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  • Review Article
  • Published:

Discoveries, drugs and skeletal disorders

Nature Reviews Drug Discovery volume 1, pages 784–796 (2002)Cite this article

Key Points

  • Disorders that alter bone function, such as osteoporosis, occur with increasing frequency in the elderly and represent a major public health problem. For example, the economic burden of osteoporosis alone is estimated to be US $14 billion per year in the United States.

  • Understanding normal bone biology is crucial to treating skeletal disease, and identification of mutated genes that cause inherited bone disorders, as well as the use of transgenic and knockout mouse models, has greatly advanced this understanding and has provided potential targets for drug development.

  • The main cell that contributes to bone formation is the osteoblast, which produces and secretes the structural components of the bone matrix (notably type I collagen) and releases minerals, growth factors and enzymes into it.

  • The cells in bone that are specialized to resorb mineralized matrix are multinucleated osteoclasts, which secrete acid to dissolve matrix minerals and proteases to degrade exposed matrix proteins, through a specialized apical cell-membrane surface that is known as the ruffled border.

  • So far, the most successful therapies for bone disease have targeted the bone-resorbing osteoclastic system. These anti-resorbing agents include bisphosphonates, oestrogens, selective oestrogen-receptor modulators (SERMs) and calcitonin.

  • Future development of anti-resorptive agents might target osteoclast formation, activity and/or cell death at multiple loci being discovered by genetic and genomic approaches.

  • The paucity of available anabolic agents for skeletal disorders makes this a particularly fruitful area for drug development. These agents should be of major benefit in systemic diseases, such as osteoporosis, when significant bone loss has already occurred, or for secondary prevention of fractures, but might also be beneficial in local disorders, such as delayed fracture healing, to accelerate bone formation.

Abstract

Bone turnover, in which cells of the osteoclast lineage resorb bone and cells of the osteoblast lineage deposit bone, normally occurs in a highly regulated manner throughout life. Perturbations to these processes underlie skeletal disorders, such as osteoporosis, which are common, chronic and disabling, and increase with age. On the basis of empirical observations or on understanding of the endocrinology of the skeleton, excellent bone-resorption inhibitors, but few anabolic agents, have been developed as therapeutics for skeletal disorders. However, powerful new genomic and genetic tools are uncovering new loci that regulate the activity of both osteoclasts and osteoblasts, and these hold great promise for future drug development.

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Figure 1: Osteoblast–osteoclast interactions.
Figure 2: Osteoblast development and presumed sites of regulation by PTH and PTHrP.
Figure 3: Model of regulation of osteoblast function by the LRP5 signalling system.
Figure 4: Osteoclast action.
Figure 5: Structures of selected non-nitrogen-containing and nitrogen-containing bisphosphonates.
Figure 6: Chemical structures of compounds that act through the oestrogen receptor.
Figure 7: Model of endochondral bone formation and selected molecular regulators.

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References

  1. Cummings, S. R. & Melton, L. J. Epidemiology and outcomes of osteoporotic fractures. Lancet 359, 1761–1767 (2002).

    Article  PubMed  Google Scholar 

  2. Doherty, D. A., Sanders, K. M., Kotowicz, M. A. & Prince, R. L. Lifetime and five-year age-specific risks of first and subsequent osteoporotic fractures in postmenopausal women. Osteoporosis Int. 12, 16–23 (2001).

    CAS  Google Scholar 

  3. Ray, N. F., Chan, J. K., Thamer, M. & Melton, L. J. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J. Bone Miner. Res. 12, 24–35 (1997).

    CAS  PubMed  Google Scholar 

  4. Burr, D. B. The contribution of the organic matrix to bone's material properties. Bone 31, 8–11 (2002).

    CAS  PubMed  Google Scholar 

  5. Kanis, J. A. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359, 1929–1936 (2002).

    PubMed  Google Scholar 

  6. Hunziker, E. B. Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthritis Cartilage 10, 432–463 (2002).

    CAS  PubMed  Google Scholar 

  7. Klareskog, L., Lorentzen, J., Padyukov, L. & Alfredsson, L. Genes and environment in arthritis: can RA be prevented? Arthritis Res. 4 (Suppl. 3), S31–S36 (2002).

    PubMed  PubMed Central  Google Scholar 

  8. Goltzman, D., Karaplis, A. C., Kremer, R. & Rabbani, S. A. Molecular basis of the spectrum of skeletal complications of neoplasia. Cancer 88 (Suppl. 12), 2903–2908 (2000).

    CAS  PubMed  Google Scholar 

  9. Gemmell, E., Yamazaki, K. & Seymour, G. J. Destructive periodontitis lesions are determined by the nature of the lymphocytic response. Crit. Rev. Oral Biol. Med. 13, 17–34 (2002).

    CAS  PubMed  Google Scholar 

  10. Reddy, S. V., Kurihara, N., Menaa, C. & Roodman, G. D. Paget's disease of bone: a disease of the osteoclast. Rev. Endocr. Metab. Disord. 2, 195–201 (2001).

    CAS  PubMed  Google Scholar 

  11. Econs, M. J. New insights into the pathogenesis of inherited phosphate wasting disorders. Bone 25, 131–135 (1999).

    CAS  PubMed  Google Scholar 

  12. White, K. E. et al. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. The ADHR Consortium. Nature Genet. 26, 345–348 (2000).The initial description of the discovery of FGF23 in a syndrome of hypophosphataemic rickets.

    CAS  Google Scholar 

  13. Mawer, E. B. & Davies, M. Vitamin D nutrition and bone disease in adults. Rev. Endocr. Metab. Disord. 2, 175–186 (2001).

    Google Scholar 

  14. Aubin, J. E. Regulation of osteoblast formation and function. Rev. Endocr. Metab. Disord. 2, 81–94 (2001).

    CAS  PubMed  Google Scholar 

  15. Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997).

    CAS  PubMed  Google Scholar 

  16. Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29 (2002).

    CAS  PubMed  Google Scholar 

  17. Sabatakos, G. et al. Overexpression of ΔFOSB transcription factor(s) increases bone formation and inhibits adipogenesis. Nature Med. 6, 985–990 (2000).

    CAS  PubMed  Google Scholar 

  18. Jochum, W. et al. Increased bone formation and osteosclerosis in mice overexpressing the transcription factor Fra-1. Nature Med. 6, 985–990 (2000).

    Google Scholar 

  19. Rouleau, M. F., Mitchell, J. & Goltzman, D. In vivo distribution of parathyroid hormone receptor in bone: evidence that a predominant osseous target cell is not the mature osteoblast. Endocrinology 123, 187–191 (1988).

    CAS  PubMed  Google Scholar 

  20. Suda, T., Kobayashi, K., Jimi, E., Udagawa, N. & Takahashi, N. The molecular basis of osteoclast differentiation and activation. Novartis Found. Symp. 232, 235–247 (2001).

    CAS  PubMed  Google Scholar 

  21. Watanuki, M. et al. Role of inducible nitric oxide synthase in skeletal adaptation to acute increases in mechanical loading. J. Bone Miner. Res. 17, 1015–1025 (2002).

    CAS  PubMed  Google Scholar 

  22. Miao, D., He, B., Karaplis, A. C. & Goltzman, D. Parathyroid hormone is essential for normal fetal bone formation. J. Clin. Invest. 109, 1173–1182 (2002).The first report of the physiological role of PTH as an anabolic agent in fetal bone.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Amizuka, N. et al. Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev. Biol. 175, 166–176 (1996).

    CAS  PubMed  Google Scholar 

  24. Miao, D. et al. Parathyroid hormone-related peptide stimulates osteogenic cell proliferation through protein kinase C activation of the Ras/mitogen-activated protein kinase signaling pathway. J. Biol. Chem. 276, 32204–32213 (2001).

    CAS  PubMed  Google Scholar 

  25. Carpio, L., Gladu, J., Goltzman, D. & Rabbani, S. A. Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. Am. J. Physiol. Endocrinol. Metab. 281, E489–E499 (2001).

    CAS  PubMed  Google Scholar 

  26. Jilka, R. L. et al. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J. Clin. Invest. 104, 439–446 (1999).A description of the inhibition of apoptosis as an important mechanism for the anabolic effect of PTH.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Rodan, G. A. & Martin, T. J. Therapeutic approaches to bone diseases. Science 289, 1508–1514 (2000).

    CAS  PubMed  Google Scholar 

  28. Dempster, D. W. et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J. Bone Miner. Res. 16, 1846–1853 (2001).

    CAS  PubMed  Google Scholar 

  29. Canalis, E. Novel treatments for osteoporosis. J. Clin. Invest. 106, 177–179 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).A ground-breaking report of the involvement of LRP5 in bone formation.

    CAS  PubMed  Google Scholar 

  31. Little, C. D. et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am. J. Hum. Genet. 70, 11–19 (2002).

    CAS  PubMed  Google Scholar 

  32. Boyden, L. M. et al. High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521 (2002).

    CAS  PubMed  Google Scholar 

  33. Kato, M. et al. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J. Cell Biol. 157, 303–314 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mao, B. et al. Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signaling. Nature 417, 664–667 (2002).

    CAS  PubMed  Google Scholar 

  35. Hunter, I., McGregor, D. & Robins, S. P. Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis. J. Bone Miner. Res. 16, 466–477 (2001).

    CAS  PubMed  Google Scholar 

  36. Marie, P. J. Role of N-cadherin in bone formation. J. Cell. Physiol. 190, 297–305 (2002).

    CAS  PubMed  Google Scholar 

  37. Lecanda, F. et al. Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J. Cell Biol. 151, 931–944 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tanaka, Y. et al. H-Ras/mitogen-activated protein kinase pathway inhibits integrin-mediated adhesion and induces apoptosis in osteoblasts. J. Biol. Chem. 277, 21446–21452 (2002).

    CAS  PubMed  Google Scholar 

  39. Bianco, P., Riminucci, M., Gronthos, S. & Robey, P. G. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19, 180–192 (2001).

    CAS  PubMed  Google Scholar 

  40. Nuttall, M. E. & Gimble, J. M. Is there a therapeutic opportunity to either prevent or treat osteopenic disorders by inhibiting marrow adipogenesis? Bone 27, 177–184 (2000).

    CAS  PubMed  Google Scholar 

  41. Capdevila, J. & Belmonte, J. C. Patterning mechanisms controlling vertebrate limb development. Annu. Rev. Cell Dev. Biol. 17, 87–132 (2001).

    CAS  PubMed  Google Scholar 

  42. Garrett, I. R. & Mundy, G. R. The role of statins as potential targets for bone formation. Arthritis Res. 4, 237–240 (2002).

    PubMed  PubMed Central  Google Scholar 

  43. Teitelbaum, S. L. Bone resorption by osteoclasts. Science 289, 1504–1508 (2000).An excellent review of the molecular regulation of osteoclast function.

    CAS  PubMed  Google Scholar 

  44. Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-Src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).

    CAS  PubMed  Google Scholar 

  45. Sanjay, A., et al. Cbl associates with Pyk2 and Src to regulate Src kinase activity, αvβ3 integrin-mediated signaling, cell adhesion, and osteoclast motility. J. Cell Biol. 152, 181–196 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hu, P. Y. et al. A splice junction mutation in intron 2 of the carbonic anhydrase II gene of osteopetrosis patients from Arabic countries. Hum. Mutat. 1, 288–292 (1992).

    CAS  PubMed  Google Scholar 

  47. Teti, A. et al. Cytoplasmic pH regulation and chloride/bicarbonate exchange in avian osteoclasts. J. Clin. Invest. 83, 227–233 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Blair, H. C., Teitelbaum, S. L., Ghiselli, R. & Gluck, S. Ostoeclastic bone resorption by a polarized vacuolar proton pump. Science 245, 855–857 (1989).

    CAS  PubMed  Google Scholar 

  49. Stroup, G. B. et al. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J. Bone Miner. Res. 16, 1747–1749 (2001).

    Google Scholar 

  50. Tondravi, M. M. et al. Osteopetrosis in mice lacking hematopoietic transcription factor PU.1. Nature 386, 81–84 (1997).

    CAS  PubMed  Google Scholar 

  51. Grigoriadis, A. E. et al. c-Fos: a key regulator of osteoclast–macrophage lineage determination and bone remodeling. Science 266, 443–448 (1994).

    CAS  PubMed  Google Scholar 

  52. Iotsova, V. et al. Osteopetrosis in mice lacking NF-κB1 and NF-κB2. Nature Med. 3, 1285–1289 (1997).

    CAS  PubMed  Google Scholar 

  53. Hodgkinson, C. A. et al. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic helix–loop–helix zipper protein. Cell 74, 395–404 (1993).

    CAS  PubMed  Google Scholar 

  54. Theill, L. E., Boyle, W. J. & Penninger, J. M. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu. Rev. Immunol. 20, 795–823 (2002).

    CAS  PubMed  Google Scholar 

  55. Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).An initial description of the role of OPG in the regulation of bone density.

    CAS  PubMed  Google Scholar 

  56. Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408, 600–605 (2000).

    CAS  PubMed  Google Scholar 

  57. Delmas, P. D. Treatment of postmenopausal osteoporosis. Lancet 359, 2018–2026 (2002).An excellent review of the current therapy for postmenopausal osteoporosis.

    CAS  PubMed  Google Scholar 

  58. Russell, R. G. et al. The pharmacology of bisphosphonates and new insights into their mechanisms of action. J. Bone Miner. Res. 14 (Suppl. 2), 53–65 (1999).

    CAS  PubMed  Google Scholar 

  59. Lehenkari, P. P. et al. Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol. Pharmacol. 61, 1255–1262 (2002).

    CAS  PubMed  Google Scholar 

  60. Lindsay, R, Hart, D. M. & Fogelman, I. Bone mass after withdrawal of oestrogen replacement. Lancet 1, 729 (1981).

  61. Manolagas, S. C., Kousteni, S. & Jilka, R. L. Sex steroids and bone. Recent Prog. Horm. Res. 57, 385–409 (2002).

    CAS  PubMed  Google Scholar 

  62. Riggs, B. L., Khosla, S. & Melton, L. J. Sex steroids and the construction and conservation of the adult skeleton. Endocr. Rev. 23, 279–302 (2002).References 61 and 62 are both comprehensive reviews of the effect of sex steroids on bone.

    CAS  PubMed  Google Scholar 

  63. Lufkin, E. G., Wong, M. & Deal, C. The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis. Rheum. Dis. Clin. North Am. 27, 163–185 (2001).

    CAS  PubMed  Google Scholar 

  64. Martin, T. J. Calcitonin, an update. Bone 24 (Suppl. 5), 63S–65S (1999).

    CAS  PubMed  Google Scholar 

  65. Nguyen, T. V. & Eisman, J. A. Genetics of fracture: challenges and opportunities. J. Bone Miner. Res. 15, 1243–1252 (2000).

    Google Scholar 

  66. Karsenty, G. & Wagner, E. F. Reaching a genetic and molecular understanding of skeletal development. Dev. Cell. 2, 389–406 (2002).

    CAS  PubMed  Google Scholar 

  67. Kim, H. J., Rice, D. P., Kettunen, P. J. & Thesleff, I. FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 125, 1241–1251 (1998).

    CAS  PubMed  Google Scholar 

  68. Suda, N. et al. Parathyroid hormone-related protein is required for normal intramembranous bone development. J. Bone Miner. Res. 16, 2182–2191 (2001).

    CAS  PubMed  Google Scholar 

  69. Zhang, X. et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J. Clin. Invest. 109, 1405–1415 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bi, W. et al. Sox9 is required for cartilage formation. Nature Genet. 22, 85–89 (1999).

    CAS  PubMed  Google Scholar 

  71. Smits, P. et al. The transcription factors l-Sox5 and Sox6 are essential for cartilage formation. Dev. Cell 1, 277–290 (2001).

    CAS  PubMed  Google Scholar 

  72. Panda, D. K. et al. The transcription factor SOX9 regulates cell cycle and differentiation genes in chondrocytic CFK2 cells. J. Biol. Chem. 276, 41229–41236 (2001).

    CAS  PubMed  Google Scholar 

  73. Amizuka, N., Warshawsky, H., Henderson, J. E., Goltzman, D. & Karaplis, A. C. Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J. Cell Biol. 126, 1611–1623 (1994).A demonstration of the crucial role of PTHrP in endochondral bone formation.

    CAS  PubMed  Google Scholar 

  74. Chung, U. I., Schipani, E., McMahon, A. P. & Kronenberg, H. M. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J. Clin. Invest. 107, 295–304 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ornitz, D. M. & Marie, P. J. FGF signaling pathways in endochondral and intramembraneous bone development and human genetic disease. Genes Dev. 16, 1446–1465 (2002).

    CAS  PubMed  Google Scholar 

  76. Zelzer, E. et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development 129, 1893–1904 (2002).

    CAS  PubMed  Google Scholar 

  77. St-Jacques, B., Hammerschmidt, M. & McMahon, A. P. Indian hedgehog signalling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072–2086 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Takeda, S. & Karsenty, G. Central control of bone formation. J. Bone Miner. Metab. 19, 195–198 (2001).

    CAS  PubMed  Google Scholar 

  79. Panda, D. K. et al. Targeted ablation of the 25-hydroxyvitamin D1 α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc. Natl Acad. Sci. USA 98, 7498–7503 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Amling, M. et al. Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology 140, 4982–4987 (1999).

    CAS  PubMed  Google Scholar 

  81. Mosekilde, L. Mechanisms of age-related bone loss. Novartis Found. Symp. 235, 150–166 (2001).

    CAS  PubMed  Google Scholar 

  82. Norman, T. L. & Wang, Z. Microdamage of human cortical bone: incidence and morphology in long bones. Bone 20, 375–379 (1997).

    CAS  PubMed  Google Scholar 

  83. Gazit, D., Zilberman, Y., Ebner, R. & Kahn, A. Bone loss (osteopenia) in old male mice results from diminished activity and availability of TGF-β. J. Cell. Biochem. 70, 478–488 (1998).

    CAS  PubMed  Google Scholar 

  84. Aerssens, J., Boonen, S., Joly, J. & Dequeker, J. Variations in trabecular bone composition with anatomical site and age: potential implications for bone quality assessment. J. Endocrinol. 155, 411–421 (1997).

    CAS  PubMed  Google Scholar 

  85. Seeman, E. Pathogenesis of bone fragility in women and men. Lancet 359, 1841–1850 (2002).

    PubMed  Google Scholar 

  86. Delmas, P. D. et al. The use of placebo-controlled and non-inferiority trials for the evaluation of new drugs in the treatment of postmenopausal osteoporosis. Osteoporosis Int. 13, 1–5 (2002).A description of the ethical dilemma in the use of placebo controls for treatment of osteoporosis.

    CAS  Google Scholar 

  87. The Writing Group for the PEPI. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 276, 1389–1396 (1996).

  88. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002).A landmark report on the effects of combinations of oestrogen and progesterone on bone and on other organs in postmenopausal women.

  89. Ettinger, B. et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 282, 637–645 (1999).

    CAS  PubMed  Google Scholar 

  90. Barrett-Connor, E. et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 287, 847–857 (2002).

    CAS  PubMed  Google Scholar 

  91. Watts, N. B. Treatment of osteoporosis with bisphosphonates. Rheum. Dis. Clin. North. Am. 27, 197–214 (2001).

    CAS  PubMed  Google Scholar 

  92. Hosking, D. et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N. Engl. J. Med. 338, 485–492 (1998).

    CAS  PubMed  Google Scholar 

  93. Mortensen, L. et al. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. J. Clin. Endocrinol. Metab. 83, 396–402 (1998).

    CAS  PubMed  Google Scholar 

  94. Schnitzer, T. et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Aging (Milano) 12, 1–12 (2000).

    CAS  Google Scholar 

  95. Cummings, S. R. et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280, 2077–2082 (1998).

    CAS  PubMed  Google Scholar 

  96. Harris, S. T. et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 282, 1344–1352 (1999).

    CAS  PubMed  Google Scholar 

  97. Black, D. M. et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348, 1535–1541 (1996).

    CAS  PubMed  Google Scholar 

  98. McClung, M. R. et al. Effect of risedronate on the risk of hip fracture in elderly women. N. Engl. J. Med. 344, 333–340 (2001).

    CAS  PubMed  Google Scholar 

  99. Ringe, J. D., Orwall, E., Daifotis, A. & Lombardi, A. Treatment of male osteoporosis: recent advances with alendronate. Osteoporosis Int. 13, 195–199 (2002).

    CAS  Google Scholar 

  100. Saag, K. G. et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N. Engl. J. Med. 339, 292–299 (1998).

    CAS  PubMed  Google Scholar 

  101. Reid, I. R. et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N. Engl. J. Med. 346, 653–661 (2002).

    CAS  PubMed  Google Scholar 

  102. Siris, E. S. Goals of treatment for Paget's disease of bone. J. Bone Miner. Res. 14 (Suppl. 2), 49–52 (1999).

    PubMed  Google Scholar 

  103. Coleman, R. E. Optimising treatment of bone metastases by Aredia and Zometa. Breast Cancer 7, 361–369 (2000).

    CAS  PubMed  Google Scholar 

  104. Glorieux, F. H. et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N. Engl. J. Med. 339, 947–952 (1998).

    CAS  PubMed  Google Scholar 

  105. Lehmann, H. J., Mouritzen, U., Christgau, S., Cloos, P. A. & Christiansen, C. Effect of bisphosphonates on cartilage turnover assessed with a newly developed assay for collagen type II degradation products. Ann. Rheum. Dis. 61, 530–533 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Chesnut, C. H. et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am. J. Med. 109, 267–276 (2000).

    CAS  PubMed  Google Scholar 

  107. Selye, H. On stimulation of new bone-formation with parathyroid extract and irradiated ergosterol. Endocrinology 16, 547–558 (1932).

    CAS  Google Scholar 

  108. Reeve, J. et al. The anabolic effect of low doses of human parathyroid hormone fragment on the skeleton in postmenopausal osteoporosis. Lancet 1, 1035–1038 (1976).

    CAS  PubMed  Google Scholar 

  109. Tam, C. S., Heersche, J. N., Murray, T. M. & Parsons, J. A. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology 110, 506–512 (1982).

    CAS  PubMed  Google Scholar 

  110. Dobnig, H. & Turner, R. T. The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology 138, 4607–4612 (1997).

    CAS  PubMed  Google Scholar 

  111. Neer, R. M. et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344, 1434–1441 (2001).The first report of the beneficial effect of PTH treatment on fractures in postmenopausal osteoporosis.

    CAS  PubMed  Google Scholar 

  112. Brown, A. J. Therapeutic uses of vitamin D analogues. Am. J. Kidney Dis. 38 (Suppl. 5), S3–S19 (2001).

    CAS  PubMed  Google Scholar 

  113. Dawson-Hughes, B., Harris, S. S., Krall, E. A. & Dallal, G. E. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N. Engl. J. Med. 337, 670–676 (1997).

    CAS  PubMed  Google Scholar 

  114. Chapuy, M. C. et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N. Engl. J. Med. 327, 1637–1642 (1992).

    CAS  PubMed  Google Scholar 

  115. Negro-Vilar, A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J. Clin. Endocrinol. Metab. 84, 3459–3462 (1999).

    CAS  PubMed  Google Scholar 

  116. Lieberman, J. R., Daluiski, A. & Einhorn, T. A. The role of growth factors in the repair of bone. Biology and clinical applications. J. Bone Joint Surg. Am. 84, A1032–A1044 (2002).

    Google Scholar 

  117. Nemeth, E. F. et al. Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J. Pharmacol. Exp. Ther. 299, 323–331 (2001).

    CAS  PubMed  Google Scholar 

  118. Meunier, P. J. et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis — a 2-year randomized placebo controlled trial. J. Clin. Endocrinol. Metab. 87, 2060–2066 (2002).

    CAS  PubMed  Google Scholar 

  119. Reginster, J. Y. Strontium ranelate in osteoporosis. Curr. Pharm. Des. 8, 19079–1916 (2002).

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, McGill University and McGill University Health Centre, 687 Pine Avenue, West Montreal, H3A 1A1, Quebec, Canada

    David Goltzman

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  1. David Goltzman
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Related links

DATABASES

Cancer.gov

breast cancer

uterine cancer

LocusLink

androgen receptor

ANG1

BMP2

cadherins

calcium receptor of the parathyroid glands

carbonic anhydrase II

catenins

cathepsin K

CBFA1

CBL

DKK

ER-α

ER-β

FGF2

FGF4

FGF18

FGF23

FGFR1

FGFR2

FGFR3

ΔFOSB

c-FOS

FRA1

frizzled

GLI

growth hormone

HMG-CoA reductase

IFN-β

IFN-γ

IGF1

IGF2

IHH

IL-6

IL-11

αv-integrin

β3-integrin

JNK

kremen

leptin

LIF

LRP5

m-CSF

microphthalmia

MMP9

MSX

NF-κB

oncostatin M

OPG

osterix

PHEX

PTC

PTH

PTHrP

PU.1

PYK2

RANK

RANKL

SMO

SOX5

SOX6

SOX9

c-Src

TGF-β

TNF

TRAF6

type I collagen

VEGF

vitronectin

Medscape DrugInfo

alendronate

calcitonin

pamidronate

premarin

raloxifene

risedronate

tamoxifen

zoledronic acid

OMIM

autosomal dominant hypophosphataemia

osteoarthritis

osteogenesis imperfecta

osteopetrosis

osteoporosis

Paget's disease

rheumatoid arthritis

X-linked hypophosphataemia

Glossary

METASTASIS

The movement or spreading of cancer cells from one tissue or organ.

BONE MINERAL DENSITY

A two-dimensional (areal) measure of the mineral content of bone in a particular skeletal region, which is performed by a technique called bone densitometry.

SUBCHONDRAL

Beneath the cartilage.

HYPERTROPHY

An increase in the size of a tissue or organ that results from an increase in the size of the cells present.

MESENCHYME

The meshwork of embryonic tissue in the mesoderm (one of the primary embryonic germ layers), from which are formed the connective tissues of the body, as well as bone, cartilage, muscle, blood and lymphatic vessels.

HAEMATOGENOUS

Produced by, or derived from, cells that give rise to blood cells.

ENDOCHONDRAL

Occurring with cartilage.

CHONDROCYTE

A cartilage cell.

VASOMOTOR

Affecting blood-vessel calibre and causing transient, episodic redness of the face and neck (hot flushes).

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Goltzman, D. Discoveries, drugs and skeletal disorders. Nat Rev Drug Discov 1, 784–796 (2002). https://doi.org/10.1038/nrd916

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