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®
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The relationship between baseline Fracture Risk Assessment Tool (FRAX®) and treatment efficacy was evaluated using data from a pivotal phase 3 study. Relative risk of vertebral, nonvertebral, and all clinical fractures decreased with increasing probability of fracture for bazedoxifene (BZA) versus placebo but remained generally constant for raloxifene (RLX).
To determine whether the FRAX® predicts osteoporosis treatment efficacy, we evaluated reductions in fracture incidence associated with BZA and RLX according to baseline fracture risk determined by FRAX® using data from a phase 3 osteoporosis treatment study.
Hazard ratios (HRs) for effects of BZA and RLX versus placebo on incidence of vertebral, nonvertebral, and all clinical fractures were calculated using a Cox regression model. Cox regression analyses were performed in subgroups at or above 10-year fracture probability thresholds determined by FRAX®.
HRs for the risk of vertebral, nonvertebral, and all clinical fractures versus placebo decreased with increasing 10-year fracture probability for BZA, while those for RLX remained stable. In all 10-year fracture probability subgroups, all BZA doses significantly reduced vertebral fracture risk versus placebo (HR = 0.22–0.66). BZA at 20, 40, and 20/40 mg significantly reduced risk of nonvertebral fractures (HR = 0.45, 0.44, and 0.45, respectively) and all clinical fractures (HR = 0.38, 0.41, and 0.40, respectively) for ≥20.0 % fracture probability. Vertebral fracture risk reductions for RLX 60 mg versus placebo were significant in subgroups at lower fracture probabilities (≥2.5– ≥ 10.0 %), but not higher (≥12.5 %), and in no subgroups for nonvertebral or all clinical fractures.
The antifracture efficacy of BZA increased with increasing baseline FRAX® score, but there was no clear relationship between RLX and baseline FRAX®. These findings provide independent confirmation of current literature, suggesting that the relationship between FRAX® and treatment efficacy varies for different agents.
- Kanis, JA (2007) Assessment of osteoporosis at the primary health care level. Technical report. WHO Collaborating Centre for Metabolic Bone Diseases. University of Sheffield, UK
- Kanis, JA, Johnell, O, Oden, A, Johansson, H, McCloskey, E (2008) FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 19: pp. 385-397 CrossRef
- World Health Organization Collaborating Centre for Metabolic Bone Diseases (2008) FRAX® WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/. Accessed 28 October 2009
- Kanis JA, Hans D, Cooper C, Baim S, Bilezikian JP, Binkley N, Cauley JA, Compston JE, wson-Hughes B, El-Hajj FG, Johansson H, Leslie WD, Lewiecki EM, Luckey M, Oden A, Papapoulos SE, Poiana C, Rizzoli R, Wahl DA, McCloskey EV (2011) Interpretation and use of FRAX in clinical practice. Osteoporos Int 22:2355–2411
- McCloskey, EV, Johansson, H, Oden, A, Vasireddy, S, Kayan, K, Pande, K, Jalava, T, Kanis, JA (2009) Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from a double-blind, placebo-controlled randomised study. Osteoporos Int 20: pp. 811-817 CrossRef
- Kanis, JA, Johansson, H, Oden, A, McCloskey, EV (2009) Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 44: pp. 1049-1054 CrossRef
- Kanis, JA, Johansson, H, Oden, A, McCloskey, EV (2010) A meta-analysis of the efficacy of raloxifene on all clinical and vertebral fractures and its dependency on FRAX. Bone 47: pp. 729-735 CrossRef
- Kanis, JA, Johansson, H, Oden, A, McCloskey, EV (2011) A meta-analysis of the effect of strontium ranelate on the risk of vertebral and non-vertebral fracture in postmenopausal osteoporosis and the interaction with FRAX((R)). Osteoporos Int 22: pp. 2347-2355 CrossRef
- McCloskey, EV, Johansson, H, Oden, A, Austin, M, Siris, E, Wang, A, Lewiecki, EM, Lorenc, R, Libanati, C, Kanis, JA (2012) Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX. J Bone Miner Res 27: pp. 1480-1486 CrossRef
- Miller, PD, Chines, AA, Christiansen, C, Hoeck, HC, Kendler, DL, Lewiecki, EM, Woodson, G, Levine, AB, Constantine, G, Delmas, PD (2008) Effects of bazedoxifene on BMD and bone turnover in postmenopausal women: 2-yr results of a randomized, double-blind, placebo-, and active-controlled study. J Bone Miner Res 23: pp. 525-535 CrossRef
- Silverman, SL, Christiansen, C, Genant, HK, Vukicevic, S, Zanchetta, JR, Villiers, TJ, Constantine, GD, Chines, AA (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: pp. 1923-1934 CrossRef
- Pfizer (2011) CONBRIZA 20 mg film-coated tablets. Summary of product characteristics.
- Pharmaceutical Business Review (2010) Pfizer introduces postmenopausal osteoporosis drug Viviant in Japan, Spain. http://drugdiscovery.pharmaceutical-business-review.com/news/pfizer-introduces-postmenopausal-osteoporosis-drug-viviant-in-japan-spain_141010. Accessed 20 January 2012
- McCloskey, E, Johansson, H, Oden, A, Chines, A, Kanis, J (2009) Assessment of the effect of bazedoxifene on non-vertebral fracture risk. J Bone Miner Res 24: pp. S140
- EVISTA (raloxifene hydrochloride) tablet for oral use [package insert]. Indianapolis Eli Lilly; 2008.
- European Medicines Agency (2009) European Public Assessment Report (EPAR). EVISTA. EPAR summary for the public. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000184/WC500031005.pdf. Accessed 29 July 2011
- Ettinger, B (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 282: pp. 637-645 CrossRef
- Delmas, PD, Genant, HK, Crans, GG, Stock, JL, Wong, M, Siris, E, Adachi, JD (2003) Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial. Bone 33: pp. 522-532 CrossRef
- Donaldson, MG, Palermo, L, Ensrud, KE, Hochberg, MC, Schousboe, JT, Cummings, SR (2012) Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial. J Bone Miner Res 27: pp. 1804-1810 CrossRef
- Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 333: pp. 1437-1443 CrossRef
- 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: pp. 2077-2082 CrossRef
- Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. N Engl J Med 338: pp. 485-492 CrossRef
- Watts, NB, Cooper, C, Lindsay, R, Eastell, R, Manhart, MD, Barton, IP, Staa, TP, Adachi, JD (2004) Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 7: pp. 255-261 CrossRef
- Miller, PD (2005) Bone density and markers of bone turnover in predicting fracture risk and how changes in these measures predict fracture risk reduction. Curr Osteoporos Rep 3: pp. 103-110 CrossRef
- Sarkar, S, Mitlak, BH, Wong, M, Stock, JL, Black, DM, Harper, KD (2002) Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 17: pp. 1-10 CrossRef
- Cummings, SR, Karpf, DB, Harris, F, Genant, HK, Ensrud, K, LaCroix, AZ, Black, DM (2002) Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 112: pp. 281-289 CrossRef
- Li, Z, Meredith, MP, Hoseyni, MS (2001) A method to assess the proportion of treatment effect explained by a surrogate endpoint. Stat Med 20: pp. 3175-3188 CrossRef
- Bruyere, O, Detilleux, J, Chines, A, Reginster, JY (2010) Relationships between changes in bone mineral density or bone turnover markers and vertebral fractures incidence in patients treated with bazedoxifene. Arthritis Rheum 62: pp. S406-S407
- Eastell, R, Barton, I, Hannon, RA, Chines, A, Garnero, P, Delmas, PD (2003) Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 18: pp. 1051-1056 CrossRef
- Melton, LJ, Khosla, S, Atkinson, EJ, O’Fallon, WM, Riggs, BL (1997) Relationship of bone turnover to bone density and fractures. J Bone Miner Res 12: pp. 1083-1091 CrossRef
- 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 (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356: pp. 1809-1822 CrossRef
- Cummings, SR, San, MJ, 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 (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361: pp. 756-765 CrossRef
- 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®
Volume 24, Issue 10 , pp 2561-2569
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- Fracture probability
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- Author Affiliations
- 1. Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Ghent, Belgium
- 2. Instituto Palacios, Salud y Medicina de la Mujer, Madrid, Spain
- 3. Cedars-Sinai Medical Center and University of California, Los Angeles, CA, USA
- 4. Pfizer, Collegeville, PA, USA