors
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Central role of estrogen
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Deletion of LRP5 results in a severe osteoporotic syndrome”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Genes determining osteoblast differentiation and function
What the sources say
- Not checked — no full text of the sourcecites [61] 61. Gong, Y., et al. 2001. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 107:513-523. source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“Decreased calcium intake, impaired intestinal absorption of calcium due to aging or disease, as well as vitamin D deficiency can result in secondary hyperparathyroidism.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Calcium, vitamin D, and parathyroid hormone
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Central role of estrogen
What the sources say
- Not checked — no full text of the sourcecites [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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Stimulators of bone resorption have been found to increase RANKL expression in osteoblasts, and some also decrease OPG expression”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Receptor activator of NF-κB, its ligand, and osteoprotegerin
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Calcium, vitamin D, and parathyroid hormone
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Central role of estrogen
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Figure 1
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“bone remodeling is accelerated at the menopause, as both markers of resorption and formation are increased”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Central role of estrogen
What the sources say
- Not checked — no full text of the sourcecites [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
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
  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.
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Cytokines, prostaglandins, NO, and leukotrienes
What the sources say
- Not checked — no full text of the sourcecites [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
- Not checked — no full text of the sourcecites [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
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“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).”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Implication for the diagnosis and treatment of osteoporosis
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
  cites [114]
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“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.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Implication for the diagnosis and treatment of osteoporosis
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
  cites [113]
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Leukotrienes, the products of lipoxygenase, can affect bone by stimulating resorption and inhibiting formation”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Cytokines, prostaglandins, NO, and leukotrienes
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be 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.
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“The clinical trials showing that bisphosphonates could provide effective and relatively safe antiresorptive therapy have had an enormous impact on the management of osteoporosis.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Implication for the diagnosis and treatment of osteoporosis
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
  cites [112]
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
  cites [114]
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Implication for the diagnosis and treatment of osteoporosis
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“Some, but not all, epidemiologic studies suggest that β-adrenergic blockers can decrease fracture risk and increase BMD (106, 107).”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Leptin and neural pathways
What the sources say
- Not checked — no full text of the sourcecites [106] 106. Rodan, G.A., and Martin, T.J. 2000. Therapeutic approaches to bone diseases. Science. 289:1508-1514. source
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
  cites [107]
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“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).”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Implication for the diagnosis and treatment of osteoporosis
What the sources say
- Not matched
  Couldn’t be matched to a paper in Crossref, so it can’t be checked.
  cites [111]
Strength:plain· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.

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.”

8 of 8

Self-check

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

Self-check results appear here once an independent check has confirmed them.

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

1 of 1

1 retracted

RETRACTION: Isosorbide Mononitrate Increases Bone Formation and Decreases Bone Resorption in Postmenopausal Women: A Randomized Trial
Jamal, S. A., Cummings, S. R., & HAWKER, G. A. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040716 · Cited by 86
Retracted
Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis
Neer, R. M., Arnaud, C. D., Zanchetta, J. R., Prince, R., Gaich, G. A., Reginster, J.-Y., Hodsman, A. B., Eriksen, E. F., Ish-Shalom, S., Genant, H. K., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200105103441904 · Cited by 4,602
Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women's Health Initiative Randomized Controlled Trial
(2004) · JAMA · doi:10.1001/jama.291.14.1701 · Cited by 4,534
Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation
Ducy, P., Zhang, R., Geoffroy, V., Ridall, A. L., & Karsenty, G. (1997) · Cell · doi:10.1016/s0092-8674(00)80257-3 · Cited by 4,246
The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation
Nakashima, K., Zhou, X., Kunkel, G., Zhang, Z., Deng, J. M., Behringer, R. R., & de Crombrugghe, B. (2002) · Cell · doi:10.1016/s0092-8674(01)00622-5 · Cited by 3,608
Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.
Bucay, N., Sarosi, I., Dunstan, C. R., Morony, S., Tarpley, J., Capparelli, C., Scully, S., Tan, H. L., Xu, W., Lacey, D. L., et al. (1998) · Genes & Development · doi:10.1101/gad.12.9.1260 · Cited by 2,483
Modulation of Osteoclast Differentiation and Function by the New Members of the Tumor Necrosis Factor Receptor and Ligand Families
Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M. T., & Martin, T. J. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.3.0367 · Cited by 2,345
LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development
Gong, Y., Slee, R. B., Fukai, N., Rawadi, G., Roman-Roman, S., Reginato, A. M., Wang, H., Cundy, T., Glorieux, F. H., Lev, D., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00571-2 · Cited by 2,235
Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications.
Lips, P. (2001) · Endocrine reviews · doi:10.1210/edrv.22.4.0437 · Cited by 2,203
Leptin Inhibits Bone Formation through a Hypothalamic Relay
Ducy, P., Amling, M., Takeda, S., Priemel, M., Schilling, A. F., Beil, F. T., Shen, J., Vinson, C., Rueger, J. M., & Karsenty, G. (2000) · Cell · doi:10.1016/s0092-8674(00)81558-5 · Cited by 2,077

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Items 901–1,000 of 1,775

Optimizing calcium and vitamin D intake through diet and supplements
Kilim, H. P., & Rosen, H. N. (2018) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.85a.17106 · Cited by 13
1,25(OH)2D3 inhibits osteogenic differentiation through activating β‑catenin signaling via downregulating bone morphogenetic protein 2
Han, X., Zhu, N., Wang, Y., & Cheng, G. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11619 · Cited by 12
“osteoporosis is a common bone disease that mainly affects the elderly, and is characterized by low bone density and microarchitectural deterioration of bone tissue (1-3).”
Background
The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation
Tsai, D., Fang, W., Wu, L.-W., Tai, M., Kao, C.-C., Huang, S., Chen, W.-T., Hsiao, P.-J., Chiu, C.-C., Su, W., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.730686 · Cited by 12
Systematic Analysis of mRNAs and ncRNAs in BMSCs of Senile Osteoporosis Patients
Geng, Y., Chen, J., Chang, C., Zhang, Y., Duan, L., Zhu, W., Mou, L., Xiong, J., & Wang, D. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.776984 · Cited by 12
“Senile osteoporosis (SOP) is an age-related skeleton disease characterized by decreased bone mass and strength, which may lead to increased risk of fragility fractures (Raisz, 2005; Brown, 2017).”
Background
Thiaplakortone B attenuates RANKL‐induced NF‐κB and MAPK signaling and dampens OVX‐induced bone loss in mice
Wang, Q., Chen, D., Wang, Y., Dong, C., Liu, J., Chen, K., Song, F., Wang, C., Yuan, J., Davis, R. A., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113622 · Cited by 14
Blackcurrants Reduce the Risk of Postmenopausal Osteoporosis: A Pilot Double-Blind, Randomized, Placebo-Controlled Clinical Trial
Nosal, B. M., Sakaki, J. R., Macdonald, Z., Mahoney, K. J., Kim, K., Madore, M. P., Thornton, S., Tran, T. D. B., Weinstock, G. M., Lee, E. C., et al. (2022) · Nutrients · doi:10.3390/nu14234971 · Cited by 12
Endocrine sequelae of hematopoietic stem cell transplantation: Effects on mineral homeostasis and bone metabolism
Miglietta, F., Iamartino, L., Palmini, G., Giusti, F., Marini, F., Iantomasi, T., & Brandi, M. L. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1085315 · Cited by 14
Enhancement of osteogenesis post‐splenectomy does not attenuate bone loss in ovariectomized rats
Sun, D., Zheng, X., Chen, Y., Jia, C., Xu, S. H., Lin, C., Zhang, P., Zhang, Z., Cai, D., Jin, D., et al. (2015) · Journal of Orthopaedic Research® · doi:10.1002/jor.22825 · Cited by 12
“The primary cause of osteoporosis in post-menopausal females is considered to be estrogen deficiency.(8) In addition to its direct effects on bone, estrogen deficiency displayed a profound stimulation of bone loss, which is mediated by immune cells (T and B lymphocytes, monocytes) and cytokines.”
Background
Fourier-Transform Raman Spectroscopy Study of the Ovariectomized Rat Model of Osteoporosis~!2009-09-30~!2010-02-11~!2010-03-25~!
de Souza, R. A., Jerônimo, D. P., Gouvêa, H. A., Xavier, M., de Souza, M. T., Miranda, H. L., Tosato, M. G., Martin, A. A., & Ribeiro, W. (2010) · The Open Bone Journal · doi:10.2174/1876525401002010024 · Cited by 14
“Osteoporosis is a disabling skeletal disorder characterized by progressive bone mass loss and microarchitecture deterioration of bone tissue which predisposes patients to increased bone fracture risk [1].”
BackgroundInfluential
Anisotropic post-yield response of cancellous bone simulated by stress–strain curves of bulk equivalent structures
Tsouknidas, A., Maliaris, G., Savvakis, S., & Michailidis, N. (2013) · Computer Methods in Biomechanics & Biomedical Engineering · doi:10.1080/10255842.2013.849342 · Cited by 12
“This is due to the adaption of bone to the mechanical loads it is subjected to, as a result of continuous bone resorption followed by bone formation during remodelling (Raisz 2005).”
Background
Normal and osteoporotic human osteoblast behaviour after 1,25-dihydroxy-vitamin D3 stimulation
Maruotti, N., Corrado, A., Grano, M., Colucci, S. C., & Cantatore, F. P. (2008) · Rheumatology International · doi:10.1007/s00296-008-0755-9 · Cited by 12
“These microarchitectural alterations are responsible for an increased risk of fragility fractures [ 1 ].”
Background
Clinical management of osteoporotic vertebral fracture treated with percutaneous vertebroplasty
Capozzi, A. (2017) · Clinical cases in mineral and bone metabolism · doi:10.11138/ccmbm/2017.14.1.161 · Cited by 13
“In particular, pre-menopausal and menopausal period (27, 28) owing to gradual reduction of estrogens and progesterone (P4), produce a higher rate of bone remodeling and a marked imbalance in Bone Multicellular Compartment (BMC) (29, 30).”
Background
The positive association of total protein intake with femoral neck strength (KNHANES IV)
Kim, B., Lee, S. H., Isales, C. M., Koh, J., & Hamrick, M. W. (2018) · Osteoporosis International · doi:10.1007/s00198-018-4451-7 · Cited by 13
“[44], but also involves diverse, indirect mechanisms, such as ROS, cytokines, and growth factors, that result in adverse outcomes of bone remodeling [45].”
Background
Retracted: Overexpression of RPN2 promotes osteogenic differentiation of hBMSCs through the JAK/STAT3 pathway
Ni, L., Yu, J., Gui, X., et al. (2019) · FEBS Open Bio · doi:10.1002/2211-5463.12766 · Cited by 12
Retracted
Potential osteogenic activity of ethanolic extract and oxoflavidin isolated from Pholidota articulata Lindley
Sharma, C., Dixit, M., Singh, R. M., et al. (2015) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2015.04.045 · Cited by 12
“Osteoporosis is one of the diseases which results from an imbalance in remodeling and is characterized by low bone mass, micro-architectural deterioration and bone composition changes ultimately leading to fracture (Raisz, 2005).”
Background
New insights into the gene function of osteoporosis
You, L. (2013) · Frontiers in bioscience · doi:10.2741/4165 · Cited by 12
Effect of endothelin-1 on osteoblastic differentiation is modified by the level of connexin43: comparative study on calvarial osteoblastic cells isolated from Cx43+/−and Cx43+/+ mice
Geneau, G., Lamiche, C., Niger, C., Strale, P., Clarhaut, J. A., Defamie, N., Debiais, F., Mesnil, M., & Cronier, L. (2010) · Cell and Tissue Research · doi:10.1007/s00441-009-0924-5 · Cited by 14
“Any disturbances to these processes can result in unsteady bone mass and pathologies (Roodman and Windle 2005; Raisz 2005).”
Background
Organ Systems Dependent on Nitric Oxide and the Potential for Nitric Oxide‐Targeted Therapies in Related Diseases
Hollenberg, N. K. (2006) · Journal of Clinical Hypertension · doi:10.1111/j.1524-6175.2006.06042.x · Cited by 13
Piper Sarmentosum: A New Hope for the Treatment of Osteoporosis
Ramli, E. S. M., Suhaimi, F. H., Ahmad, F., Shuid, A. N., Mohamad, N., & Soelaiman, I. N. (2013) · Current Drug Targets · doi:10.2174/13894501113146660228 · Cited by 11
“Osteoporosis is characterized by loss of bone mass and strength that occurs due to imbalance of the remodeling process leading to bone fragility and fracture [5].”
BackgroundInfluential
Evaluation of Bone and Mineral Metabolism in Patients Recently Diagnosed With Leprosy
Ribeiro, F. B., Pereira, F. D. A., Muller, É., et al. (2007) · The American Journal of the Medical Sciences · doi:10.1097/maj.0b013e318142bafb · Cited by 12
Iron loading in humans: A risk factor for enhanced morbidity and mortality
Weinberg, E. D. (2007) · Journal of Nutritional & Environmental Medicine · doi:10.1080/13590840601167685 · Cited by 12
“For instance, among established causes of osteoporosis are deficiencies in vitamin D, ascorbic acid or calcium; hyperparathyroidism; or prolonged therapy with thyroid hormone or steroids [4].”
Background
The role of sclerostin in lipid and glucose metabolism disorders
Jiang, H., Li, D., Han, Y., Li, N., Tao, X., Liu, J., Zhang, Z., Yu, Y., Wang, L., Yu, S., et al. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115694 · Cited by 12
Pathophysiology and Therapeutic Management of Bone Loss in Patients with Critical Illness
Kim, T. J., & Kim, H. (2023) · Pharmaceuticals · doi:10.3390/ph16121718 · Cited by 13
“Because of age-related hormonal changes, both male and female populations have equal rates of bone loss by the age of 60 years and are at risk of developing osteoporosis [17,18].”
Background
Systems genetics and bioinformatics analyses using ESR1-correlated genes identify potential candidates underlying female bone development
Bajpai, A. K., Gu, Q., Jiao, Y., Starlard‐Davenport, A., Gu, W., Quarles, L. D., Xiao, Z., & Lu, L. (2023) · Genomics · doi:10.1016/j.ygeno.2023.110769 · Cited by 11
“The increase in osteoclastic resorption is due to the low levels of estrogen, which weakens the inhibition of both osteoclastogenesis and osteoclast activity [1,2].”
Background
Sex differences and age-related changes in the mandibular alveolar bone mineral density using a computer-aided measurement system for intraoral radiography
Ono, R., Katsumata, A., Fujikawa, Y., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-57805-5 · Cited by 11
“After menopause, women experienced a notable age-related decrease in al-BMD similar to that observed in other skeletal sites 17 , which can be explained by the increase in bone resorption under estrogen-deficient conditions 18 .”
Building bones by knocking down genes
Rosen, C. J. (2012) · Nature Medicine · doi:10.1038/nm.2630 · Cited by 11
Gene Expression and Distribution of Key Bone Turnover Markers in the Callus of Estrogen-Deficient, Vitamin D-Depleted Rats
Melhus, G., Brorson, S. H., Bækkevold, E. S., Andersson, G., Jemtland, R., Olstad, O. K., & Reinholt, F. P. (2010) · Calcified Tissue International · doi:10.1007/s00223-010-9371-2 · Cited by 11
“and bone resorption [3, 4] influences healing of fractures in OP individuals remain to be answered.”
Background
Aging adult skull remains through radiological density estimates: A comparison of different computed tomography systems and the use of computer simulations to judge the accuracy of results
Obert, M., Kubelt, C., Schaaf, T. K., et al. (2013) · Forensic Science International · doi:10.1016/j.forsciint.2013.02.006 · Cited by 11
Re-evaluation of Pleistocene and Holocene long bone robusticity trends with regards to age-at-death estimates and size standardization procedures
Friedl, L., Eisová, S., & Holliday, T. W. (2016) · Journal of Human Evolution · doi:10.1016/j.jhevol.2016.05.013 · Cited by 11
Uncoupled bone remodeling is characteristic of bone damage in premenopausal women with new-onset systemic lupus erythematosus
Zhu, L., Zhang, J., Wang, J., Lv, X., Pu, D., Wang, Y., Men, Q., & He, L. (2021) · Lupus · doi:10.1177/09612033211005067 · Cited by 12
“Osteoporosis is caused by abnormal bone remodeling, including excessive bone resorption and inadequate formation response.(22) However, the effects of disease activity on bone formation are unclear.”
Background
MicroRNA-1270 Inhibits Cell Proliferation, Migration, and Invasion via Targeting IRF8 in Osteoblast-like Cell Lines
Ramírez-Salazar, E. G., Almeraya, E. V., López-Pérez, T. V., Jiménez‐Salas, Z., Patiño, N., & Velázquez‐Cruz, R. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44030077 · Cited by 11
“Bone tissue is very dynamic and complex, and its metabolism is modulated via a life-long process of demodulation regulated by osteoblasts and osteoclasts [9,10].”
Background
Toxoplasma gondii infection as a risk factor for osteoporosis: a case–control study
Zhu, K., Liu, K., Huang, J., Weng, X., Chen, Q., Gao, T., Chen, K., Jing, C., Wang, J., & Yang, G. (2022) · Parasites & Vectors · doi:10.1186/s13071-022-05257-z · Cited by 11
“In normal circumstances, osteoblasts and osteoclasts maintain a certain number and constrain each other, the bone formation and bone resorption mediated by them are in balance [14].”
Background
The role of metabolites under the influence of genes and lifestyles in bone density changes
Lv, X., Jiang, Y., Yang, D., Zhu, C., Yuan, H., Yuan, Z., Suo, C., Chen, X., & Xu, K. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.934951 · Cited by 11
Isolation, purification, and antiosteoporosis activity of donkey bone collagen from discarded bone and its antioxidant peptides
Wang, J., Hou, H., Li, Y., Tang, W., Gao, D., Liu, Z., Gao, X., Zhao, F., Feng, S., Tan, H., et al. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e23531 · Cited by 12
“The main underlying cause of osteoporosis is the disruption of this steady-state environment, leading to diminished bone formation, elevated bone resorption, and, ultimately, decreased bone density [2].”
Background
A Direct Comparison of the Effects of the Antiretroviral Drugs Stavudine, Tenofovir and the Combination Lopinavir/Ritonavir on Bone Metabolism in a Rat Model
Conradie, M., van de Vyver, M., Andrag, E., Conradie, M., & Ferris, W. F. (2017) · Calcified Tissue International · doi:10.1007/s00223-017-0290-3 · Cited by 11
“Even though it has been proposed that the catabolic skeletal effects are due to an increase in bone turnover [21], where formation rates do not match resorption, or due to uncoupling of the two processes [22], the mechanisms whereby ARV therapy contributes to bone loss are yet to be fully understood.”
Somatic maturation and the relationship between bone mineral variables and types of sports among adolescents: cross-sectional study
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Beneficial Role of Hydro-alcoholic Seed Extract of Trigonella foenum graecum on Bone Structure and Strength in Menopause Induced Osteopenia
Anjaneyulu, K., Bhat, K. M. R., Srinivasa, S. R., Devkar, R. A., & Henry, T. (1970) · Ethiopian Journal of Health Sciences · doi:10.4314/ejhs.v28i6.14 · Cited by 11
“These are the principal causes of bone fragility and fracture (1).”
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The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption, but without affecting bone formation
Chen, W., Xie, Z., Tang, P., Wang, Y., Jie, Z., Qin, A., Jiang, X., Hu, Z., & Fan, S. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1914-5 · Cited by 11
Pathophysiology of the risk factors associated with osteoporosis and their correlation to the T-score value in patients with osteopenia and osteoporosis in the United Arab Emirates
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“[1] However, other studies indicated that both markers of bone resorption and formation also increased, leading to accelerated bone remodeling at menopause.”
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Vitamin D receptor and cellular retinol-binding protein-1 immunohistochemical expression in normal, hyperplastic and neoplastic endometrium: Possible diagnostic and therapeutic implications
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Solid-State Nuclear Magnetic Resonance Identifies Abnormal Calcium Phosphate Formation in Diseased Bones
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Andrographolide prevents bone loss via targeting estrogen‐related receptor‐α‐regulated metabolic adaption of osteoclastogenesis
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“Excessive bone resorption by abnormal activation of osteoclasts is responsible for imbalance bone remodelling contributing to postmenopausal osteoporosis (Carson & Manolagas, 2015; Raisz, 2005).”
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Genkwanin Prevents Lipopolysaccharide-Induced Inflammatory Bone Destruction and Ovariectomy-Induced Bone Loss
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Prostaglandins, Leukotrienes, and Related Compounds
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Characterization of steroid sulfatase in the MC3T3-E1 mouse pre-osteoblastic cell line
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New Target Sites for Treatment of Osteoporosis
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Abundant expression of tetraspanin CD9 in activated osteoclasts in ovariectomy-induced osteoporosis and in bone erosions of collagen-induced arthritis
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Progress and prospect of minicircle as a minimized non-viral DNA vector in gene therapy and regenerative medicine
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“220 To manage postmenopausal osteoporosis, two groups of therapeutics are commonly prescribed, anti-resorptive agents and anabolic agents.”
Gut microbiota-metabolome remodeling associated with low bone mass: an integrated multi-omics study in fracture patients
Zhao, X., Wu, B., Han, P., Wang, Z., Cao, R., Chen, S., Cheng, C., Lian, H., Zha, Y., & Li, M. K. W. (2025) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2025.1646361 · Cited by 11
“…for more than 3 months within the 6 months; (Burge et al., 2007); presence of diseases known to significantly affect bone metabolism (e.g., hyperparathyroidism, end-stage renal disease, Paget’s disease); and (Raisz, 2005) a history of inflammatory bowel disease or major intestinal surgery.”
Exploring the Association Between Emphysema Phenotypes and Low Bone Mineral Density in Smokers with and without COPD
González, J., Rivera‐Ortega, P., Rodríguez‐Fraile, M., Restituto, P., Colina, I., Calleja, M. D. L. D., Alcaide, A. B., Campo, A., Bertó, J., Seijo, L. M., et al. (2020) · International Journal of COPD · doi:10.2147/copd.s257918 · Cited by 11
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“In a parallel trajectory, elderly men confront a gradual reduction in bone mineral density, a phenomenon intricately linked to fluctuations in sex hormone-binding globulin levels (Raisz 2005; Arceo-Mendoza and Camacho 2021).”
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Low Bone Mineral Density and the Risk of Benign Paroxysmal Positional Vertigo
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Longitudinal evaluation of hepatic osteodystrophy in children and adolescents with chronic cholestatic liver disease
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“and androgen) are among the crucial modulators of bone health, particularly in protecting bones from weakness and regulating bone minerals to optimum levels [5-7].”
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Low TSH Levels Within Euthyroid Range Could Play a Negative Role on Bone Mineral Density in Postmenopausal Women with Type 2 Diabetes
Liu, C., Pan, J., Wen, S., Nguyen, T., Xu, D., Wang, C., Yuan, X., Wen, Z., & Zhou, L. (2021) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s307633 · Cited by 10
“The active and unbalanced bone remodeling results in thinness or fracture of trabecular bones, increased cortical bone porosity, and reduced bone strength.(35) Our study showed that low normal TSH levels could lead to decreased BMD at the femoral neck and hip joint in women, but not in men.”
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Menopause care in women living with HIV in the UK - A review
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The Local Release of Teriparatide Incorporated in 45S5 Bioglass Promotes a Beneficial Effect on Osteogenic Cells and Bone Repair in Calvarial Defects in Ovariectomized Rats
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Caixas, U., Tariq, S., Morelló, J., et al. (2023) · AIDS Care · doi:10.1080/09540121.2023.2216008 · Cited by 10
“…to experience menopause at an earlier age (Andany et al., 2020; Van Ommen et al., 2021), and that they have a high prevalence of menopausal symptoms such as vasomotor symptoms, sexual dysfunction and mood changes (Marcus et al., 2016; Pathak et al., 2019; Raisz,2005 ; Toorabally et al., 2020).”
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Effects of early and late treatments of low-intensity, high-frequency mechanical vibration on bone parameters in rats
Sasso, G. R. D. S., Florencio‐Silva, R., dos Santos, M. A., Teixeira, C. D. P., Reginato, R. D., Simões, M. D. J., & Katchburian, E. (2015) · Gynecological Endocrinology · doi:10.3109/09513590.2015.1075198 · Cited by 10
“density (BMD), progressive bone loss, and microarchitecture deterioration of bone tissue, with consequent increased risk of bone fracture [1].”
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BPCO et métabolisme osseux: une mise à jour clinique
Lehouck, A., Remoortel, H. V., Troosters, T., Decramer, M., & Janssens, W. (2010) · Revue des Maladies Respiratoires · doi:10.1016/j.rmr.2010.10.007 · Cited by 11
In vitro and in vivo enhanced osteogenesis by kaempferol found by a high-throughput assay using human mesenchymal stromal cells
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Fatty acid consumption and the risk of osteoporotic fracture
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Echinocystic acid inhibits RANKL-induced osteoclastogenesis by regulating NF-κB and ERK signaling pathways
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Evaluation of the Effects of Photobiomodulation on Biomechanical Properties and Hounsfield Unit of Partial Osteotomy Healing in an Experimental Rat Model of Type I Diabetes and Osteoporosis
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“38 Decreased bone density and a delayed healing process can lead to fracture nonunion.”
Bone-targeting parathyroid hormone conjugates outperform unmodified PTH in the anabolic treatment of osteoporosis in rats
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Gossypol Promotes Bone Formation in Ovariectomy-Induced Osteoporosis through Regulating Cell Apoptosis
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Formation of calcium phosphate nanoparticles mediated by animal protein hydrolysates enhances calcium absorption by murine small intestine ex vivo
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MicroRNA‐142 regulates osteoblast differentiation and apoptosis of mouse pre‐osteoblast cells by targeting bone morphogenetic protein 2
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Novel transplant of combined platelet-rich fibrin Releasate and bone marrow stem cells prevent bone loss in Ovariectomized osteoporotic mice
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Inorganic Polyphosphates: Biologically Active Biopolymers for Biomedical Applications
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“This degenerative bone disorder is characterized by a reduced OPG expression and hence an increased bone resorption due to an enhanced osteoclast activity (Raisz 2005).”
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Sphingosine 1-phosphate and osteoporosis: pathophysiology and therapeutic aspects—a narrative review
Tian, J., Ma, S., Xie, W., Zhang, Y., Tao, L., Li, Y., & Xiao, W. (2021) · Annals of Palliative Medicine · doi:10.21037/apm-20-1255 · Cited by 12
“However, once bones have been weakened by osteoporosis, patients might show signs and symptoms, including back pain, loss of stature, and a curved posture, and there is a risk of bone fracture (33,34).”
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Associations of dietary intakes of calcium, magnesium and soy isoflavones with osteoporotic fracture risk in postmenopausal women: a prospective study
Cui, Y., Cai, H., Gao, Y., Dai, Q., Yang, G., Zheng, W., & Shu, X. (2022) · Journal of Nutritional Science · doi:10.1017/jns.2022.52 · Cited by 10
“Estrogen plays an important role in skeletal homeostasis and regulates bone remodelling((15,16)), while the decline in estrogen levels associated with menopause causes bone loss in women((17)).”
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Accessibility of 3 H-Secoisolariciresinol Diglycoside Lignan Metabolites in Skeletal Tissue of Ovariectomized Rats
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Decreased sleep duration: A risk of progression of degenerative lumbar scoliosis
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Disruption of claudin-18 diminishes ovariectomy-induced bone loss in mice
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“ESTROGEN DEFICIENCY IN MENOPAUSAL WOMEN is a serious health issue due to increased bone turnover, resulting in osteoporosis and increased fracture risk consequent to deterioration of microarchitectural bone structure (32).”
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Identification of drug candidate for osteoporosis by computational bioinformatics analysis of gene expression profile
Yu, G., Wang, L., Li, Y., Ma, Z., & Li, Y. (2013) · European journal of medical research · doi:10.1186/2047-783x-18-5 · Cited by 10
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Bone histomorphometric study of young rats following oestrogen deficiency
Estai, M., Suhaimi, F. H., Soelaiman, I. N., Shuid, A. N., & Das, S. (2011) · AFRICAN JOURNAL OF BIOTECHNOLOGY · Cited by 10
The Osteogenic Potential of the Marine-Derived Multi-Mineral Formula Aquamin Is Enhanced by the Presence of Vitamin D
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Targeting Ferroptosis: Emerging Insights into Osteoporosis Mechanisms
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A RETROSPECTIVE STUDY OF CLINICAL PROFILE AND DRUG PRESCRIBING PATTERN IN OSTEOPOROSIS IN A TERTIARY CARE HOSPITAL
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A novel miR-466l-3p/FGF23 axis promotes osteogenic differentiation of human bone marrow mesenchymal stem cells
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Does strontium coated titanium implants enhance the osseointegration in animal models under osteoporotic condition? A systematic review and meta-analysis
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“…bone density and deterioration of the microarch-itecture of the bone tissue due to high bone turnover rates and imbalance in bone remodeling, where bone resorption exceeds bone formation, leading to bone fragility with greater risk of bone fracture and decreased capacity of bone to repair [6, 7].”
Screening of genes co-associated with osteoporosis and chronic HBV infection based on bioinformatics analysis and machine learning
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“OP is a bone disease characterized by low bone density and deterioration of bone tissue structure, leading to fragile bones and an increased risk of fractures (6, 7).”
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Targeting lipid raft-related stomatin to ameliorate osteoporosis in preclinical models
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Nakamura, A., & Towheed, T. (2023) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2023.152345 · Cited by 11
Serum metabolomics analyses reveal biomarkers of osteoporosis and the mechanism of Quanduzhong capsules
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Dual Effect of Chrysanthemum indicum Extract to Stimulate Osteoblast Differentiation and Inhibit Osteoclast Formation and Resorption In Vitro
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Background

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: bronze
doi.org
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

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Pathogenesis of osteoporosis: concepts, conflicts, and prospects

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