G Model MAT-6218; No. of Pages 7
ARTICLE IN PRESS Maturitas xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Use of FRAX® -based fracture risk assessments to identify patients who will benefit from osteoporosis therapy Stuart L. Silverman a,∗ , Barry S. Komm b,1 , Sebastian Mirkin c,2 a b c
Cedars-Sinai Medical Center and University of California, Los Angeles, CA, USA Pfizer Inc., Collegeville, PA, USA Therapeutics MD, Boca Raton, FL, USA
a r t i c l e
i n f o
Article history: Received 28 May 2014 Accepted 8 July 2014 Available online xxx Keywords: FRAX Fracture Osteoporosis Bazedoxifene Selective estrogen receptor modulator (SERM) Bisphosphonates
a b s t r a c t Several pharmacological interventions, including selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, and strontium ranelate have demonstrated efficacy in reducing the incidence of osteoporotic fractures, the most severe consequence of postmenopausal osteoporosis. Until recently, bone mineral density (BMD) was the primary factor used to determine which postmenopausal women may require osteoporosis treatment. However, clinical guidelines now recommend the use of the Fracture Risk Assessment Tool (FRAX® ), a computer-based algorithm introduced by the World Health Organization, to help primary care physicians identify postmenopausal women who may be candidates for pharmacological osteoporosis therapy based on the level of fracture risk. Beyond its utility as a resource for determining whether or not to initiate osteoporosis treatment, clinical studies have begun to evaluate the correlation between FRAX® -based 10-year fracture probability and efficacy of different osteoporosis treatments. Bazedoxifene, clodronate, and denosumab have shown greater fracture risk reduction at higher FRAX® -based 10-year fracture probabilities, but the efficacy of raloxifene, alendronate, and strontium ranelate were relatively stable regardless of fracture probability. In summary, these data suggest that the relationship between FRAX® -based fracture probability and efficacy of different osteoporosis treatments varies depending upon the agent in question. © 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uses of FRAX® in clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The efficacy of osteoporosis treatments By FRAX® -based fracture risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Selective estrogen receptor modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Bazedoxifene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Raloxifene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Alendronate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Clodronate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. RANK ligand inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Denosumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: BMD, bone mineral density; BZA, bazedoxifene; FRAX, Fracture Risk Assessment Tool; RLX, raloxifene; SERMs, selective estrogen receptor modulators. ∗ Corresponding author at: 8641 Wilshire Boulevard, Suite 301, Beverly Hills, CA 90211, USA. Tel.: +1 310 358 2234; fax: +1 310 659 2841. E-mail addresses: [email protected] (S.L. Silverman), Barry.Komm@pfizer.com (B.S. Komm), [email protected] (S. Mirkin). 1 Pfizer Inc., 500 Arcola Road, Collegeville, PA 19426, USA. 2 Formerly with Pfizer. Current address: 6800 Broken Sound Parkway NW, 3rd Floor, Boca Raton, FL 33487, USA http://dx.doi.org/10.1016/j.maturitas.2014.07.007 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Silverman SL, et al. Use of FRAX® -based fracture risk assessments to identify patients who will benefit from osteoporosis therapy. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.07.007
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3.4.
4.
Elemental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Strontium ranelate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The burden of osteoporosis is substantial, affecting more than 8 million women over the age of 50 in the United States [1] and from 40% to 90% of women over the age of 50 in Europe, with prevalence increasing with age [2]. Fractures represent the most severe consequence of osteoporosis and are associated with functional impairment, reduced quality of life, and increased mortality [3–5]. Pharmacological interventions, including selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, teriparatide, and strontium ranelate, have been shown to reduce the incidence of osteoporotic fractures [6] and are recommended for the treatment of postmenopausal women with osteoporosis [7]. Until recently, the identification of candidates for osteoporosis treatment represented a significant challenge. Bone mineral density (BMD) was considered to be the primary criterion for identifying individuals at an increased risk for osteoporotic fracture, but BMD measures alone provide an incomplete view of fracture risk [8,9]. Additional clinical risk factors need to be considered for assessing osteoporotic fracture risk [9]. The Fracture Risk Assessment Tool (FRAX® ), which was introduced by the World Health Organization in 2008, is a computer-based algorithm (http://www.shef.ac.uk/FRAX) that uses key clinical factors to calculate the 10-year probability of hip fracture and major osteoporotic fracture (wrist, humerus, hip, or clinical vertebral fracture) [10–13]. This tool was originally developed for use by primary care physicians to help identify patients at risk of fracture who would benefit from osteoporosis treatment [13,14]. FRAX® models are country-specific and incorporate age, sex, body mass index, and 7 dichotomized risk variables (prior fragility fracture, parental history of hip fracture, tobacco use, consumption of ≥3 units of alcohol daily, long-term oral glucocorticoid use, rheumatoid arthritis, and other causes of secondary osteoporosis), with or without femoral neck BMD [11,12]. Intervention thresholds may be determined using FRAX® score alone, or a combination of FRAX® score and economic modeling data [14,15]. FRAX® is becoming more widely accepted for use in treatment decisions and as a post hoc method of evaluating clinical trial data [11]. This article describes the current use of FRAX® in clinical practice and reviews the association between FRAX® -based fracture risk assessments and anti-fracture efficacy of current and emerging osteoporosis treatments. 2. Uses of FRAX® in clinical practice In recent clinical guidelines, FRAX® has been recommended to assist in the identification of patients who are candidates for pharmacological osteoporosis therapy [7,15]. For example, the National Osteoporosis Foundation recommends treatment for postmenopausal women at least 50 years of age with a low bone mass (T-score between −1.0 and −2.5) who have a FRAX® -based 10-year hip fracture risk ≥3% or a FRAX® -based 10-year major osteoporotic fracture risk ≥20% [15]. However, the use of FRAX® is context-specific. It is currently recommended only to assist with the decision to initiate pharmacological treatment [7,15] and may
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be used to identify patients who would benefit from BMD testing [16]. FRAX® is not indicated for patients who are already receiving osteoporosis therapy or for those in whom treatment is clearly required [12]. Nevertheless, new evidence suggests that FRAX® may predict fracture risk even for patients currently receiving osteoporosis therapy [17]. FRAX® -predicted fracture rates correlated with the observed incidence of major osteoporotic fractures in both untreated patients and in women who were adherent to osteoporosis treatment, indicating that FRAX® could potentially evaluate the need for continued treatment [17]. However, FRAX® cannot be used to monitor decreases in fracture risk over time, as the BMD changes as a result of therapy represent only a small proportion of factors that make up FRAX® . Beyond assisting clinicians with the decision to initiate osteoporosis treatment, FRAX® has been applied to the efficacy evaluations of several osteoporosis treatments according to individual fracture risk [18–23] (Table 1). 3. The efficacy of osteoporosis treatments By FRAX® -based fracture risk 3.1. Selective estrogen receptor modulators 3.1.1. Bazedoxifene Bazedoxifene (BZA) is a novel SERM that is currently in development for the prevention and treatment of postmenopausal osteoporosis [25]. BZA has been shown to reduce the risk of fractures in a phase 3 study of 7492 postmenopausal women with osteoporosis, significantly reducing the incidence of new vertebral fractures compared with placebo [26]. BZA was also associated with a significant reduction in the risk of nonvertebral fractures compared with placebo in a subgroup of women with a higher fracture risk (femoral neck BMD T-score ≤ −3.0 and/or ≥1 moderate or severe vertebral fracture) [26]. A post hoc analysis from this phase 3 treatment study assessed the efficacy of BZA for preventing fractures as a function of FRAX® -based fracture risk [18]. Ten-year fracture probabilities were evaluated by FRAX® using patient demographic and baseline clinical data, including femoral neck BMD [18]. BZA (20 and 40 mg daily combined) was associated with a significant 39% decrease in incident morphometric vertebral fractures compared with placebo (hazard ratio [HR], 0.61; 95% CI, 0.43–0.86; p = 0.005) and a 16% decrease in all clinical fractures compared with placebo, but the difference failed to reach statistical significance (HR, 0.84; 95% CI, 0.67–1.06; p = 0.14). HRs for BZA compared with placebo for both morphometric vertebral and all clinical fractures decreased with increasing baseline FRAX® -based 10-year probability of a major osteoporotic fracture (Fig. 1 and Table 1), although the interactions failed to reach statistical significance [18]. Of note, BZA treatment was associated with significant decreases in risk of morphometric vertebral and all clinical fractures for patients with 10-year major osteoporotic fracture probabilities at or above 6.9% and 16%, respectively (equivalent to the 41st and 80th percentile of the distribution of the study population, respectively) [18].
Please cite this article in press as: Silverman SL, et al. Use of FRAX® -based fracture risk assessments to identify patients who will benefit from osteoporosis therapy. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.07.007
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Table 1 Interaction between osteoporosis treatments and FRAX® -based 10-year probability of a major osteoporotic fracture calculated with femoral neck BMD. Drug
Bazedoxifene BZA 20/40 mg vs placebog [18]
Percentile
10th 25th 50th 75th 90th
BZA 20/40 mg vs placebo [24]
Raloxifene RLX 60 mg vs placebo [24]
RLX 60/120 mg vs placeboh [20]
10th 25th 50th 75th 90th
Alendronate Alendronate vs placebo [19] Clodronate Clodronate vs placebo [22] Denosumab Denosumab vs placebo [23] Strontium ranelate Strontium ranelate vs placebo [21]
Probability (%)
All clinical fractures
Morphometric vertebral fractures
Nonvertebral fractures
HR
95% CI
HR
95% CI
HR
95% CI
2.8 4.5 8.2–8.3 14.0–14.5 21.7–22.4 ≥5.0 ≥10.0 ≥15.0 ≥20.0
1.02 0.98 0.91 0.80 0.68 0.756 0.711 0.654 0.395
0.74–1.40 0.73–1.32 0.71–1.17 0.63–1.02 0.49–0.93 0.582–0.983 0.506–0.999 0.432–0.991 0.223–0.701
0.73 0.71 0.65 0.58 0.49 0.524 0.459 0.469 0.244
0.45–1.18 0.45–1.10 0.45–0.95 0.41–0.82 0.31–0.79 0.357–0.769 0.285–0.738 0.254–0.865 0.097–0.611
NR NR NR NR NR 0.771 0.722 0.673 0.447
NR NR NR NR NR 0.584–1.018 0.499–1.044 0.427–1.061 0.244–0.819
≥5.0 ≥10.0 ≥15.0 ≥20.0 8.4 13.3 21.1 30.3 40.1
0.963 1.063 0.746 0.697 0.74 0.76 0.80 0.84 0.90
0.720–1.288 0.738–1.530 0.463–1.200 0.387–1.255 0.59–0.92 0.63–0.91 0.69–0.92 0.72–0.99 0.72–1.12
0.570 0.581 0.595 0.458 0.48 0.50 0.54 0.59 0.64
0.361–0.899 0.338–0.999 0.298–1.187 0.183–1.149 0.35–0.64 0.39–0.64 0.44–0.65 0.49–0.70 0.51–0.81
0.945 1.075 0.755 0.700 NR NR NR NR NR
0.692–1.289 0.723–1.598 0.447–1.274 0.369–1.326 NR NR NR NR NR
≥20
ARTICLE IN PRESS Maturitas xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Use of FRAX® -based fracture risk assessments to identify patients who will benefit from osteoporosis therapy Stuart L. Silverman a,∗ , Barry S. Komm b,1 , Sebastian Mirkin c,2 a b c
Cedars-Sinai Medical Center and University of California, Los Angeles, CA, USA Pfizer Inc., Collegeville, PA, USA Therapeutics MD, Boca Raton, FL, USA
a r t i c l e
i n f o
Article history: Received 28 May 2014 Accepted 8 July 2014 Available online xxx Keywords: FRAX Fracture Osteoporosis Bazedoxifene Selective estrogen receptor modulator (SERM) Bisphosphonates
a b s t r a c t Several pharmacological interventions, including selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, and strontium ranelate have demonstrated efficacy in reducing the incidence of osteoporotic fractures, the most severe consequence of postmenopausal osteoporosis. Until recently, bone mineral density (BMD) was the primary factor used to determine which postmenopausal women may require osteoporosis treatment. However, clinical guidelines now recommend the use of the Fracture Risk Assessment Tool (FRAX® ), a computer-based algorithm introduced by the World Health Organization, to help primary care physicians identify postmenopausal women who may be candidates for pharmacological osteoporosis therapy based on the level of fracture risk. Beyond its utility as a resource for determining whether or not to initiate osteoporosis treatment, clinical studies have begun to evaluate the correlation between FRAX® -based 10-year fracture probability and efficacy of different osteoporosis treatments. Bazedoxifene, clodronate, and denosumab have shown greater fracture risk reduction at higher FRAX® -based 10-year fracture probabilities, but the efficacy of raloxifene, alendronate, and strontium ranelate were relatively stable regardless of fracture probability. In summary, these data suggest that the relationship between FRAX® -based fracture probability and efficacy of different osteoporosis treatments varies depending upon the agent in question. © 2014 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uses of FRAX® in clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The efficacy of osteoporosis treatments By FRAX® -based fracture risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Selective estrogen receptor modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Bazedoxifene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Raloxifene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Alendronate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Clodronate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. RANK ligand inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.1. Denosumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
00 00 00 00 00 00 00 00 00 00 00
Abbreviations: BMD, bone mineral density; BZA, bazedoxifene; FRAX, Fracture Risk Assessment Tool; RLX, raloxifene; SERMs, selective estrogen receptor modulators. ∗ Corresponding author at: 8641 Wilshire Boulevard, Suite 301, Beverly Hills, CA 90211, USA. Tel.: +1 310 358 2234; fax: +1 310 659 2841. E-mail addresses: [email protected] (S.L. Silverman), Barry.Komm@pfizer.com (B.S. Komm), [email protected] (S. Mirkin). 1 Pfizer Inc., 500 Arcola Road, Collegeville, PA 19426, USA. 2 Formerly with Pfizer. Current address: 6800 Broken Sound Parkway NW, 3rd Floor, Boca Raton, FL 33487, USA http://dx.doi.org/10.1016/j.maturitas.2014.07.007 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Silverman SL, et al. Use of FRAX® -based fracture risk assessments to identify patients who will benefit from osteoporosis therapy. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.07.007
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3.4.
4.
Elemental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Strontium ranelate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The burden of osteoporosis is substantial, affecting more than 8 million women over the age of 50 in the United States [1] and from 40% to 90% of women over the age of 50 in Europe, with prevalence increasing with age [2]. Fractures represent the most severe consequence of osteoporosis and are associated with functional impairment, reduced quality of life, and increased mortality [3–5]. Pharmacological interventions, including selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, teriparatide, and strontium ranelate, have been shown to reduce the incidence of osteoporotic fractures [6] and are recommended for the treatment of postmenopausal women with osteoporosis [7]. Until recently, the identification of candidates for osteoporosis treatment represented a significant challenge. Bone mineral density (BMD) was considered to be the primary criterion for identifying individuals at an increased risk for osteoporotic fracture, but BMD measures alone provide an incomplete view of fracture risk [8,9]. Additional clinical risk factors need to be considered for assessing osteoporotic fracture risk [9]. The Fracture Risk Assessment Tool (FRAX® ), which was introduced by the World Health Organization in 2008, is a computer-based algorithm (http://www.shef.ac.uk/FRAX) that uses key clinical factors to calculate the 10-year probability of hip fracture and major osteoporotic fracture (wrist, humerus, hip, or clinical vertebral fracture) [10–13]. This tool was originally developed for use by primary care physicians to help identify patients at risk of fracture who would benefit from osteoporosis treatment [13,14]. FRAX® models are country-specific and incorporate age, sex, body mass index, and 7 dichotomized risk variables (prior fragility fracture, parental history of hip fracture, tobacco use, consumption of ≥3 units of alcohol daily, long-term oral glucocorticoid use, rheumatoid arthritis, and other causes of secondary osteoporosis), with or without femoral neck BMD [11,12]. Intervention thresholds may be determined using FRAX® score alone, or a combination of FRAX® score and economic modeling data [14,15]. FRAX® is becoming more widely accepted for use in treatment decisions and as a post hoc method of evaluating clinical trial data [11]. This article describes the current use of FRAX® in clinical practice and reviews the association between FRAX® -based fracture risk assessments and anti-fracture efficacy of current and emerging osteoporosis treatments. 2. Uses of FRAX® in clinical practice In recent clinical guidelines, FRAX® has been recommended to assist in the identification of patients who are candidates for pharmacological osteoporosis therapy [7,15]. For example, the National Osteoporosis Foundation recommends treatment for postmenopausal women at least 50 years of age with a low bone mass (T-score between −1.0 and −2.5) who have a FRAX® -based 10-year hip fracture risk ≥3% or a FRAX® -based 10-year major osteoporotic fracture risk ≥20% [15]. However, the use of FRAX® is context-specific. It is currently recommended only to assist with the decision to initiate pharmacological treatment [7,15] and may
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be used to identify patients who would benefit from BMD testing [16]. FRAX® is not indicated for patients who are already receiving osteoporosis therapy or for those in whom treatment is clearly required [12]. Nevertheless, new evidence suggests that FRAX® may predict fracture risk even for patients currently receiving osteoporosis therapy [17]. FRAX® -predicted fracture rates correlated with the observed incidence of major osteoporotic fractures in both untreated patients and in women who were adherent to osteoporosis treatment, indicating that FRAX® could potentially evaluate the need for continued treatment [17]. However, FRAX® cannot be used to monitor decreases in fracture risk over time, as the BMD changes as a result of therapy represent only a small proportion of factors that make up FRAX® . Beyond assisting clinicians with the decision to initiate osteoporosis treatment, FRAX® has been applied to the efficacy evaluations of several osteoporosis treatments according to individual fracture risk [18–23] (Table 1). 3. The efficacy of osteoporosis treatments By FRAX® -based fracture risk 3.1. Selective estrogen receptor modulators 3.1.1. Bazedoxifene Bazedoxifene (BZA) is a novel SERM that is currently in development for the prevention and treatment of postmenopausal osteoporosis [25]. BZA has been shown to reduce the risk of fractures in a phase 3 study of 7492 postmenopausal women with osteoporosis, significantly reducing the incidence of new vertebral fractures compared with placebo [26]. BZA was also associated with a significant reduction in the risk of nonvertebral fractures compared with placebo in a subgroup of women with a higher fracture risk (femoral neck BMD T-score ≤ −3.0 and/or ≥1 moderate or severe vertebral fracture) [26]. A post hoc analysis from this phase 3 treatment study assessed the efficacy of BZA for preventing fractures as a function of FRAX® -based fracture risk [18]. Ten-year fracture probabilities were evaluated by FRAX® using patient demographic and baseline clinical data, including femoral neck BMD [18]. BZA (20 and 40 mg daily combined) was associated with a significant 39% decrease in incident morphometric vertebral fractures compared with placebo (hazard ratio [HR], 0.61; 95% CI, 0.43–0.86; p = 0.005) and a 16% decrease in all clinical fractures compared with placebo, but the difference failed to reach statistical significance (HR, 0.84; 95% CI, 0.67–1.06; p = 0.14). HRs for BZA compared with placebo for both morphometric vertebral and all clinical fractures decreased with increasing baseline FRAX® -based 10-year probability of a major osteoporotic fracture (Fig. 1 and Table 1), although the interactions failed to reach statistical significance [18]. Of note, BZA treatment was associated with significant decreases in risk of morphometric vertebral and all clinical fractures for patients with 10-year major osteoporotic fracture probabilities at or above 6.9% and 16%, respectively (equivalent to the 41st and 80th percentile of the distribution of the study population, respectively) [18].
Please cite this article in press as: Silverman SL, et al. Use of FRAX® -based fracture risk assessments to identify patients who will benefit from osteoporosis therapy. Maturitas (2014), http://dx.doi.org/10.1016/j.maturitas.2014.07.007
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Table 1 Interaction between osteoporosis treatments and FRAX® -based 10-year probability of a major osteoporotic fracture calculated with femoral neck BMD. Drug
Bazedoxifene BZA 20/40 mg vs placebog [18]
Percentile
10th 25th 50th 75th 90th
BZA 20/40 mg vs placebo [24]
Raloxifene RLX 60 mg vs placebo [24]
RLX 60/120 mg vs placeboh [20]
10th 25th 50th 75th 90th
Alendronate Alendronate vs placebo [19] Clodronate Clodronate vs placebo [22] Denosumab Denosumab vs placebo [23] Strontium ranelate Strontium ranelate vs placebo [21]
Probability (%)
All clinical fractures
Morphometric vertebral fractures
Nonvertebral fractures
HR
95% CI
HR
95% CI
HR
95% CI
2.8 4.5 8.2–8.3 14.0–14.5 21.7–22.4 ≥5.0 ≥10.0 ≥15.0 ≥20.0
1.02 0.98 0.91 0.80 0.68 0.756 0.711 0.654 0.395
0.74–1.40 0.73–1.32 0.71–1.17 0.63–1.02 0.49–0.93 0.582–0.983 0.506–0.999 0.432–0.991 0.223–0.701
0.73 0.71 0.65 0.58 0.49 0.524 0.459 0.469 0.244
0.45–1.18 0.45–1.10 0.45–0.95 0.41–0.82 0.31–0.79 0.357–0.769 0.285–0.738 0.254–0.865 0.097–0.611
NR NR NR NR NR 0.771 0.722 0.673 0.447
NR NR NR NR NR 0.584–1.018 0.499–1.044 0.427–1.061 0.244–0.819
≥5.0 ≥10.0 ≥15.0 ≥20.0 8.4 13.3 21.1 30.3 40.1
0.963 1.063 0.746 0.697 0.74 0.76 0.80 0.84 0.90
0.720–1.288 0.738–1.530 0.463–1.200 0.387–1.255 0.59–0.92 0.63–0.91 0.69–0.92 0.72–0.99 0.72–1.12
0.570 0.581 0.595 0.458 0.48 0.50 0.54 0.59 0.64
0.361–0.899 0.338–0.999 0.298–1.187 0.183–1.149 0.35–0.64 0.39–0.64 0.44–0.65 0.49–0.70 0.51–0.81
0.945 1.075 0.755 0.700 NR NR NR NR NR
0.692–1.289 0.723–1.598 0.447–1.274 0.369–1.326 NR NR NR NR NR
≥20
