Pathogenesis of osteoporosis: concepts, conflicts, and prospects

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”

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

In the paper

“sclerostin, the product of the SOST gene, has been shown to inhibit both BMP2 and Wnt signaling”

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

In the paper

“overexpression of OPG produced osteopetrosis, while OPG-knockout mice had a phenotype of severe osteoporosis with a high incidence of fractures”

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

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”

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

In the paper

“Inactivating mutations of this gene can produce the high-bone-mass disorder Van Buchem disease or sclerosteosis”

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

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.”

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”

In the paper

“calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute”

In the paper

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

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.”

In the paper

“NO is produced by bone cells and is a cofactor for the anabolic response to mechanical loading”

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

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”

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

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”

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

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”

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.

In the paper

“Deletion of LRP5 results in a severe osteoporotic syndrome”

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

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.”

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.

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”

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

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.”

In the paper

“Stimulators of bone resorption have been found to increase RANKL expression in osteoblasts, and some also decrease OPG expression”

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.

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.”

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”

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.

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”

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.

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”

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

In the paper

“bone remodeling is accelerated at the menopause, as both markers of resorption and formation are increased”

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.

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”

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

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).”

What the sources say

• ?Not matched

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

  cites [114]

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.”

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.”

What the sources say

• ?Not matched

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

  cites [113]

In the paper

“Leukotrienes, the products of lipoxygenase, can affect bone by stimulating resorption and inhibiting formation”

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.

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.”

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]

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.”

In the paper

“Some, but not all, epidemiologic studies suggest that β-adrenergic blockers can decrease fracture risk and increase BMD (106, 107).”

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]

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).”

What the sources say

• ?Not matched

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

  cites [111]