The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies

D L Kendler, A Chines, M L Brandi, S Papapoulos, E M Lewiecki, J-Y Reginster, M Muñoz Torres, A Wang, H G Bone, D L Kendler, A Chines, M L Brandi, S Papapoulos, E M Lewiecki, J-Y Reginster, M Muñoz Torres, A Wang, H G Bone

Abstract

This post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.

Introduction: This analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment.

Methods: In FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Here we compare subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM.

Results: During FREEDOM, 438 placebo- and 272 denosumab-treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43-0.81]; P = 0.0012).

Conclusions: These data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.

Keywords: Denosumab; Fracture; Osteoporosis; Subsequent fracture.

Conflict of interest statement

DL Kendler: Received research grants from Amgen Inc., Eli Lilly, Astellas, and AstraZeneca; consulting fees from Amgen Inc. and Eli Lilly; and honoraria from Amgen Inc., Pfizer, Eli Lilly, and Merck.

A Chines and A Wang: Employees of and stockholders in Amgen Inc.

ML Brandi: Received honoraria from Amgen, Bruno Farmaceutici, and Kyowa Kirin; received academic grants and/or was a speaker for Abiogen, Alexion, Amgen, Bruno Farmaceutici, Eli Lilly, Kyowa Kirin, MSD, NPS, Servier, Shire, and SPA; served as a consultant to Alexion, Bruno Farmaceutici, Kyowa Kirin, Servier, and Shire.

S Papapoulos: Received consulting fees or lecture fees as an advisory group member or speaker from Amgen Inc. and Merck & Co. Received consulting fees as an ad hoc consultant from Axsome, Gador, and UCB. Received consulting fees as an advisory group member from Radius Health. Received speaking fees from Teva.

EM Lewiecki: Received consulting fees or grants as a member of a medical advisory board or study investigator from/for Amgen Inc., Merck & Co., Eli Lilly, and Radius.

J-Y Reginster: Received consulting fees or paid advisory boards from IBSA-Genevrier, Mylan, Radius Health, and Pierre Fabre. Received lecture fees when speaking at the invitation of sponsor from IBSA-Genevrier, Mylan, Cniel, and Dairy Research Council (DRC). Received grant support (all through institution) from IBSA-Genevrier, Mylan, Cniel, and Radius Health.

M Muñoz Torres: Received lecture fees from Lilly and consulting fees as a member of a medical advisory board member from Amgen Inc.

HG Bone: Received consulting fees from Amgen Inc., Merck, Radius, and Shire. Received lecture fees from Amgen Inc. and Shire. Received research grants as an investigator from Amgen Inc., Merck, and Shire. Received fees as a data safety monitoring board member from Grunenthal.

Figures

Fig. 1
Fig. 1
FREEDOM and FREEDOM Extension study design. This analysis included women who had received ≥ 2 doses of investigational product (placebo or denosumab) during FREEDOM or the Extension, had an osteoporotic fracture (new vertebral, including clinical vertebral, or nonvertebral) while on treatment, and continued treatment post-fracture. Q6M = every 6 months; SC = subcutaneously
Fig. 2
Fig. 2
Subsequent osteoporotic fracture rate per 100 subject-years among placebo- and denosumab-treated subjects with incident osteoporotic fracture. HR = hazard ratio; CI = confidence interval
Fig. 3
Fig. 3
Time to first subsequent osteoporotic fracture among subjects in FREEDOM placebo, FREEDOM denosumab, and combined denosumab groups
Fig. 4
Fig. 4
Exposure-adjusted subject incidence of subsequent osteoporotic fracture in subjects with and without baseline vertebral fracture

References

    1. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348(9041):1535–1541. doi: 10.1016/S0140-6736(96)07088-2.
    1. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P, Leung PC, Man Z, Martinez RLM, Tan M, Ruzycky ME, Su G, Eastell R. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT) J Bone Miner Res. 2012;27(2):243–254. doi: 10.1002/jbmr.1494.
    1. 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):1923–1934. doi: 10.1359/jbmr.080710.
    1. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–765. doi: 10.1056/NEJMoa0809493.
    1. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA, 3rd, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000;15(4):721–739. doi: 10.1359/jbmr.2000.15.4.721.
    1. Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas P, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone. 2004;35(2):375–382. doi: 10.1016/j.bone.2004.03.024.
    1. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):1527–1535. doi: 10.1016/S0140-6736(03)14739-3.
    1. Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016;10(4):1011–1021. doi: 10.1016/j.jacl.2016.04.013.
    1. Diez-Perez A, Gonzalez-Macias J. Inadequate responders to osteoporosis treatment: proposal for an operational definition. Osteoporos Int. 2008;19(11):1511–1516. doi: 10.1007/s00198-008-0659-2.
    1. Diez-Perez A, Olmos JM, Nogues X, Sosa M, Diaz-Curiel M, Perez-Castrillon JL, et al. Risk factors for prediction of inadequate response to antiresorptives. J Bone Miner Res. 2012;27(4):817–824. doi: 10.1002/jbmr.1496.
    1. Diez-Perez A, Adachi JD, Agnusdei D, Bilezikian JP, Compston JE, Cummings SR, et al. Treatment failure in osteoporosis. Osteoporos Int. 2012;23(12):2769–2774. doi: 10.1007/s00198-012-2093-8.
    1. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwinski E, et al. 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. doi: 10.1002/jbmr.1479.
    1. Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, et al. 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):4483–4492. doi: 10.1210/jc.2013-1597.
    1. Ferrari S, Adachi JD, Lippuner K, Zapalowski C, Miller PD, Reginster JY, Törring O, Kendler DL, Daizadeh NS, Wang A, O’Malley CD, Wagman RB, Libanati C, Lewiecki EM. Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years. Osteoporos Int. 2015;26(12):2763–2771. doi: 10.1007/s00198-015-3179-x.
    1. Papapoulos S, Lippuner K, Roux C, Lin CJ, Kendler DL, Lewiecki EM, et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study. Osteoporos Int. 2015;26(12):2773–2783. doi: 10.1007/s00198-015-3234-7.
    1. Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwiński E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513–523. doi: 10.1016/S2213-8587(17)30138-9.
    1. McClung MR, Boonen S, Torring O, Roux C, Rizzoli R, Bone HG, et al. Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res. 2012;27(1):211–218. doi: 10.1002/jbmr.536.
    1. Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, Roux C, Törring O, Valter I, Wang AT, Brown JP (2018) Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension. J Bone Miner Res 33(2):190-198
    1. Brown JP, Roux C, Torring O, Ho PR, Beck Jensen JE, Gilchrist N, et al. Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. J Bone Miner Res. 2013;28(4):746–752. doi: 10.1002/jbmr.1808.

Source: PubMed

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