1932

Abstract

Current osteoporosis medications reduce fractures significantly but have rare and serious adverse effects (osteonecrosis of the jaw, atypical femoral fractures) that may limit their safety for long-term use. Insights from basic bone biology and genetic disorders have led to recent advances in therapeutics for osteoporosis. New approaches now in clinical use include the antisclerostin monoclonal antibody romosozumab, as well as the parathyroid hormone–related peptide analog abaloparatide. Clinical trial data show significant antifracture benefits with recently approved romosozumab. Studies using abaloparatide build on our longstanding experience with teriparatide and the importance of consolidating the bone mineral density gains achieved from an anabolic agent by following it with an antiresorptive. Combination and sequential treatments using osteoporosis medications with different mechanisms of action have also been tested with promising results. On the horizon is the potential for cell-based therapies (e.g., mesenchymal stem cells) and drugs that target the elimination of senescent cells in the bone microenvironment.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-052218-020620
2020-01-27
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/med/71/1/annurev-med-052218-020620.html?itemId=/content/journals/10.1146/annurev-med-052218-020620&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Eastell R, Lambert H. 2002. Strategies for skeletal health in the elderly. Proc. Nutr. Soc. 61:173–80
    [Google Scholar]
  2. 2. 
    Burge R, Dawson-Hughes B, Solomon DH et al. 2007. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J. Bone Miner. Res. 22:465–75
    [Google Scholar]
  3. 3. 
    Cheloha RW, Gellman SH, Vilardaga JP, Gardella TJ 2015. PTH receptor-1 signalling—mechanistic insights and therapeutic prospects. Nat. Rev. Endocrinol. 11:712–24
    [Google Scholar]
  4. 4. 
    Chapurlat RD, Genant HK. 2016. Osteoporosis: treatment. See Reference 50 1208–9
    [Google Scholar]
  5. 5. 
    Black DM, Delmas PD, Eastell R et al. 2007. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N. Engl. J. Med. 356:1809–22
    [Google Scholar]
  6. 6. 
    Cummings SR, San Martin J, McClung MR et al. 2009. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361:756–65
    [Google Scholar]
  7. 7. 
    Rossouw JE, Anderson GL, Prentice RL et al. 2002. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288:321–33
    [Google Scholar]
  8. 8. 
    Ettinger B, Black DM, Mitlak BH et al. 1999. 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 282:637–45
    [Google Scholar]
  9. 9. 
    Silverman SL, Christiansen C, Genant HK et al. 2008. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J. Bone Miner. Res. 23:1923–34
    [Google Scholar]
  10. 10. 
    Cummings SR, Eckert S, Krueger KA et al. 1999. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 281:2189–97
    [Google Scholar]
  11. 11. 
    Neer RM, Arnaud CD, Zanchetta JR et al. 2001. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med. 344:1434–41
    [Google Scholar]
  12. 12. 
    Kendler DL, Marin F, Zerbini CAF et al. 2018. Effects of teriparatide and risedronate on new fractures in postmenopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet 391:230–40
    [Google Scholar]
  13. 13. 
    Miller PD, Hattersley G, Riis BJ et al. 2016. Effect of abaloparatide versus placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA 316:722–33
    [Google Scholar]
  14. 14. 
    Bone HG, Cosman F, Miller PD et al. 2018. ACTIVExtend: 24 months of alendronate after 18 months of abaloparatide or placebo for postmenopausal osteoporosis. J. Clin. Endocrinol. Metab. 103:2949–57
    [Google Scholar]
  15. 15. 
    Maes C, Kronenberg HM. 2016. Bone development and remodeling. See Reference 50 1050–51
    [Google Scholar]
  16. 16. 
    Whyte MJ. 2016. Hereditary disorders of the skeleton: sclerosing bone disorders. See Reference 50 1037–80
    [Google Scholar]
  17. 17. 
    McColm J, Hu L, Womack T et al. 2014. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J. Bone Miner. Res. 29:935–43
    [Google Scholar]
  18. 18. 
    Recker R, Benson C, Matsumoto T et al. 2015. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J. Bone Miner. Res. 30:216–24
    [Google Scholar]
  19. 19. 
    Cosman F, Crittenden DB, Adachi JD et al. 2016. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375:1532–43
    [Google Scholar]
  20. 20. 
    Saag KG, Petersen J, Brandi ML et al. 2017. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N. Engl. J. Med. 377:1417–27
    [Google Scholar]
  21. 21. 
    Langdahl BL, Libanati C, Crittenden DB et al. 2017. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet 390:1585–94
    [Google Scholar]
  22. 22. 
    Evenity® (romosozumab) [package insert] Thousand Oaks, CA: Amgen 2019.
  23. 23. 
    Ke HZ, Richards WG, Li X, Ominsky MS 2012. Sclerostin and dickkopf-1 as therapeutic targets in bone diseases. Endocr. Rev. 33:747–83
    [Google Scholar]
  24. 24. 
    Glantschnig H, Scott K, Hampton R et al. 2011. A rate-limiting role for dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody. J. Pharmacol. Exp. Ther. 338:568–78
    [Google Scholar]
  25. 25. 
    Li X, Grisanti M, Fan W et al. 2011. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury. J. Bone Miner. Res. 26:2610–21
    [Google Scholar]
  26. 26. 
    Florio M, Gunasekaran K, Stolina M et al. 2016. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat. Commun. 27:11505
    [Google Scholar]
  27. 27. 
    Black DM, Greenspan SL, Ensrud KE et al. 2003. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N. Engl. J. Med. 349:1207–15
    [Google Scholar]
  28. 28. 
    Schafer AL, Sellmeyer DE, Palermo L et al. 2012. Six months of parathyroid hormone (1–84) administered concurrently versus sequentially with monthly ibandronate over two years: the PTH and Ibandronate Combination Study (PICS) randomized trial. J. Clin. Endocrinol. Metab. 97:3522–29
    [Google Scholar]
  29. 29. 
    Cosman F, Eriksen EF, Recknor C et al. 2011. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis. J. Bone Miner. Res. 26:503–11
    [Google Scholar]
  30. 30. 
    Deal C, Omizo M, Schwartz EN et al. 2005. Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial. J. Bone Miner. Res. 20:1905–11
    [Google Scholar]
  31. 31. 
    Cosman F, Nieves J, Woelfert L et al. 2001. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J. Bone Miner. Res. 16:925–31
    [Google Scholar]
  32. 32. 
    Tsai JN, Uihlein AV, Lee H et al. 2013. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 382:50–56
    [Google Scholar]
  33. 33. 
    Leder BZ, Tsai JN, Uihlein AV et al. 2014. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (the DATA Extension Study): a randomized controlled trial. J. Clin. Endocrinol. Metab. 99:1694–700
    [Google Scholar]
  34. 34. 
    Leder BZ, Tsai JN, Uihlein AV et al. 2015. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet 386:1147–55
    [Google Scholar]
  35. 35. 
    Hu L, Yin C, Zhao F et al. 2018. Mesenchymal stem cells: cell fate decision to osteoblast or adipocyte and application in osteoporosis treatment. Int. J. Mol. Sci. 19:360
    [Google Scholar]
  36. 36. 
    Aghebati-Maleki L, Dolati S, Zandi R et al. 2019. Prospect of mesenchymal stem cells in therapy of osteoporosis: a review. J. Cell. Physiol. 234:8570–78
    [Google Scholar]
  37. 37. 
    Sanghani-Kerai A, McCreary D, Lancashire H et al. 2018. Stem cell interventions for bone healing: fractures and osteoporosis. Curr. Stem Cell. Res. Ther. 13:369–77
    [Google Scholar]
  38. 38. 
    Ichioka N, Inaba M, Kushida T et al. 2002. Prevention of senile osteoporosis in SAMP6 mice by intrabone marrow injection of allogeneic bone marrow cells. Stem Cells 20:542–51
    [Google Scholar]
  39. 39. 
    Wang Z, Goh J, Das De S et al. 2006. Efficacy of bone marrow-derived stem cells in strengthening osteoporotic bone in a rabbit model. Tissue Eng 12:1753–61
    [Google Scholar]
  40. 40. 
    Ocarino Nde M, Boeloni JN, Jorgetti V et al. 2010. Intra-bone marrow injection of mesenchymal stem cells improves the femur bone mass of osteoporotic female rats. Conn. Tiss. Res. 51:426–33
    [Google Scholar]
  41. 41. 
    Sui B, Hu C, Zhang X et al. 2016. Allogeneic mesenchymal stem cell therapy promotes osteoblastogenesis and prevents glucocorticoid-induced osteoporosis. Stem Cells Transl. Med. 5:1238–46
    [Google Scholar]
  42. 42. 
    Kiernan J, Hu S, Grynpas MD et al. 2016. Systemic mesenchymal stromal cell transplantation prevents functional bone loss in a mouse model of age-related osteoporosis. Stem Cells Transl. Med. 5:683–93
    [Google Scholar]
  43. 43. 
    Cho SW, Sun HJ, Yang JY et al. 2012. Human adipose tissue-derived stromal cell therapy prevents bone loss in ovariectomized nude mouse. Tissue Eng. Part A 18:1067–78
    [Google Scholar]
  44. 44. 
    Ye X, Zhang P, Xue S et al. 2014. Adipose-derived stem cells alleviate osteoporosis by enhancing osteogenesis and inhibiting adipogenesis in a rabbit model. Cytotherapy 16:1643–55
    [Google Scholar]
  45. 45. 
    Mirsaidi A, Genelin K, Vetsch JR et al. 2014. Therapeutic potential of adipose-derived stromal cells in age-related osteoporosis. Biomaterials 35:7326–35
    [Google Scholar]
  46. 46. 
    Wu JY. 2015. Pluripotent stem cells and skeletal regeneration–promise and potential. Curr. Osteoporos. Rep. 13:342–50
    [Google Scholar]
  47. 47. 
    Li F, Zhou C, Xu L et al. 2016. Effect of stem cell therapy on bone mineral density: a meta-analysis of preclinical studies in animal models of osteoporosis. PLOS ONE 11:e0149400
    [Google Scholar]
  48. 48. 
    Pignolo RJ, Samsonraj RM, Law SF et al. 2019. Targeting cell senescence for the treatment of age-related bone loss. Curr. Osteoporos. Rep. 17:70–85
    [Google Scholar]
  49. 49. 
    Farr JN, Xu M, Weivoda MM et al. 2017. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23:1072–79
    [Google Scholar]
  50. 50. 
    Jameson JL, DeGroot LJ, eds. 2016. Endocrinology: Adult and Pediatric Philadelphia: Saunders Elsevier. , 7th ed..
/content/journals/10.1146/annurev-med-052218-020620
Loading
/content/journals/10.1146/annurev-med-052218-020620
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error