Skip to main content

Advertisement

SpringerLink
Log in

Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development.

Introduction

ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis.

Methods

Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ − 2.5 to ≥ − 4.0 without prior vertebral fracture or ≤ − 1.5 to ≥ − 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo.

Results

Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups.

Conclusion

Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial.

Trial registration

Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The data sharing policy of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, including restrictions, is available at http://engagezone.merck.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

References

  1. Willson T, Nelson SD, Newbold J, Nelson RE, LaFleur J (2015) The clinical epidemiology of male osteoporosis: a review of the recent literature. Clin Epidemiol 7:65–76

    PubMed  PubMed Central  Google Scholar 

  2. Johnell O, Kanis J (2005) Epidemiology of osteoporotic fractures. Osteoporos Int 16(Suppl 2):S3–S7

    Article  Google Scholar 

  3. Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17:1726–1733

    Article  CAS  Google Scholar 

  4. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB (2009) Incidence and mortality of hip fractures in the United States. JAMA 302:1573–1579

    Article  CAS  Google Scholar 

  5. Costa AG, Cusano NE, Silva BC, Cremers S, Bilezikian JP (2011) Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. Nat Rev Rheumatol 7:447–456

    Article  CAS  Google Scholar 

  6. Reid IR, Miller PD, Brown JP, Kendler DL, Fahrleitner-Pammer A, Valter I, Maasalu K, Bolognese MA, Woodson G, Bone H, Ding B, Wagman RB, San Martin J, Ominsky MS, Dempster DW, Denosumab Phase 3 Bone Histology Study Group (2010) Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res 25:2256–2265

    Article  CAS  Google Scholar 

  7. Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, Samadfam R, Goetzmann JE, Scott BB, Kimmel DB, Duong LT (2012) Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res 27:509–523

    Article  CAS  Google Scholar 

  8. D’Amelio P, Grimaldi A, Cristofaro MA, Ravazzoli M, Molinatti PA, Pescarmona GP, Isaia GC (2010) Alendronate reduces osteoclast precursors in osteoporosis. Osteoporos Int 21:1741–1750

    Article  Google Scholar 

  9. D’Amelio P, Grimaldi A, Di Bella S, Tamone C, Brianza SZ, Ravazzoli MG, Bernabei P, Cristofaro MA, Pescarmona GP, Isaia G (2008) Risedronate reduces osteoclast precursors and cytokine production in postmenopausal osteoporotic women. J Bone Miner Res 23:373–379

    Article  Google Scholar 

  10. Migliaccio S, Brama M, Spera G (2007) The differential effects of bisphosphonates, SERMS (selective estrogen receptor modulators), and parathyroid hormone on bone remodeling in osteoporosis. Clin Interv Aging 2:55–64

    Article  CAS  Google Scholar 

  11. Leung P, Pickarski M, Zhuo Y, Masarachia PJ, Duong LT (2011) The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking. Bone 49:623–635

    Article  CAS  Google Scholar 

  12. Bone HG, McClung MR, Roux C, Recker RR, Eisman JA, Verbruggen N, Hustad CM, DaSilva C, Santora AC, Ince BA (2010) 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

    PubMed  Google Scholar 

  13. Rizzoli R, Benhamou CL, Halse J, Miller PD, Reid IR, Rodríguez Portales JA, DaSilva C, Kroon R, Verbruggen N, Leung AT, Gurner D (2016) Continuous treatment with odanacatib for up to 8 years in postmenopausal women with low bone mineral density: a phase 2 study. Osteoporos Int 27:2099–2107

    Article  CAS  Google Scholar 

  14. Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SAM, Sebba A, Kagan R, Chen E, Thompson DE, de Papp AE (2006) Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab 91:2631–2637

    Article  CAS  Google Scholar 

  15. Reid DM, Hosking D, Kendler D, Brandi ML, Wark JD, Marques-Neto JF, Weryha G, Verbruggen N, Hustad CM, Mahlis EM, Melton ME (2008) A comparison of the effect of alendronate and risedronate on bone mineral density in postmenopausal women with osteoporosis: 24-month results from FACTS-International. Int J Clin Pract 62:575–584

    Article  CAS  Google Scholar 

  16. McClung MR, O’Donoghue ML, Papapoulos SE, Bone H, Langdahl B, Saag KG, Reid IR, Kiel DP, Cavallari I, Bonaca MP, Wiviott SD, de Villiers T, Ling X, Lippuner K, Nakamura T, Reginster J-Y, Rodriguez-Portales JA, Roux C, Zanchetta J, Zerbini CAF, Park J-G, Im K, Cange A, Grip LT, Heyden N, DaSilva C, Cohn D, Massaad R, Scott BB, Verbruggen N, Gurner D, Miller DL, Blair ML, Polis AB, Stoch SA, Santora A, Lombardi A, Leung AT, Kaufman KD, Sabatine MS, Investigators LOFT (2019) Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study. Lancet Diabetes Endocrinol 7:899–911

    Article  CAS  Google Scholar 

  17. Whitaker M, Guo J, Kehoe T, Benson G (2012) Bisphosphonates for osteoporosis--where do we go from here? N Engl J Med 366:2048–2051

    Article  CAS  Google Scholar 

  18. Black DM, Bauer DC, Schwartz AV, Cummings SR, Rosen CJ (2012) Continuing bisphosphonate treatment for osteoporosis--for whom and for how long? N Engl J Med 366:2051–2053

    Article  CAS  Google Scholar 

  19. Eisman JA, Bone HG, Hosking DJ, McClung MR, Reid IR, Rizzoli R, Resch H, Verbruggen N, Hustad CM, DaSilva C, Petrovic R, Santora AC, Ince BA, Lombardi A (2011) Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J Bone Miner Res 26:242–251

    Article  CAS  Google Scholar 

  20. Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Johnston CC Jr, Lindsay R (1998) Updated data on proximal femur bone mineral levels of US adults. Osteoporos Int 8:468–489

    Article  CAS  Google Scholar 

  21. Genant HK, Wu CY, van Kuijk C, Nevitt MC (1993) Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148

    Article  CAS  Google Scholar 

  22. Dempster D, Compston JE, Drezner MK, Glorieux F, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM (2013) Standardized, nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 28:2–17

    Article  Google Scholar 

  23. Zeger SL, Liang KY (1986) Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42:121–130

    Article  CAS  Google Scholar 

  24. Golds G, Houdek D, Arnason T (2017) Male hypogonadism and osteoporosis: the effects, clinical consequences, and treatment of testosterone deficiency in bone health. Int J Endocrinol 2017:4602129

    Article  Google Scholar 

  25. Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, Yoshikawa H, Tanaka Y, Tanaka S, Sone T, Nakano T, Ito M, Matsui S, Yoneda T, Takami H, Watanabe K, Osakabe T, Shiraki M, Fukunaga M (2014) Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab 99:2599–2607

    Article  CAS  Google Scholar 

  26. Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, Adami S, Weber K, Lorenc R, Pietschmann P, Vandormael K, Lombardi A (2000) Alendronate for the treatment of osteoporosis in men. N Engl J Med 343:604–610

    Article  CAS  Google Scholar 

  27. Duong LT, Pickarsky M, Clark S, Giezek H, Cohn D, Massaad R, Stoch SA (2016) Differential effects of odanacatib therapy on markers of bone resorption and formation in postmenopausal women with osteoporosis: a subgroup study of the 5-year data from the extension of the phase 3 Long-term Odanacatib Fracture Trial (LOFT). American Society for Bone and Mineral Research (ASBMR), 2016 September 16–19, Atlanta, Georgia, USA. Abstract SA0299

  28. Recker R, Dempster D, Langdahl B, Giezek H, Clark S, Ellis G, de Villiers T, Valter I, Zerbini CAF, Cohn D, Santora A, Duong LT (2020) Effects of odanacatib on bone structure and quality in postmenopausal women with osteoporosis: 5-year data from the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its extension. J Bone Miner Res 35(7):1289–1299.

  29. Mullard A (2016) Merck & Co. drops osteoporosis drug odanacatib. Nat Rev Drug Discov 15:669

    PubMed  PubMed Central  Google Scholar 

  30. Barnard K, Lakey WC, Batch BC, Chiswell K, Tasneem A, Green JB (2016) Recent clinical trials in osteoporosis: a firm foundation or falling short? PLoS One 11:e0156068

    Article  Google Scholar 

  31. Boonen S, Orwoll ES, Wenderoth D, Stoner KJ, Eusebio R, Delmas PD (2009) Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J Bone Miner Res 24:719–725

    Article  CAS  Google Scholar 

  32. Boonen S, Reginster JY, Kaufman JM, Lippuner K, Zanchetta J, Langdahl B, Rizzoli R, Lipschitz S, Dimai HP, Witvrouw R, Eriksen E, Brixen K, Russo L, Claessens F, Papanastasiou P, Antunez O, Su G, Bucci-Rechtweg C, Hruska J, Incera E, Vanderschueren D, Orwoll E (2012) Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 367:1714–1723

    Article  CAS  Google Scholar 

  33. Langdahl BL, Teglbjaerg CS, Ho PR et al (2015) A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial. J Clin Endocrinol Metab 100:1335–1342

    Article  CAS  Google Scholar 

  34. Orwoll E, Teglbjaerg CS, Langdahl BL et al (2012) A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab 97:3161–3169

    Article  CAS  Google Scholar 

  35. Orwoll ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A, Kaufman JM, Clancy AD, Gaich GA (2003) The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 18:9–17

    Article  CAS  Google Scholar 

  36. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mellström D, Oefjord ES, Marcinowska-Suchowierska E, Salmi J, Mulder H, Halse J, Sawicki AZ, Mitlak BH (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Medical writing, under the direction of the authors, was provided by Annette Smith, PhD, of CMC AFFINITY, McCann Health Medical Communications, in accordance with Good Publication Practice (GPP3) guidelines. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. We also acknowledge Steven Doleckyj for prior clinical trial, data and operations management.

Funding

Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Author information

Authors and Affiliations

  1. University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    N. Binkley

  2. Oregon Health & Science University, Portland, OR, USA

    E. Orwoll

  3. INSERM UMR 1033, Université de Lyon, Hôpital Édouard Herriot, Lyon, France

    R. Chapurlat

  4. Aarhus University Hospital, Aarhus, Denmark

    B. L. Langdahl

  5. Merck & Co., Inc., Kenilworth, NJ, USA

    B. B. Scott & A. C. Santora

  6. MSD Europe Inc., Brussels, Belgium

    H. Giezek

Authors
  1. N. Binkley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Orwoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Chapurlat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. L. Langdahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. B. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H. Giezek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. C. Santora
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N. Binkley.

Ethics declarations

Conflicts of interest

BBS, HG, and ACS are, or were at the time of study conduct, employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in the company. NB has received research support from Radius and is a consultant for Amgen. RC has been a consultant and/or has given talks for AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Janssen-Cilag, Lilly, MSD, Pfizer, Radius, Sandoz, and UCB. BLL has received research grants (institution) from Amgen and Novo Nordisk and has been involved in advisory boards and lecturing for Amgen, Eli Lilly, MSD, and UCB. EO has received research support from Lilly and Mereo and provides consulting for Bayer and Amgen. ACS is currently a consultant and Chief Medical Officer of Entera Bio Ltd.

Ethics approval

The study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.

Consent to participate

All participants provided written informed consent before any study procedure was initiated.

Consent for publication

Not applicable.

Code availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PDF 310 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Binkley, N., Orwoll, E., Chapurlat, R. et al. Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis. Osteoporos Int 32, 173–184 (2021). https://doi.org/10.1007/s00198-020-05701-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-020-05701-9

Keywords

Search

Navigation