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 accessAbstract
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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25 Sources not found · 15 No full text of the sources · 11 No basis given · 10 Own interpretation · 8 Partly supported · 3 Supported · 3 Not checked yet · 2 Couldn’t confirm · 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
- Supportedcites [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
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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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 supportedcites [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
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)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
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
- Supportedcites [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
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)
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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 supportedcites [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
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)
- 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
plainconditional- Asserted: passes — The authors put it forward as true.
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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 supportedcites [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
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)
plainconditional- Asserted: passes — The authors put it forward as true.
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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 supportedcites [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
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)
- 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
plainconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
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 verifycites [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
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)
- 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
plainconditional- Asserted: passes — The authors put it forward as true.
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- Could not verify
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 verifycites [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
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)
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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
“osteoporosis is likely to be caused by complex interactions among local and systemic regulators of bone cell function”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“failure to produce a skeleton of optimal mass and strength during growth”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Basic pathogenetic mechanisms
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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 supportedcites [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
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)
- 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
- Supportedcites [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
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)
- 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
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
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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 supportedcites [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
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)
- Partly supportedcites [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
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
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
- Supportedcites [46] 46. Bucay, N., et al. 1998. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12:1260-1268. source
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
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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 supportedcites [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
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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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 supportedcites [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
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)
- Partly supportedcites [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
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the process begins with the activation of hematopoietic precursors to become osteoclasts, which normally requires an interaction with cells of the osteoblastic lineage”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Basic pathogenetic mechanisms
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration of the skeleton”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Basic pathogenetic mechanisms
plaindirect- Asserted: passes — The authors put it forward as true.
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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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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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 matchedcites [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.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Not matched
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 matchedcites [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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“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.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Receptor activator of NF-κB, its ligand, and osteoprotegerin
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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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 matchedcites [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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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
“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.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Basic pathogenetic mechanisms
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 matchedcites [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.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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 matchedcites [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.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 matchedcites [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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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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 matchedcites [114]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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
“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.”
§ Pathogenesis of osteoporosis: concepts, conflicts, and prospects > Collagen abnormalities
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 matchedcites [113]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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 matchedcites [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.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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 matchedcites [112]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites [114]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 matchedcites [107]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 matchedcites [111]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
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.”
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.
A note, not an issue: for example, a cited work that was retracted only after this paper was published, which its authors could not have known.
Cited work 10.1359/jbmr.040716 · retraction date not known · this paper published 2005-12-01
Citations
Cites
1 retracted
Jamal, S. A., Cummings, S. R., & HAWKER, G. A. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040716 · Cited by 86
RetractedNeer, 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
Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation
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Cited by
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Items 1,501–1,600 of 1,775
Corticosteroids and Osteporosis
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Patient Quality of Life Safeguarding: The Primary Aim in Nonmetastatic Prostate Cancer Patients
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The art of treating osteoporosis: Bisphosphonates
Мазуренко, С. О. (2012) · Modern Rheumatology Journal · doi:10.14412/1996-7012-2012-716
Lasofoxifene: a new-generation SERM for the treatment of postmenopausal osteoporosis
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Tetracycline effects on diabetic bone regeneration
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García, D. F. (2011) · Institutional Repository of the University of Granada (University of Granada)
Er det en sammenheng mellom melkeinntak og beinbrudd i Tromsøs befolkning
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Immunodeficiency Provides Partial Protection from Bone Loss Induced by Castration and Ovariectomy
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Osteoporosis y polimorfismos del gen del receptor de vitamina D
de Talamoni, N. T. (2007) · Endocrinología y Nutrición · doi:10.1016/s1575-0922(07)71413-4
Multiple Atraumatic Osteoporotic Vertebral Fractures: Unusual Cause of Pain in Adult
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review article Estrogen Therapy for Postmenopausal Osteoporosis
Fitzpatrick, L. A. (2006)
Khalil, N. (2007) · D-Scholarship@Pitt (University of Pittsburgh)
Joppke, M., Fuchs, H., & Hierholzer, J. (2012) · RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren · doi:10.1055/s-0032-1311293
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Buzzai, A. C. (2013) · Murdoch University Research Portal
TRANSIZIONE PERIMENOPAUSALE: METABOLISMO SCHELETRICO, RISCHIO OSTEOPOROTICO E DI FRATTURA
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Prevalence of osteoporosis in patients with acute coronary syndrome
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Management of Osteoporotic Bone
Ziewacz, J. E., Lau, D., Berven, S., Awad, A. J., & Mummaneni, P. V. (2013) · Springer eBooks · doi:10.1007/978-3-7091-1407-0_15
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IMPACT OF TECHNOGENIC FACTORS ON OSTEOPOROSIS ONSET AND PROGRESSION: EXPERIMENTAL MODELING
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UNIVERSIDADE ESTADUAL PAULISTA "JÚLIO DE MESQUITA FILHO"
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THE ROLE OF TNF-β AND IL-17A IN POSTMENOPAUSAL OSTEOPOROSIS
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UPDATE Update in Osteoporosis and Metabolic Bone Disorders
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THE EFFECT OF METFORMIN ON MARKERS OF BONE METABOLISM IN MALE PATIENTS WITH TYPE 2 DIABETES MELLITUS
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Metadata
- Authors
- Raisz, L. G.
- Affiliations
- UConn Health (US)
- Corresponding author
- Raisz, L. G.
- Venue
- Journal of Clinical Investigation
- Published
- 2005-12-01
- Volume
- 115
- Issue
- 12
- Pages
- 3318-3325
- ISSN
- 0021-9738 (ISSN-L)
- 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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