Skip to main content
SpringerLink
Log in

Antiresorptives

  • Chapter
Book cover The Duration and Safety of Osteoporosis Treatment

Abstract

The use of drugs that inhibit bone resorption (“antiresorptives”) continues to dominate the therapy of bone diseases, many of which are characterized by enhanced bone destruction. These disorders include not just osteoporosis but also Paget’s disease of bone, myeloma, and bone metastases secondary to breast, prostate, and other cancers, as well as many less common acquired or inherited diseases such as osteogenesis imperfecta.

For osteoporosis, treatments have historically included hormones, such as estrogens as well as calcitonins. Several SERMs (selective estrogen receptor modulators) have been developed, among which raloxifene and bazedoxifene are quite widely used. Currently, the mainstay of treatment worldwide is still with bisphosphonates, which have been used clinically for more than 40 years and can reduce fracture occurrence at vertebral and non-vertebral sites, including hips.

The most recently introduced new drug is the anti-RANK-ligand antibody, denosumab, which is also effective against these fractures. Several cathepsin K inhibitors have also been studied, but, among these, only odanacatib is close to being likely to be registered for clinical use.

The pharmacological basis for the action of each of these drug classes is different, but reasonably well understood, and needs to be considered when determining the optimal ways they can be used in clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    *Important References

References

*Important References

  1. Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res. 2005;20(2):177–84.

    Article  PubMed  CAS  Google Scholar 

  2. Appelman-Dijkstra NM, Papapoulos SE. Prevention of incident fractures in patients with prevalent fragility fractures: current and future approaches. Best Pract Res Clin Rheumatol. 2013;27(6):805–20.

    Article  PubMed  Google Scholar 

  3. Lems WF, Geusens P. Established and forthcoming drugs for the treatment of osteoporosis. Curr Opin Rheumatol. 2014;26(3):245–51.

    Article  PubMed  CAS  Google Scholar 

  4. *Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013;9(9):522–36. *An excellent review of the multiple genetic mechanisms underlying human osteopetrotic syndromes.

    Article  PubMed  CAS  Google Scholar 

  5. Fleisch H, Russell RGG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science. 1969;165:1262–4.

    Article  PubMed  CAS  Google Scholar 

  6. *Russell RG. Bisphosphonates: the first 40 years. Bone. 2011;49(1):2–19. *A review of the history of bisphosphonates from bench to bedside.

    Article  PubMed  CAS  Google Scholar 

  7. Burr D, Russell RG. Special issue of bone to mark the 40th anniversary of bisphosphonates. Bone. 2011;49(1):1.

    Article  PubMed  Google Scholar 

  8. Plotkin LI, Bellido T. Beyond gap junctions: connexin43 and bone cell signaling. Bone. 2013;52(1):157–66.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Ebetino FH, Hogan AM, Sun S, Tsoumpra MK, Duan X, Triffitt JT, Kwaasi AA, Dunford JE, Barnett BL, Oppermann U, Lundy MW, Boyde A, Kashemirov BA, McKenna CE, Russell RG. The relationship between the chemistry and biological activity of the bisphosphonates. Bone. 2011;49:20–33.

    Article  PubMed  CAS  Google Scholar 

  10. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008;19:733–59.

    Article  PubMed  CAS  Google Scholar 

  11. Shapiro JR, Byers PH. Osteogenesis imperfecta. A translational approach to Brittle Bone Disease. In: Glorieux FH, Sponseller PD, editors. Elsevier Publishers USA; 2014. ISBN: 978-0-12-397165-4.

    Google Scholar 

  12. *McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, Hanley DA, Kendler DL, Yuen CK, Lewiecki EM. Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med. 2013;126(1):13–20. *A good discussion of bisphosphonate therapy.

    Article  PubMed  CAS  Google Scholar 

  13. Pazianas M, Cooper C, Ebetino FH, Russell RG. Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. Ther Clin Risk Manag. 2010;6:325–43.

    PubMed  CAS  PubMed Central  Google Scholar 

  14. Pazianas M, Abrahamsen B, Ferrari S, Russell RG. Eliminating the need for fasting with oral administration of bisphosphonates. Ther Clin Risk Manag. 2013;9:395–402.

    Article  PubMed  PubMed Central  Google Scholar 

  15. *Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48(4):677–92. *A review of the differential effects of denosumab compared with bisphosphonates.

    Article  PubMed  CAS  Google Scholar 

  16. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756–65.

    Google Scholar 

  17. Boonen S, Adachi JD, Man Z, Cummings SR, Lippuner K, Törring O, Gallagher JC, Farrerons J, Wang A, Franchimont N, San Martin J, Grauer A, McClung M. Treatment with denosumab reduces the incidence of new vertebral and hip fractures in postmenopausal women at high risk. J Clin Endocrinol Metab. 2011;96(6):1727–36.

    Article  PubMed  CAS  Google Scholar 

  18. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwiński E, Krieg MA, Man Z, Mellström D, Radominski SC, Reginster JY, Resch H, Román Ivorra JA, Roux C, Vittinghoff E, Austin M, Daizadeh N, Bradley MN, Grauer A, Cummings SR, Bone HG. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012;27(3):694–701.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Scott LJ. Denosumab: a review of its use in postmenopausal women with osteoporosis. Drugs Aging. 2014;31(7):555–76.

    Article  PubMed  CAS  Google Scholar 

  20. *Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Mellström D, Radominski SC, Reginster JY, Resch H, Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013;98(11):4483–92. *Important follow up study of denosumab from the FREEDOM trial.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J, 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. 2002;288(3):321–33.

    Article  PubMed  CAS  Google Scholar 

  22. Wells G, Tugwell P, Shea B, Guyatt G, Peterson J, Zytaruk N, Robinson V, Henry D, O’Connell D, Cranney A, Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev. 2002;23(4):529–39.

    Article  PubMed  CAS  Google Scholar 

  23. Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH, Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(7 Suppl 1):s1–66.

    Article  PubMed  CAS  Google Scholar 

  24. Sarrel PM, Njike VY, Vinante V, Katz DL. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years. Am J Public Health. 2013;103(9):1583–8.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nelson ER, Wardell SE, McDonnell DP. The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone. 2013;53(1):42–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Komm BS, Chines AA. An update on selective estrogen receptor modulators for the prevention and treatment of osteoporosis. Maturitas. 2012;71(3):221–6.

    Article  PubMed  CAS  Google Scholar 

  27. *Komm BS, Mirkin S. An overview of current and emerging SERMs. J Steroid Biochem Mol Biol. 2014;143:207–22. *An excellent review of SERMS and their actions.

    Article  PubMed  CAS  Google Scholar 

  28. Pinkerton JV, Thomas S. Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol. 2014;142:142–54.

    Article  PubMed  CAS  Google Scholar 

  29. Santen RJ, Kagan R, Altomare CJ, Komm B, Mirkin S, Taylor HS. Current and evolving approaches to individualizing estrogen receptor-based therapy for menopausal women. J Clin Endocrinol Metab. 2014;99(3):733–47.

    PubMed  CAS  Google Scholar 

  30. Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, Constantine GD, Chines AA. 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. 2008;23(12):1923–34.

    Article  PubMed  CAS  Google Scholar 

  31. Silverman SL, Chines AA, Kendler DL, Kung AW, Teglbjærg CS, Felsenberg D, Mairon N, Constantine GD, Adachi JD, Bazedoxifene Study Group. Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study. Osteoporos Int. 2012;23(1):351–63.

    Article  PubMed  CAS  Google Scholar 

  32. Kaufman JM, Palacios S, Silverman S, Sutradhar S, Chines A. An evaluation of the Fracture Risk Assessment Tool (FRAX®) as an indicator of treatment efficacy: the effects of bazedoxifene and raloxifene on vertebral, nonvertebral, and all clinical fractures as a function of baseline fracture risk assessed by FRAX®. Osteoporos Int. 2013;24(10):2561–9.

    Article  PubMed  CAS  Google Scholar 

  33. Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, Goldstein S, Sriram U, Lee A, Thompson J, Armstrong RA, Thompson DD, Powles T, Zanchetta J, Kendler D, Neven P, Eastell R, PEARL Study Investigators. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med. 2010;362(8):686–96. Erratum in: N Engl J Med. 2011 Jan 20;364(3):290. Kucukdeveci A [corrected to Kucukdeveci, A].

    Google Scholar 

  34. Bolland MJ, Grey A. A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record. BMJ Open. 2014;7:4(10).

    Google Scholar 

  35. Stepan JJ. Strontium ranelate: in search for the mechanism of action. J Bone Miner Metab. 2013;31(6):606–12.

    Article  PubMed  CAS  Google Scholar 

  36. Wijkmans J, Gossen J. Inhibitors of cathepsin K: a patent review (2004–2010). Expert Opin Ther Pat. 2011;21(10):1611–29.

    Article  PubMed  CAS  Google Scholar 

  37. Black WC. Peptidomimetic inhibitors of cathepsin K. Curr Top Med Chem. 2010;10(7):745–51.

    Article  PubMed  CAS  Google Scholar 

  38. Kometani M, Nonomura K, Tomoo T, Niwa S. Hurdles in the drug discovery of cathepsin K inhibitors. Curr Top Med Chem. 2010;10(7):733–44.

    Article  PubMed  CAS  Google Scholar 

  39. Costa AG, Cusano NE, Silva BC, Cremers S, Bilezikian JP. Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol. 2011;7(8):447–56.

    Article  PubMed  CAS  Google Scholar 

  40. Kumar S, Dare L, Vasko-Moser JA, James IE, Blake SM, Rickard DJ, Hwang SM, Tomaszek T, Yamashita DS, Marquis RW, Oh H, Jeong JU, Veber DF, Gowen M, Lark MW, Stroup G. A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone. 2007;40(1):122–31.

    Article  PubMed  CAS  Google Scholar 

  41. Ochi Y, Yamada H, Mori H, Nakanishi Y, Nishikawa S, Kayasuga R, Kawada N, Kunishige A, Hashimoto Y, Tanaka M, Sugitani M, Kawabata K. Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism. Bone. 2011;49(6):1351–6.

    Article  PubMed  CAS  Google Scholar 

  42. Eastell R, Nagase S, Ohyama M, Small M, Sawyer J, Boonen S, Spector T, Kuwayama T, Deacon S. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: the OCEAN study. J Bone Miner Res. 2011;26(6):1303–12.

    Article  PubMed  CAS  Google Scholar 

  43. Gauthier JY, Chauret N, Cromlish W, Desmarais S, le Duong T, Falgueyret JP, Kimmel DB, Lamontagne S, Léger S, LeRiche T, Li CS, Massé F, McKay DJ, Nicoll-Griffith DA, Oballa RM, Palmer JT, Percival MD, Riendeau D, Robichaud J, Rodan GA, Rodan SB, Seto C, Thérien M, Truong VL, Venuti MC, Wesolowski G, Young RN, Zamboni R, Black WC. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008;18(3):923–8.

    Article  PubMed  CAS  Google Scholar 

  44. Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, Denker A, Lombardi A, Le Bailly De Tilleghem C, Dasilva C, Rosenberg E, Leung A. Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res. 2012;27(11):2251–8.

    Article  PubMed  CAS  Google Scholar 

  45. *http://www.mercknewsroom.com/news-release/research-and-development-news/merck-announces-data-pivotal-phase-3-fracture-outcomes-st. *Press release announcing outcome of LOFT trial with odanacatib.

  46. Jamal SA, Reid LS, Hamilton CJ. The effects of organic nitrates on osteoporosis: a systematic review. Osteoporos Int. 2013;24(3):763–70.

    Article  PubMed  CAS  Google Scholar 

  47. Bolland MJ, Grey A, Reid IR. Calcium supplements and cardiovascular risk: 5 years on. Ther Adv Drug Saf. 2013;4(5):199–210.

    Article  PubMed  PubMed Central  Google Scholar 

  48. *Tella SH, Gallagher JC. Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol. 2014;142:155–70. *An excellent review of the current and future treatments.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Cosman F. Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches. Curr Osteoporos Rep. 2014;12(4):385–95.

    Article  PubMed  Google Scholar 

  50. Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol. 2014 Sep 30.

    Google Scholar 

  51. Aspenberg P. Special review: accelerating fracture repair in humans: a reading of old experiments and recent clinical trials. Bonekey Rep. 2013;2:244.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Rao SK, Rao AP. A literature review and case series of accelerating fracture healing in postmenopausal osteoporotic working women. J Orthop. 2014;11(3):150–2.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Little DG, McDonald M, Bransford R, Godfrey CB, Amanat N. Manipulation of the anabolic and catabolic responses with OP-1 and zoledronic acid in a rat critical defect model. J Bone Miner Res. 2005;20:2044–52.

    Google Scholar 

  54. Wilkinson JM, Little DG. Bisphosphonates in orthopedic applications. Bone. 2011;49(1):95–102.

    Article  PubMed  CAS  Google Scholar 

  55. Wilkinson JM, Eagleton AC, Stockley I, Peel NF, Hamer AJ, Eastell R. Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial. J Orthop Res. 2005;23:1–8.

    Google Scholar 

  56. Aspenberg P. Bisphosphonates and implants: an overview. Acta Orthop. 2009;80(1):119–23.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lai KA, Shen WJ, Yang CY, Shao CJ, Hsu JT, Lin RM. The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study. J Bone Joint Surg Am. 2005;87(10):2155–9.

    Google Scholar 

  58. Reginster JY, Neuprez A, Beaudart C, Lecart MP, Sarlet N, Bernard D, Disteche S, Bruyere O. Antiresorptive drugs beyond bisphosphonates and selective oestrogen receptor modulators for the management of postmenopausal osteoporosis. Drugs Aging. 2014;31(6):413–24.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Costa AG, Bilezikian JP. Sclerostin: therapeutic horizons based upon its actions. Curr Osteoporos Rep. 2012;10(1):64–72.

    Article  PubMed  Google Scholar 

  60. Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev. 2012;33(5):747–83.

    Article  PubMed  CAS  Google Scholar 

  61. *Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014;13(7):513–32. *An excellent review of the wnt pathway.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. *McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster JY, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang YC, Libanati C, Bone HG. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370(5):412–20. *The first report of the clinical effects of the anti-sclerostin antibody romosozumab on bone density and turnover.

    Article  PubMed  CAS  Google Scholar 

  63. Tella SH, Gallagher JC. Biological agents in management of osteoporosis. Eur J Clin Pharmacol. 2014;70(11):1291–301.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The Botnar Research Centre and Oxford University Institute of Musculoskeletal Sciences, Oxford, UK

    R. Graham G. Russell MD, PhD, FRS, Maria K. Tsoumpra MRes, DPhil & Michael Pazianas MD

  2. Department of Oncology and Human Metabolism, The Mellanby Centre for Bone Research, The University of Sheffield Medical School, Sheffield, UK

    R. Graham G. Russell MD, PhD, FRS, Michelle A. Lawson PhD & Andrew D. Chantry MD, PhD

  3. Chemistry Department, University of Rochester, Rochester, NY, USA

    Frank H. Ebetino PhD

Authors
  1. R. Graham G. Russell MD, PhD, FRS
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria K. Tsoumpra MRes, DPhil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michelle A. Lawson PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew D. Chantry MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Frank H. Ebetino PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Pazianas MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Graham G. Russell MD, PhD, FRS .

Editor information

Editors and Affiliations

  1. Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Center; University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California, USA

    Stuart Silverman

  2. Institute of Clinical Research; Department of Medicine, Holbæk, Denmark, University of Southern Denmark, Odense Patient Data Explorative Network; Holbæk Hospital, Odense, Denmark

    Bo Abrahamsen

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Russell, R.G.G., Tsoumpra, M.K., Lawson, M.A., Chantry, A.D., Ebetino, F.H., Pazianas, M. (2016). Antiresorptives. In: Silverman, S., Abrahamsen, B. (eds) The Duration and Safety of Osteoporosis Treatment. Springer, Cham. https://doi.org/10.1007/978-3-319-23639-1_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-23639-1_2

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-23638-4

  • Online ISBN: 978-3-319-23639-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation