, Volume 41, Issue 1, pp 58–69 | Cite as

New understanding and treatments for osteoporosis

  • G. Mazziotti
  • J. Bilezikian
  • E. Canalis
  • D. Cocchi
  • A. Giustina
New Horizons in


To summarize promising areas of investigation in osteoporosis and to stimulate further research in this area, as discussed in a recent international conference. Over the recent years, there has been an improvement in the knowledge of molecular pathways involved in bone formation and resorption with the development of new drugs to treat osteoporosis. Intact parathyroid hormone, teriparatide, and anti-sclerostin monoclonal antibody are anabolic drugs, whereas denosumab and odanacatib are anti-resorptive drugs with more reversible effects as compared to bisphosphonates. Anabolic and anti-resorptive agents have different effects on bone, and research in this area includes the efficacy of combination and sequential therapies with them. New insights in the molecular pathways of bone remodeling have clarified the mechanisms responsible for skeletal fragility in several forms of secondary osteoporosis, such as that occurring in type 2 diabetes, following drug exposure and systemic inflammatory diseases. Future research is needed to address the efficacy of anti-osteoporotic drugs in these more recently recognized conditions of skeletal fragility. Osteoporosis continues to be an important field of biomedical research.


Osteoporosis Osteoblasts Osteoclasts PTH RANKL Cathepsin K Sclerostin Diabetes 



We acknowledge the contributions of those who lectured in the 4th Skeletal Endocrinology meeting held in Brescia on April 15th 2011: J. Compston (UK), L. Hofbauer (Germany), L. Idolazzi (Italy), S. Manolagas (USA), C. Marcocci (Italy), R. Nuti (Italy), R. Pacifici (USA), J. Potts (USA), L. Rejnmark (Denmark), L. Sinigaglia (Italy), A.H. Van Lierop (The Netherlands), P. Vestergaard (Denmark).


G.M. received lecture fee from Eli Lilly. J.B. is a consultant for Merck, Eli Lilly, Novartis, Amgen, Radius Pharmaceuticals, Johnson & Johnson; received research support from NPS Pharmaceuticals. E.C. is a consultant for Eli Lilly and received lecture fees from Eli Lilly and Amgen.D.C has nothing to declare. A.G. is a consultant for Eli Lilly and received lecture fees from Eli Lilly and Amgen.


  1. 1.
    E.A. Chrischilles, C.D. Butler, C.S. Davis, R.B. Wallace, A model of lifetime osteoporosis impact. Arch. Intern. Med. 51, 2026–2032 (1991)CrossRefGoogle Scholar
  2. 2.
    S. Khosla, S. Amin, E. Orwoll, Osteoporosis in men. Endocr. Rev. 29, 441–464 (2008)PubMedCrossRefGoogle Scholar
  3. 3.
    M. Almeida, L. Han, E. Ambrogini, S.M. Bartell, S.C. Manolagas, Oxidative stress stimulates apoptosis and activates NF-kappaB in osteoblastic cells via a PKCbeta/p66shc signaling cascade: counter regulation by estrogens or androgens. Mol. Endocrinol. 24, 2030–2037 (2010)PubMedCrossRefGoogle Scholar
  4. 4.
    E. Ambrogini, M. Almeida, M. Martin-Millan, J.H. Paik, R.A. Depinho, L. Han, J. Goellner, R.S. Weinstein, R.L. Jilka, C.A. O’Brien, S.C. Manolagas, FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. Cell Metab. 11, 136–146 (2010)PubMedCrossRefGoogle Scholar
  5. 5.
    S.C. Manolagas, De-fense! De-fense! De-fense: scavenging H2O2 while making cholesterol. Endocrinology 149, 3264–3266 (2008)PubMedCrossRefGoogle Scholar
  6. 6.
    M. Almeida, M. Martin-Millan, E. Ambrogini III, R. Bradsher, L. Han, X.D. Chen, P.K. Roberson, R.S. Weinstein, C.A. O’Brien, R.L. Jilka, S.C. Manolagas, Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the ERalpha. J. Bone Miner. Res. 25, 769–781 (2010)PubMedGoogle Scholar
  7. 7.
    S.C. Manolagas, From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr. Rev. 31, 266–300 (2010)PubMedCrossRefGoogle Scholar
  8. 8.
    S. Zanotti, E. Canalis, Notch and the skeleton. Mol. Cell. Biol. 30, 886–896 (2010)PubMedCrossRefGoogle Scholar
  9. 9.
    Y. Nam, P. Sliz, L. Song, J.C. Aster, S.C. Blacklow, Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124, 973–983 (2006)PubMedCrossRefGoogle Scholar
  10. 10.
    V. Deregowski, E. Gazzerro, L. Priest, S. Rydziel, E. Canalis, Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-Catenin but not bone morphogenetic protein signaling. J. Biol. Chem. 281, 6203–6210 (2006)PubMedCrossRefGoogle Scholar
  11. 11.
    S. Zanotti, A. Smerdel-Ramoya, L. Stadmeyer, D. Durant, F. Radtke, E. Canalis, Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology 149, 3890–3899 (2008)PubMedCrossRefGoogle Scholar
  12. 12.
    M.J. Hilton, X. Tu, X. Wu, S. Bai, H. Zhao, T. Kobayashi, H.M. Kronenberg, S.L. Teitelbaum, F.P. Ross, R. Kopan, F. Long, Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat. Med. 14, 306–314 (2008)PubMedCrossRefGoogle Scholar
  13. 13.
    N. Sethi, X. Dai, C.G. Winter, J. Kang, Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19, 192–205 (2011)PubMedCrossRefGoogle Scholar
  14. 14.
    J. Tao, A. Erez, B. Lee, One NOTCH further: Jagged 1 in bone metastasis. Cancer Cell 19, 159–161 (2011)PubMedCrossRefGoogle Scholar
  15. 15.
    S. Zanotti, A. Smerdel-Ramoya, E. Canalis, Reciprocal regulation of Notch and nuclear factor of activated T-cells (NFAT) c1 transactivation in osteoblasts. J. Biol. Chem. 286, 4576–4588 (2011)PubMedCrossRefGoogle Scholar
  16. 16.
    B. Isidor, P. Lindenbaum, O. Pichon, S. Bézieau, C. Dina, S. Jacquemont, D. Martin-Coignard, C. Thauvin-Robinet, M. Le Merrer, J.L. Mandel, A. David, L. Faivre, V. Cormier-Daire, R. Redon, C. Le Caignec, Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat. Genet. 43, 306–308 (2011)PubMedCrossRefGoogle Scholar
  17. 17.
    M.A. Simpson, M.D. Irving, E. Asilmaz, M.J. Gray, D. Dafou, F.V. Elmslie, S. Mansour, S.E. Holder, C.E. Brain, B.K. Burton, K.H. Kim, R.M. Pauli, S. Aftimos, H. Stewart, C.A. Kim, M. Holder-Espinasse, S.P. Robertson, W.M. Drake, R.C. Trembath, Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss. Nat. Genet. 43, 303–305 (2011)PubMedCrossRefGoogle Scholar
  18. 18.
    M.M. Dvorak, A. Siddiqua, D.T. Ward, D.H. Carter, S.L. Dallas, E.F. Nemeth, D. Riccardi, Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc. Natl Acad. Sci. USA 101, 5140–5145 (2004)PubMedCrossRefGoogle Scholar
  19. 19.
    N. Chattopadhyay, S. Yano, J. Tfelt-Hansen, P. Rooney, D. Kanuparthi, S. Bandyopadhyay, X. Ren, E. Terwilliger, E.M. Brown, Mitogenic action of calcium-sensing receptor on rat calvarial osteoblasts. Endocrinology 145, 3451–3462 (2004)PubMedCrossRefGoogle Scholar
  20. 20.
    T. Kameda, H. Mano, Y. Yamada, H. Takai, N. Amizuka, M. Kobori, N. Izumi, H. Kawashima, H. Ozawa, K. Ikeda, A. Kameda, Y. Hakeda, M. Kumegawa, Calcium-sensing receptor in mature osteoclasts, which are bone resorbing cells. Biochem. Biophys. Res. Commun. 245, 419–422 (1998)PubMedCrossRefGoogle Scholar
  21. 21.
    E.M. Brown, R.J. MacLeod, Extracellular calcium sensing and extracellular calcium signaling. Physiol. Rev. 81, 239–297 (2001)PubMedGoogle Scholar
  22. 22.
    K. Ballen, Targeting the stem cell niche: squeezing blood from bones. Bone Marrow Transplant. 39, 655–660 (2007)PubMedCrossRefGoogle Scholar
  23. 23.
    E. Canalis, Novel treatments for osteoporosis. J. Clin. Invest. 106, 177–179 (2000)PubMedCrossRefGoogle Scholar
  24. 24.
    P.J. Marie, The calcium-sensing receptor in bone cells: a potential therapeutic target in osteoporosis. Bone 46, 571–576 (2010)PubMedCrossRefGoogle Scholar
  25. 25.
    E. Canalis, A. Giustina, J.P. Bilezikian, Mechanisms of anabolic therapies for osteoporosis. N. Engl. J. Med. 357, 905–916 (2007)PubMedCrossRefGoogle Scholar
  26. 26.
    R. Pacifici, T cells: critical bone regulators in health and disease. Bone 47, 461–471 (2010)PubMedCrossRefGoogle Scholar
  27. 27.
    Y. Gao, X. Wu, M. Terauchi, F. Grassi, S. Galley, X. Yang, M.N. Weitzmann, R. Pacifici, T cells potentiate PTH-induced cortical bone loss through CD40L signaling. Cell Metab. 8, 132–145 (2008)PubMedCrossRefGoogle Scholar
  28. 28.
    H. Tawfeek, B. Bedi, J.Y. Li, J. Adams, T. Kobayashi, M.N. Weitzmann, H.M. Kronenberg, R. Pacifici, Disruption of PTH receptor 1 in T cells protects against PTH-induced bone loss. PLoS ONE 5, e12290 (2010)PubMedCrossRefGoogle Scholar
  29. 29.
    R.M. Neer, C.D. Arnaud, J.R. Zanchetta, R. Prince, G.A. Gaich, J.Y. Reginster, A.B. Hodsman, E.F. Eriksen, S. Ish-Shalom, H.K. Genant, O. Wang, B.H. Mitlak, 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)PubMedCrossRefGoogle Scholar
  30. 30.
    S.L. Greenspan, H.G. Bone, M.P. Ettinger, D.A. Hanley, R. Lindsay, J.R. Zanchetta, C.M. Blosch, A.L. Mathisen, S.A. Morris, T.B. Marriott, Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann. Intern. Med. 146, 326–339 (2007)PubMedGoogle Scholar
  31. 31.
    J.P. Bilezikian, Combination anabolic and antiresorptive therapy for osteoporosis: opening the anabolic window. Curr. Osteoporos. Rep. 6, 24–30 (2008)PubMedCrossRefGoogle Scholar
  32. 32.
    K.G. Saag, E. Shane, S. Boonen, F. Marín, D.W. Donley, K.A. Taylor, G.P. Dalsky, R. Marcus, Teriparatide or alendronate in glucocorticoid-induced osteoporosis. N. Engl. J. Med. 357, 2028–2039 (2007)PubMedCrossRefGoogle Scholar
  33. 33.
    K.G. Saag, J.R. Zanchetta, J.P. Devogelaer, R.A. Adler, R. Eastell, K. See, J.H. Krege, K. Krohn, M.R. Warner, Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum. 60, 3346–3355 (2009)PubMedCrossRefGoogle Scholar
  34. 34.
    F. Cosman, R.A. Wermers, C. Recknor, K.F. Mauck, L. Xie, E.V. Glass, J.H. Krege, Effects of teriparatide in postmenopausal women with osteoporosis on prior alendronte or raloxifene: differences between stopping and continuing the antiresorptive agent. J. Clin. Endocrinol. Metab. 94, 3772–3780 (2009)PubMedCrossRefGoogle Scholar
  35. 35.
    J.S. Finkelstein, J.J. Wyland, B.Z. Leder, S.M. Burnett-Bowie, H. Lee, H. Jüppner, R.M. Neer, Effects of teriparatide retreatment in osteoporotic men and women. J. Clin. Endocrinol. Metab. 94, 2495–2501 (2009)PubMedCrossRefGoogle Scholar
  36. 36.
    N.E. Cusano, J.P. Bilezikian, Teriparatide: variations on the theme of a 2-year therapeutic course. BoneKey 7, 84–87 (2010)CrossRefGoogle Scholar
  37. 37.
    N.E. Cusano, J.P. Bilezikian, Combination antiresorptive and osteoanabolic therapy for osteoporosis: we are not there yet. Curr. Med. Res. Opin. (2011) [Epub ahead of print, PMID 21740288]Google Scholar
  38. 38.
    J. Compston, The use of combination therapy in the treatment of postmenopausal osteoporosis. Endocrine (2011) [Epub ahead of print]Google Scholar
  39. 39.
    S. Boonen, K. Milison, E. Gielen, D. Vanderschueren, Sequential therapy in the treatment of osteoporosis. Curr. Med. Res. Opin. 27, 1149–1155 (2011)PubMedCrossRefGoogle Scholar
  40. 40.
    D.M. Black, S.L. Greenspan, K.E. Ensrud, L. Palermo, J.A. McGowan, T.F. Lang, P. Garnero, M.L. Bouxsein, J.P. Bilezikian, C.J. Rosen, The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N. Engl. J. Med. 349, 1207–1215 (2003)PubMedCrossRefGoogle Scholar
  41. 41.
    F. Cosman, E.F. Eriksen, C. Recknor, P.D. Miller, N. Guañabens, C. Kasperk, P. Papanastasiou, A. Readie, H. Rao, J.A. Gasser, C. Bucci-Rechtweg, S. Boonen, Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J. Bone Miner. Res. 26, 503–511 (2011)PubMedCrossRefGoogle Scholar
  42. 42.
    J.P. Bilezikian, A. Khan, J.T. Potts Jr., M.L. Brandi, B.L. Clarke, D. Shoback, H. Jüppner, P. D’Amour, J. Fox, L. Rejnmark, L. Mosekilde, M.R. Rubin, D. Dempster, R. Gafni, M.T. Collins, J. Sliney, J. Sanders, Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target organ involvement, treatment, and challenges for future research. J. Bone Miner. Res. (2011). doi:  10.1002/jbmr.483. [Epub ahead of print]
  43. 43.
    K.K. Winer, N. Sinaii, J. Reynolds, D. Peterson, K. Dowdy, G.B. Cutler Jr, Long term therapy of 12 children with chronic hypoparathyroidism: a randomized trail comparing synthetic human parathyroid hormone (1–34) vs calcitriol and calcium. J. Clin. Endocrinol. Metab. 95, 2680–2688 (2010)PubMedCrossRefGoogle Scholar
  44. 44.
    M.R. Rubin, J.P. Bilezikian, Hypoparathyroidism: clinical features, skeletal microstructure and parathyroid hormone replacement. Braz. Arch. Endocrinol. Metab. 54, 220–226 (2010)CrossRefGoogle Scholar
  45. 45.
    T. Sikjaer, L. Rejnmark, L. Rolighed, L. Heickendorff, L. Mosekilde, The effect of adding PTH(1–84) to conventional treatment of hypoparathyroidism–A randomized, placebo-controlled study. J. Bone Miner. Res. 26, 2358–2370 (2011)PubMedCrossRefGoogle Scholar
  46. 46.
    W.J. Boyle, W.S. Simonet, D.L. Lacey, Osteoclast differentiation and activation. Nature 423, 337–342 (2003)PubMedCrossRefGoogle Scholar
  47. 47.
    W.S. Simonet, D.L. Lacey, C.R. Dunstan, M. Kelley, M.S. Chang, R. Lüthy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, G. Shimamoto, M. DeRose, R. Elliott, A. Colombero, H.L. Tan, G. Trail, J. Sullivan, E. Davy, N. Bucay, L. Renshaw-Gegg, T.M. Hughes, D. Hill, W. Pattison, P. Campbell, S. Sander, G. Van, J. Tarpley, P. Derby, R. Lee, W.J. Boyle, Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997)PubMedCrossRefGoogle Scholar
  48. 48.
    N. Bucay, I. Sarosi, C.R. Dunstan, S. Morony, J. Tarpley, C. Capparelli, S. Scully, H.L. Tan, W. Xu, D.L. Lacey, W.J. Boyle, W.S. Simonet, Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12, 1260–1268 (1998)PubMedCrossRefGoogle Scholar
  49. 49.
    L.C. Hofbauer, C.A. Kühne, V. Viereck, The OPG/RANKL/RANK system in metabolic bone diseases. J. Musculoskelet. Neuronal Interact. 4, 268–275 (2004)PubMedGoogle Scholar
  50. 50.
    P.J. Kostenuik, C. Capparelli, S. Morony, S. Adamu, G. Shimamoto, V. Shen, D.L. Lacey, C.R. Dunstan, OPG and PTH-(1–34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology 142, 4295–4304 (2001)PubMedCrossRefGoogle Scholar
  51. 51.
    P.J. Bekker, D. Holloway, A. Nakanishi, M. Arrighi, P.T. Leese, C.R. Dunstan, The effect of a single dose of osteoprotegerin in postmenopausal women. J. Bone Miner. Res. 16, 348–360 (2001)PubMedCrossRefGoogle Scholar
  52. 52.
    P.J. Bekker, D.L. Holloway, A.S. Rasmussen, R. Murphy, S.W. Martin, P.T. Leese, G.B. Holmes, C.R. Dunstan, A.M. DePaoli, A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J. Bone Miner. Res. 19, 1059–1066 (2004)PubMedCrossRefGoogle Scholar
  53. 53.
    H.G. Bone, M.A. Bolognese, C.K. Yuen, D.L. Kendler, P.D. Miller, Y.C. Yang, L. Grazette, J. San Martin, J.C. Gallagher, Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J. Clin. Endocrinol. Metab. 96, 972–980 (2011)PubMedCrossRefGoogle Scholar
  54. 54.
    T.D. Rachner, S. Khosla, L.C. Hofbauer, Osteoporosis: now and the future. Lancet 377, 1276–1287 (2011)PubMedCrossRefGoogle Scholar
  55. 55.
    S.R. Cummings, J. San Martin, M.R. McClung, E.S. Siris, R. Eastell, I.R. Reid, P. Delmas, H.B. Zoog, M. Austin, A. Wang, S. Kutilek, S. Adami, J. Zanchetta, C. Libanati, S. Siddhanti, C. Christiansen, Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756–765 (2009)PubMedCrossRefGoogle Scholar
  56. 56.
    S. Boonen, J.D. Adachi, Z. Man, S.R. Cummings, K. Lippuner, O. Törring, J.C. Gallagher, J. Farrerons, A. Wang, N. Franchimont, J. San Martin, A. Grauer, M. McClung, Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J. Clin. Endocrinol. Metab. 96, 1727–1736 (2011)PubMedCrossRefGoogle Scholar
  57. 57.
    C. von Keyserlingk, R. Hopkins, A. Anastasilakis, K. Toulis, R. Goeree, J.E. Tarride, F. Xie, Clinical efficacy and safety of Denosumab in postmenopausal women with low bone mineral density and osteoporosis: a meta-analysis. Semin. Arthritis Rheum. 41, 178–186 (2011)CrossRefGoogle Scholar
  58. 58.
    G. Mazziotti, E. Canalis, A. Giustina, Drug-induced osteoporosis: mechanisms and clinical implications. Am. J. Med. 123, 877–884 (2010)PubMedCrossRefGoogle Scholar
  59. 59.
    M.R. Smith, B. Egerdie, N. Hernández Toriz, R. Feldman, T.L. Tammela, F. Saad, J. Heracek, M. Szwedowski, C. Ke, A. Kupic, B.Z. Leder, C. Goessl, Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N. Engl. J. Med. 361, 745–755 (2009)PubMedCrossRefGoogle Scholar
  60. 60.
    G.K. Ellis, H.G. Bone, R. Chlebowski, D. Paul, S. Spadafora, J. Smith, M. Fan, S. Jun, Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J. Clin. Oncol. 26, 4875–4882 (2008)PubMedCrossRefGoogle Scholar
  61. 61.
    O. Sezer, U. Heider, I. Zavrski, C.A. Kühne, L.C. Hofbauer, RANK ligand and osteoprotegerin in myeloma bone disease. Blood 101, 2094–2098 (2003)PubMedCrossRefGoogle Scholar
  62. 62.
    U. Heider, C. Langelotz, C. Jakob, I. Zavrski, C. Fleissner, J. Eucker, K. Possinger, L.C. Hofbauer, O. Sezer, Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma. Clin. Cancer Res. 9, 1436–1440 (2003)PubMedGoogle Scholar
  63. 63.
    S. Roux, V. Meignin, J. Quillard, G. Meduri, A. Guiochon-Mantel, J.P. Fermand, E. Milgrom, X. Mariette, RANK (receptor activator of nuclear factor-kappaB) and RANKL expression in multiple myeloma. Br. J. Haematol. 117, 86–92 (2002)PubMedCrossRefGoogle Scholar
  64. 64.
    N. Giuliani, S. Colla, R. Sala, M. Moroni, M. Lazzaretti, S. La Monica, S. Bonomini, M. Hojden, G. Sammarelli, S. Barillè, R. Bataille, V. Rizzoli, Human myeloma cells stimulate the receptor activator of NF-kappaB ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood 100, 4615–4621 (2002)PubMedCrossRefGoogle Scholar
  65. 65.
    G.D. Roodman, Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004)PubMedCrossRefGoogle Scholar
  66. 66.
    A.T. Stopeck, A. Lipton, J.J. Body, G.G. Steger, K. Tonkin, R.H. de Boer, M. Lichinitser, Y. Fujiwara, D.A. Yardley, M. Viniegra, M. Fan, Q. Jiang, R. Dansey, S. Jun, A. Braun, Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. 28, 5132–5139 (2010)PubMedCrossRefGoogle Scholar
  67. 67.
    K. Fizazi, M. Carducci, M. Smith, R. Damião, J. Brown, L. Karsh, P. Milecki, N. Shore, M. Rader, H. Wang, Q. Jiang, S. Tadros, R. Dansey, C. Goessl, Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011)PubMedCrossRefGoogle Scholar
  68. 68.
    D.H. Henry, L. Costa, F. Goldwasser, V. Hirsh, V. Hungria, J. Prausova, G.V. Scagliotti, H. Sleeboom, A. Spencer, S. Vadhan-Raj, R. von Moos, W. Willenbacher, P.J. Woll, J. Wang, Q. Jiang, S. Jun, R. Dansey, H. Yeh, Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J. Clin. Oncol. 29, 1125–1132 (2011)PubMedCrossRefGoogle Scholar
  69. 69.
    A.K. Gough, J. Lilley, S. Eyre, R.L. Holder, P. Emery, Generalized bone loss in patients with rheumatoid arthritis. Lancet 344, 23–27 (1994)PubMedCrossRefGoogle Scholar
  70. 70.
    K. Nemeth, M. Schoppet, N. Al-Fakhri, S. Helas, R. Jessberger, L.C. Hofbauer, C. Goettsch, The role of osteoclast-associated receptor in osteoimmunology. J. Immunol. 186, 13–18 (2011)PubMedCrossRefGoogle Scholar
  71. 71.
    E. Romas, N.A. Sims, D.K. Hards, M. Lindsay, J.W. Quinn, P.F. Ryan, C.R. Dunstan, T.J. Martin, M.T. Gillespie, Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am. J. Pathol. 161, 1419–1427 (2002)PubMedCrossRefGoogle Scholar
  72. 72.
    S.B. Cohen, R.K. Dore, N.E. Lane, P.A. Ory, C.G. Peterfy, J.T. Sharp, D. van der Heijde, L. Zhou, W. Tsuji, R. Newmark, Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 58, 1299–1309 (2008)PubMedCrossRefGoogle Scholar
  73. 73.
    M.P. Whyte, The long and the short of bone therapy. N. Engl. J. Med. 354, 860–863 (2006)PubMedCrossRefGoogle Scholar
  74. 74.
    D.H. Jones, T. Nakashima, O.H. Sanchez, I. Kozieradzki, S.V. Komarova, I. Sarosi, S. Morony, E. Rubin, R. Sarao, C.V. Hojilla, V. Komnenovic, Y.Y. Kong, M. Schreiber, S.J. Dixon, S.M. Sims, R. Khokha, T. Wada, J.M. Penninger, Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440, 692–696 (2006)PubMedCrossRefGoogle Scholar
  75. 75.
    N. Frazl-Zelman, A. Valenta, P. Roschger, A. Nader, B.D. Gelb, P. Fratzl, K. Klaushofer, Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J. Clin. Endocrinol. Metab. 89, 1538–1547 (2004)CrossRefGoogle Scholar
  76. 76.
    J.Y. Gauthier, N. Chauret, W. Cromlish, S. Desmarais, T. Duong le, J.P. Falgueyret, D.B. Kimmel, S. Lamontagne, S. Léger, T. LeRiche, C.S. Li, F. Massé, D.J. McKay, D.A. Nicoll-Griffith, R.M. Oballa, J.T. Palmer, M.D. Percival, D. Riendeau, J. Robichaud, G.A. Rodan, S.B. Rodan, C. Seto, M. Thérien, V.L. Truong, M.C. Venuti, G. Wesolowski, R.N. Young, R. Zamboni, W.C. Black, The discovery of odanacatib (MK0822), a selective inhibitor of cathepsin-K. Bioorg. Med. Chem. Lett. 18, 923–928 (2008)PubMedCrossRefGoogle Scholar
  77. 77.
    S. Nagase, M. Ohyama, Y. Hashimoto, M. Small, T. Kuwayama, S. Deacon, Pharmacodynamic effects on biochemical markers of bone turnover and pharmacokinetics of the cathepsin K inhibitor, ONO-5334, in an ascending multiple-dose, phase 1 study. J. Clin. Pharmacol. (2011) [Epub ahead of print]Google Scholar
  78. 78.
    H.G. Bone, M.R. McClung, C. Roux, R.R. Recker, J.A. Eisman, N. Verbruggen, C.M. Hustad, C. DaSilva, A.C. Santora, B.A. Ince, Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J. Bone Miner. Res. 25, 937–947 (2010)PubMedGoogle Scholar
  79. 79.
    S.E. Papapoulos, Targeting sclerostin as potential treatment of osteoporosis. Ann. Rheum. Dis. 70(Suppl 1), 19–22 (2011)CrossRefGoogle Scholar
  80. 80.
    X. Li, M.S. Ominsky, K.S. Warmington, S. Morony, J. Gong, J. Cao, Y. Gao, V. Shalhoub, B. Tipton, R. Haldankar, Q. Chen, A. Winters, T. Boone, Z. Geng, Q.T. Niu, H.Z. Ke, P.J. Kostenuik, W.S. Simonet, D.L. Lacey, C. Paszty, Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578–588 (2009)PubMedCrossRefGoogle Scholar
  81. 81.
    M.S. Ominsky, F. Vlasseros, J. Jolette, S.Y. Smith, B. Stouch, G. Doellgast, J. Gong, Y. Gao, J. Cao, K. Graham, B. Tipton, J. Cai, R. Deshpande, L. Zhou, M.D. Hale, D.J. Lightwood, A.J. Henry, A.G. Popplewell, A.R. Moore, M.K. Robinson, D.L. Lacey, W.S. Simonet, C. Paszty, Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density and bone strength. J. Bone Miner. Res. 25, 948–959 (2010)PubMedCrossRefGoogle Scholar
  82. 82.
    D. Padhi, G. Jang, B. Stouch, L. Fang, E. Posvar, Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J. Bone Miner. Res. 26, 19–26 (2011)PubMedCrossRefGoogle Scholar
  83. 83.
    R.H. Giles, J.K. van Es, H. Clevers, Caught up in a Wnt storm: Wnt signalling in cancer. Biochem. Biophys. Acta 1653, 1–24 (2003)PubMedGoogle Scholar
  84. 84.
    M. Kansara, M. Tsang, L. Kodjabachian, N.A. Sims, M.K. Trivett, M. Ehrich, A. Dobrovic, J. Slavin, P.F. Choong, P.J. Simmons, I.B. Dawid, D.M. Thomas, Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. J. Clin. Invest. 119, 837–851 (2009)PubMedCrossRefGoogle Scholar
  85. 85.
    A.A. Khan, G.K.B. Sandor, E. Dore, A.D. Morrison, M. Alsahli, F. Amin, E. Peters, D.A. Hanley, S.R. Chaudry, B. Lentle, D.W. Dempster, F.H. Glorieux, A.J. Neville, R.M. Talwar, C.M. Clokie, M.A. Mardini, T. Paul, S. Khosla, R.G. Josse, S. Sutherland, D.K. Lam, R.P. Carmichael, N. Blanas, D. Kendler, S. Petak, L.G. Ste-Marie, J. Brown, A.W. Evans, L. Rios, J.E. Compston, Bisphosphonate associated osteonecrosis of the jaw. J. Reumathol. 36, 478–490 (2009)Google Scholar
  86. 86.
    J.C. Lo, F.S. O’Ryan, N.P. Gordon, J. Yang, R.L. Hui, D. Martin, M. Hutchinson, P.V. Lathon, G. Sanchez, P. Silver, M. Chandra, C.A. McCloskey, J.A. Staffa, M. Willy, J.V. Selby, A.S. Go, Predicting risk of osteonecrosis of the jaw with oral bisphosphonate exposure (PROBE) investigators. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J. Oral Maxillofac. Surg. 68, 243–253 (2010)PubMedCrossRefGoogle Scholar
  87. 87.
    S.L. Ruggiero, T.B. Dodson, L.A. Assael, R. Landesberg, R.E. Marx, B. Mehrotra, American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonates-related osteonecrosis of the jaws: 2009 update. J. Oral Maxillofac. Surg. 67(Suppl 5), 2–12 (2009)PubMedGoogle Scholar
  88. 88.
    J.E. Compston, Bisphosphonates and atypical femoral fractures: a time for reflection. Maturitas 65, 3–4 (2010)PubMedCrossRefGoogle Scholar
  89. 89.
    E.M. Lewiecki, Safety of long-term bisphosphonate therapy for the management of osteoporosis. Drugs 71, 791–814 (2011)PubMedCrossRefGoogle Scholar
  90. 90.
    M. Pazianas, J. Compston, C.L. Huang, Atrial fibrillation and bisphosphonate therapy. J. Bone Miner. Res. 25, 2–10 (2010)PubMedCrossRefGoogle Scholar
  91. 91.
    E. Barrett-Connor, A.S. Swern, C.M. Hustad, H.G. Bone, U.A. Liberman, S. Papapoulos, H. Wang, A. de Papp, A.C. Santora, Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials. Osteoporos. Int. (2011) [Epub ahead of print]Google Scholar
  92. 92.
    W. Wang, X. Zhang, J. Zheng, J. Yang, High glucose stimulates adipogenic and inhibits osteogenic differentiation in MG-63 cells through cAMP/protein kinase A/extracellular signalregulated kinase pathway. Mol. Cell. Biochem. 338, 115–122 (2010)PubMedCrossRefGoogle Scholar
  93. 93.
    R.A. Kayal, D. Tsatsas, M.A. Bauer, B. Allen, M.O. Al-Sebaei, S. Kakar, C.W. Leone, E.F. Morgan, L.C. Gerstenfeld, T.A. Einhorn, D.T. Graves, Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity. J. Bone Miner. Res. 22, 560–568 (2007)PubMedCrossRefGoogle Scholar
  94. 94.
    Y. Hamada, S. Kitazawa, R. Kitazawa, K. Kono, S. Goto, H. Komaba, H. Fujii, Y. Yamamoto, H. Yamamoto, M. Usami, M. Fukagawa, The effects of the receptor for advanced glycation end products (RAGE) on bone metabolism under physiological and diabetic conditions. Endocrine 38, 369–376 (2010)PubMedCrossRefGoogle Scholar
  95. 95.
    M. Alikhani, Z. Alikhani, C. Boyd, C.M. MacLellan, M. Raptis, R. Liu, N. Pischon, P.C. Trackman, L. Gerstenfeld, D.T. Graves, Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone 40, 345 (2007)PubMedCrossRefGoogle Scholar
  96. 96.
    A. Giustina, G. Mazziotti, E. Canalis, Growth hormone, insulin-like growth factors, and the skeleton. Endocr. Rev. 29, 535–559 (2008)PubMedCrossRefGoogle Scholar
  97. 97.
    A. Räkel, O. Sheehy, E. Rahme, J. LeLorier, Osteoporosis among patients with type 1 and type 2 diabetes. Diabetes Metab. 34, 193–205 (2008)PubMedCrossRefGoogle Scholar
  98. 98.
    P. Vestergaard, L. Rejnmark, L. Mosekilde, Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia 48, 1292–1299 (2005)PubMedCrossRefGoogle Scholar
  99. 99.
    P. Vestergaard, Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes—a meta-analysis. Osteoporos. Int. 18, 427–444 (2007)PubMedCrossRefGoogle Scholar
  100. 100.
    S. Bonadonna, G. Mazziotti, M. Nuzzo, A. Bianchi, A. Fusco, L. De Marinis, A. Giustina, Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women. J. Bone Miner. Res. 20, 1837–1844 (2005)PubMedCrossRefGoogle Scholar
  101. 101.
    G. Mazziotti, A. Angeli, J.P. Bilezikian, E. Canalis, A. Giustina, Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol. Metab. 17, 144–149 (2006)PubMedCrossRefGoogle Scholar
  102. 102.
    G. Mazziotti, A. Bianchi, S. Bonadonna, M. Nuzzo, V. Cimino, A. Fusco, L. De Marinis, A. Giustina, Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. J. Bone Miner. Res. 21, 520–528 (2006)PubMedCrossRefGoogle Scholar
  103. 103.
    G. Mazziotti, A. Bianchi, S. Bonadonna, V. Cimino, I. Patelli, A. Fusco, A. Pontecorvi, L. De Marinis, A. Giustina, Prevalence of vertebral fractures in men with acromegaly. J. Clin. Endocrinol. Metab. 93, 4649–4655 (2008)PubMedCrossRefGoogle Scholar
  104. 104.
    G. Mazziotti, M. Gola, A. Bianchi, T. Porcelli, A. Giampietro, V. Cimino, M. Doga, C. Gazzaruso, L. De Marinis, A. Giustina, Influence of diabetes mellitus on vertebral fractures in men with acromegaly. Endocrine 40, 102–108 (2011)PubMedCrossRefGoogle Scholar
  105. 105.
    G. Mazziotti, T. Mancini, M. Mormando, E. De Menis, A. Bianchi, M. Doga, T. Porcelli, P.P. Vescovi, L. De Marinis, A. Giustina, High prevalence of radiological vertebral fractures in women with prolactin-secreting pituitary adenomas. Pituitary 14, 299–306 (2011)PubMedCrossRefGoogle Scholar
  106. 106.
    G. Mazziotti, T. Porcelli, M. Mormando, E. De Menis, A. Bianchi, C. Mejia, T. Mancini, L. De Marinis, A. Giustina, Vertebral fractures in males with prolactinoma. Endocrine 39, 288–293 (2011)PubMedCrossRefGoogle Scholar
  107. 107.
    M. Viégas, C. Costa, A. Lopes, L. Griz, M.A. Medeiro, F. Bandeira, Prevalence of osteoporosis and vertebral fractures in postmenopausal women with type 2 diabetes mellitus and their relationship with duration of the disease and chronic complications. J. Diabetes Complications 25, 216–221 (2011)PubMedCrossRefGoogle Scholar
  108. 108.
    P. Vestergaard, Risk of newly diagnosed type 2 diabetes is reduced in users of alendronate. Calcif. Tissue. Intern. (2011) [Epub ahead of print]Google Scholar
  109. 109.
    M.S. Molinuevo, L. Schurman, A.D. McCarthy, A.M. Cortizo, M.J. Tolosa, M.V. Gangoiti, V. Arnol, C. Sedlinsky, Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J. Bone Miner. Res. 25, 211–221 (2010)PubMedCrossRefGoogle Scholar
  110. 110.
    P. Ma, B. Gu, J. Ma, X. Wu, J. Cao, H. Liu, Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism 59, 359–366 (2010)PubMedCrossRefGoogle Scholar
  111. 111.
    V. Gopalakrishnan, R.C. Vignesh, J. Arunakaran, M.M. Aruldhas, N.E. Srinivasan, Effects of glucose and its modulation by insulin and estradiol on BMSC differentiation into osteoblastic lineages. Biochem. Cell Biol. 84, 93–101 (2006)PubMedCrossRefGoogle Scholar
  112. 112.
    B. Nuche-Berenguer, S. Portal-Núñez, P. Moreno, N. González, A. Acitores, A. López-Herradón, P. Esbrit, I. Valverde, M.L. Villanueva-Peñacarrillo, Presence of a functional receptor for GLP-1 in osteoblastic cells, independent of the cAMP-linked GLP-1 receptor. J. Cell. Physiol. 225, 585–592 (2010)PubMedCrossRefGoogle Scholar
  113. 113.
    A. Grey, Skeletal consequences of thiazolidinedione therapy. Osteoporos. Int. 19, 129–137 (2008)PubMedCrossRefGoogle Scholar
  114. 114.
    Y.K. Loke, S. Singh, C.D. Furberg, Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. Can. Med. Assoc. J. 180, 32–39 (2009)CrossRefGoogle Scholar
  115. 115.
    T. Mancini, G. Mazziotti, M. Doga, R. Carpinteri, N. Simetovic, P.P. Vescovi, A. Giustina, Vertebral fractures in males with type 2 diabetes treated with rosiglitazone. Bone 45, 784–788 (2009)PubMedCrossRefGoogle Scholar
  116. 116.
    I.J. Douglas, S.J. Evans, S. Pocock, L. Smeeth, The risk of fractures associated with thiazolidinediones: a self-controlled case-series study. PLoS Med. 6, e1000154 (2009)PubMedCrossRefGoogle Scholar
  117. 117.
    C.R. Dormuth, G. Carney, B. Carleton, K. Bassett, J.M. Wright, Thiazolidinediones and fractures in men and women. Arch. Intern. Med. 169, 1395–1402 (2009)PubMedCrossRefGoogle Scholar
  118. 118.
    I. Kanazawa, T. Yamaguchi, M. Yamamoto, M. Yamauchi, S. Yano, T. Sugimoto, Relationships between serum adiponectin levels versus bone mineral density, bone metabolic markers, and vertebral fractures in type 2 diabetes mellitus. Eur. J. Endocrinol. 160, 265–273 (2009)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • G. Mazziotti
    • 1
    • 2
  • J. Bilezikian
    • 3
  • E. Canalis
    • 4
    • 5
  • D. Cocchi
    • 6
  • A. Giustina
    • 1
  1. 1.Department of Medical and Surgical SciencesUniversity of BresciaBresciaItaly
  2. 2.Department of Medicine, Endocrine and Bone UnitAzienda Ospedaliera “Carlo Poma”MantuaItaly
  3. 3.Department of Medicine, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  4. 4.Department of ResearchSaint Francis Hospital and Medical CenterHartfordUSA
  5. 5.University of Connecticut School of Medicine FarmingtonUSA
  6. 6.Department of Biomedical Sciences and BiotechnologiesUniversity of BresciaBresciaItaly

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