Top

Published in:

Open Access 01-12-2015 | Original Article

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

Authors: S. Ferrari, J. D. Adachi, K. Lippuner, C. Zapalowski, P. D. Miller, J.-Y. Reginster, O. Törring, D. L. Kendler, N. S. Daizadeh, A. Wang, C. D. O’Malley, R. B. Wagman, C. Libanati, E. M. Lewiecki

Published in: Osteoporosis International | Issue 12/2015

Abstract

Summary

Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4–7 versus years 1–3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis.

Introduction

This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates.

Methods

Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1–3 of denosumab with that of the fourth year and with the rate during years 4–7 was evaluated.

Results

For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1–3 were compared to years 4–7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD).

Conclusions

Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Abrahamsen B, van Staa T, Ariely R, Olson M, Cooper C (2009) Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos Int 20:1633–1650CrossRefPubMed

Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR (2009) Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 301:513–521CrossRefPubMed

Bliuc D, Nguyen TV, Eisman JA, Center JR (2014) The impact of non-hip non-vertebral fractures in elderly women and men. J Clin Endocrinol Metab 99:415–423CrossRefPubMed

Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541CrossRefPubMed

Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR, Trial HPF (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822CrossRefPubMed

Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082CrossRefPubMed

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, Trial F (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765CrossRefPubMed

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 RL, Tan M, Ruzycky ME, Su G, Eastell R (2012) 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 27:243–254PubMedCentralCrossRefPubMed

Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora AC, Cummings SR, Group FR (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938CrossRefPubMed

10.

Sorensen OH, Crawford GM, Mulder H, Hosking DJ, Gennari C, Mellstrom D, Pack S, Wenderoth D, Cooper C, Reginster JY (2003) Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone 32:120–126CrossRefPubMed

11.

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

12.

Cavalli L, Brandi ML (2012) Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility. Ther Clin Risk Manag 8:253–266PubMedCentralPubMed

13.

McClung MR (2013) Denosumab. In: Rosen CJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. John Wiley & Sons, pp 420–424

14.

Bone HG, Chapurlat R, Brandi ML, Brown JP, Czerwinski E, Krieg MA, Man Z, Mellstrom D, Radominski SC, Reginster JY, Resch H, Roman Ivorra JA, Roux C, Vittinghoff E, Daizadeh NS, Wang A, Bradley MN, Franchimont N, Geller ML, Wagman RB, Cummings SR, Papapoulos S (2013) The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 98:4483–4492PubMedCentralCrossRefPubMed

15.

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

16.

Austin M, Yang YC, Vittinghoff E, Adami S, Boonen S, Bauer DC, Bianchi G, Bolognese MA, Christiansen C, Eastell R, Grauer A, Hawkins F, Kendler DL, Oliveri B, McClung MR, Reid IR, Siris ES, Zanchetta J, Zerbini CA, Libanati C, Cummings SR, Trial F (2012) Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures. J Bone Miner Res 27:687–693PubMedCentralCrossRefPubMed

17.

Bolognese MA, Teglbjaerg CS, Zanchetta JR, Lippuner K, McClung MR, Brandi ML, Hoiseth A, Lakatos P, Moffett AH, Lorenc RS, Wang A, Libanati C (2013) Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. J Clin Densitom 16:147–153CrossRefPubMed

18.

Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA, Alendronate Phase IIIOTSG (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199CrossRefPubMed

19.

Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S, Feldstein A, Haskell WL, Hochberg MC, Torner JC, Lombardi A, Black DM, Fracture Intervention Trial Long-Term Extension Research G (2004) Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 19:1259–1269CrossRefPubMed

20.

Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS (2011) Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone 49:151–161CrossRefPubMed

21.

Ominsky MS, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith SY, Kostenuik PJ (2011) Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone 49:162–173CrossRefPubMed

22.

Zebaze RM, Libanati C, Austin M, Ghasem-Zadeh A, Hanley DA, Zanchetta JR, Thomas T, Boutroy S, Bogado CE, Bilezikian JP, Seeman E (2014) Differing effects of denosumab and alendronate on cortical and trabecular bone. Bone 59:173–179CrossRefPubMed

23.

Iolascon G, Napolano R, Gioia M, Moretti A, Riccio I, Gimigliano F (2013) The contribution of cortical and trabecular tissues to bone strength: insights from denosumab studies. Clin Cases Miner Bone Metab 10:47–51PubMedCentralPubMed

24.

McClung MR, Lewiecki EM, Geller ML, Bolognese MA, Peacock M, Weinstein RL, Ding B, Rockabrand E, Wagman RB, Miller PD (2013) Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial. Osteoporos Int 24:227–235PubMedCentralCrossRefPubMed

25.

Genant HK, Engelke K, Hanley DA, Brown JP, Omizo M, Bone HG, Kivitz AJ, Fuerst T, Wang H, Austin M, Libanati C (2010) Denosumab improves density and strength parameters as measured by QCT of the radius in postmenopausal women with low bone mineral density. Bone 47:131–139CrossRefPubMed

26.

Simon JA, Recknor C, Moffett AH Jr, Adachi JD, Franek E, Lewiecki EM, McClung MR, Mautalen CA, Ragi-Eis S, Nicholson GC, Muschitz C, Nuti R, Torring O, Wang A, Libanati C (2013) Impact of denosumab on the peripheral skeleton of postmenopausal women with osteoporosis: bone density, mass, and strength of the radius, and wrist fracture. Menopause 20:130–137PubMed

27.

Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B (2001) Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 12:989–995CrossRefPubMed

28.

Krege JH, Wan X, Lentle BC, Berger C, Langsetmo L, Adachi JD, Prior JC, Tenenhouse A, Brown JP, Kreiger N, Olszynski WP, Josse RG, Goltzman D, CaMos Research G (2013) Fracture risk prediction: importance of age, BMD and spine fracture status. Bonekey Rep 2:404PubMedCentralCrossRefPubMed

29.

Bouxsein M (2006) Biomechanics of osteoporotic fractures. Clin Rev Bone Miner Metab 4:143–153CrossRef

30.

Keaveny TM, Bouxsein ML (2008) Theoretical implications of the biomechanical fracture threshold. J Bone Miner Res 23:1541–1547PubMedCentralCrossRefPubMed

31.

Kopperdahl DL, Aspelund T, Hoffmann PF, Sigurdsson S, Siggeirsdottir K, Harris TB, Gudnason V, Keaveny TM (2014) Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans. J Bone Miner Res 29:570–580PubMedCentralCrossRefPubMed

32.

Adachi JD, Ho PR, Lin CJF, Bolognese MA, Bone HG, Hadji P, Papapoulos S, Recknor C, Daizadeh NS, Dakin P, Wagman RB, Ferrari S (2014) Evolution of subject characteristics in FREEDOM and its extension for up to 8 years. J Bone Miner Res 29:S470

Title: 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
Authors: S. Ferrari
J. D. Adachi
K. Lippuner
C. Zapalowski
P. D. Miller
J.-Y. Reginster
O. Törring
D. L. Kendler
N. S. Daizadeh
A. Wang
C. D. O’Malley
R. B. Wagman
C. Libanati
E. M. Lewiecki
Publication date: 01-12-2015
Publisher: Springer London
Published in: Osteoporosis International / Issue 12/2015
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-015-3179-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Summary

Introduction

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 12/2015

Denosumab after 8 years

Life-course approach to nutrition

High fracture probability predicts fractures in a 4-year follow-up in women from the RAC-OST-POL study

Spectacular improvement in vitamin D status in elderly osteoporotic women: 8-year analysis of an osteoporotic population treated in a dedicated fracture liaison service

The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM Extension study

A phase IV, two-armed, randomized, cross-over study comparing compliance with once-a-month administration of vitamin D3 to compliance with daily administration of a fixed-dose combination of vitamin D3 and calcium during two 6-month periods