Abstract
Fragility fractures are a significant, independent risk factor for new fractures, but treatment uptake in subjects with prevalent fractures is disappointing. We addressed the question of the efficacy of pharmacological interventions in reducing the risk of incident fractures in patients with prevalent fragility fractures. For this, we reviewed randomised controlled trials (RCTs), pre-planned and post-hoc analyses of RCTs of approved agents for the treatment of osteoporosis. Results showed that a number of agents decrease the risk of incident vertebral and nonvertebral fractures in subjects with prevalent vertebral fractures, justifying the recommendation of treating such patients independently of the level of bone mineral density (BMD). By contrast, the evidence of antifracture efficacy of these agents in patients with prevalent nonvertebral fractures is limited. Advances in our understanding of the regulation of bone metabolism at the molecular level have identified targets for the development of new therapeutics for osteoporosis, some of which are currently in phase 3 clinical development.
Introduction
Osteoporotic fractures are common, their incidence increases with age and causes significant morbidity, deterioration of the quality of life and increased mortality . Furthermore, the presence of a fragility fracture significantly increases the risk of new fractures as demonstrated in numerous observational and prospective studies and has been included as an independent risk factor in the calculation of the Fracture Risk Assessment Tool (FRAX) algorithm . Despite the compelling evidence of the importance of prevalent fractures for future fracture risk, initiation of treatment of patients with prevalent fractures, even those with hip fractures, has been disappointingly low .
For these reasons, worldwide campaigns, such as the International Osteoporosis Foundation (IOF)’s ‘Capture the fracture’ and the American Society for Bone and Mineral Research (ASBMR)’s ‘Making the first fracture the last’, were initiated . The proposed establishment of Fracture Liaison Services (FLS) has improved the identification and treatment of patients at risk for a new fracture, demonstrating also that this is a cost-effective approach . Unfortunately, such services are not widely available. The question that arises is whether currently available management strategies can reliably reduce the risk of new fractures in patients who have already sustained a fragility fracture. In the present chapter, we address this question by reviewing the evidence of the efficacy of pharmacological interventions in patients with prevalent factures.
Management
The care of patients with fractures includes general measures, non-pharmacological interventions that aim mainly at reducing the frequency and impact of falls and pharmacological interventions. Of the general measures, the most important is the correction of deficiencies or insufficiencies of vitamin D and calcium. It has been repeatedly shown that patients with fractures, particularly hip fractures, have low serum 25-hydroxyvitamin D (25-OHD) concentrations . While the exact concentration of serum 25-OHD that defines vitamin D adequacy is debated, concentrations above 50 nmol/l (20 ng/ml) are essential and sufficient for bone health, and vitamin D supplementation with 800 IU/d should be the first step in the management of patients with fragility fractures . Adjustment of the daily calcium intake to 1200 mg (diet and supplements) is also recommended. Patients included in prospective clinical trials of anti-osteoporotic treatments with fracture endpoints usually receive vitamin D and calcium supplements, and any effects of pharmacological interventions on fracture prevention are above those that can be obtained by vitamin D and calcium alone. In addition, the evidence of efficacy of most pharmacological interventions has been obtained from studies of concurrent administration of the agent with vitamin D, and it has been reported that such co-administration is more effective in increasing BMD than administration of the agent alone . A daily intake of protein 1 g/kg body weight is also recommended, particularly in elderly individuals with a recent hip fracture, and it should also be part of the management strategy .
The pathophysiological basis of osteoporosis provides the rationale for the development and use of pharmacological interventions. In brief, in osteoporosis, there is an imbalance between bone resorption and bone formation (resorption > formation), leading to increased bone loss and deterioration of the architecture of cancellous and cortical bones. When this negative balance is accompanied by an increase in the rate of activation of new bone remodelling units (high bone turnover), as this generally occurs after menopause, the changes in bone mass and architecture are amplified . There is an increase in the number and depth of resorption cavities, perforation of trabecular plates and loss of trabecular elements of cancellous bone and thinning and porosity of cortical bone . In addition, the degree of mineralisation of the bone matrix and the amount of collagen decrease, and the maturation and cross-linking of collagen may also be impaired . Thus, structure, material composition and bone mass can all be affected and contribute to compromised bone strength. These pathophysiological considerations form the basis of treatments for osteoporosis, which have been aimed mainly at correcting the imbalance between bone resorption and bone formation and, thereby, preserving skeletal integrity and reducing the risk of fractures by different mechanisms of action. Consequently, pharmacological interventions are distinguished into those that decrease bone resorption and turnover, those that stimulate bone formation and those that do not have a clear effect on bone remodelling ( Table 1 ). All these agents have been shown in randomised clinical trials to reduce the incidence of fractures in women with osteoporosis with variable efficacy and favourable safety profile, particularly those that also reduce the risk of hip fractures . However, based on risk/benefit analysis, intranasal calcitonin and tibolone are no longer considered in the treatment of postmenopausal osteoporosis, while hormone therapy is not a first treatment option anymore. These agents are, therefore, not included in our analysis. In addition, the use and prescription of strontium ranelate have been restricted by the European Regulatory Authority to patients with severe osteoporosis at high risk of fractures and to physicians experienced in the treatment of osteoporosis, respectively .
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Selection of patients for inclusion in randomised controlled trials (RCTs) of the efficacy of treatments on the incidence of fractures is generally based on the level of BMD in patients with or without vertebral fractures. In only one clinical trial, patients were selected on the basis of a prevalent nonvertebral fracture (hip) and no BMD criteria . Therefore, in order to address the question formulated in the Introduction, we searched the literature for additional pre-planned or post-hoc analyses of RCTs of the efficacy of interventions in patients with prevalent vertebral or nonvertebral fractures. The evidence provided by post-hoc analyses is weaker than that of RCTs and pre-planned analyses of RCTs and should be considered exploratory rather than confirmatory. We performed a Medline, Cochrane and EMBASE search using the keywords bisphosphonates, alendronate, clodronate, minodronate, pamidronate, risedronate, zoledronic acid, SERMs, denosumab (DMAb), teriparatide, parathyroid hormone, strontium ranelate, fractures, osteoporosis. We restricted our search to randomised trials. In the following paragraphs, we review the results of the efficacy of these agents in reducing the risk of new fractures in patients with prevalent fragility fractures.
Management
The care of patients with fractures includes general measures, non-pharmacological interventions that aim mainly at reducing the frequency and impact of falls and pharmacological interventions. Of the general measures, the most important is the correction of deficiencies or insufficiencies of vitamin D and calcium. It has been repeatedly shown that patients with fractures, particularly hip fractures, have low serum 25-hydroxyvitamin D (25-OHD) concentrations . While the exact concentration of serum 25-OHD that defines vitamin D adequacy is debated, concentrations above 50 nmol/l (20 ng/ml) are essential and sufficient for bone health, and vitamin D supplementation with 800 IU/d should be the first step in the management of patients with fragility fractures . Adjustment of the daily calcium intake to 1200 mg (diet and supplements) is also recommended. Patients included in prospective clinical trials of anti-osteoporotic treatments with fracture endpoints usually receive vitamin D and calcium supplements, and any effects of pharmacological interventions on fracture prevention are above those that can be obtained by vitamin D and calcium alone. In addition, the evidence of efficacy of most pharmacological interventions has been obtained from studies of concurrent administration of the agent with vitamin D, and it has been reported that such co-administration is more effective in increasing BMD than administration of the agent alone . A daily intake of protein 1 g/kg body weight is also recommended, particularly in elderly individuals with a recent hip fracture, and it should also be part of the management strategy .
The pathophysiological basis of osteoporosis provides the rationale for the development and use of pharmacological interventions. In brief, in osteoporosis, there is an imbalance between bone resorption and bone formation (resorption > formation), leading to increased bone loss and deterioration of the architecture of cancellous and cortical bones. When this negative balance is accompanied by an increase in the rate of activation of new bone remodelling units (high bone turnover), as this generally occurs after menopause, the changes in bone mass and architecture are amplified . There is an increase in the number and depth of resorption cavities, perforation of trabecular plates and loss of trabecular elements of cancellous bone and thinning and porosity of cortical bone . In addition, the degree of mineralisation of the bone matrix and the amount of collagen decrease, and the maturation and cross-linking of collagen may also be impaired . Thus, structure, material composition and bone mass can all be affected and contribute to compromised bone strength. These pathophysiological considerations form the basis of treatments for osteoporosis, which have been aimed mainly at correcting the imbalance between bone resorption and bone formation and, thereby, preserving skeletal integrity and reducing the risk of fractures by different mechanisms of action. Consequently, pharmacological interventions are distinguished into those that decrease bone resorption and turnover, those that stimulate bone formation and those that do not have a clear effect on bone remodelling ( Table 1 ). All these agents have been shown in randomised clinical trials to reduce the incidence of fractures in women with osteoporosis with variable efficacy and favourable safety profile, particularly those that also reduce the risk of hip fractures . However, based on risk/benefit analysis, intranasal calcitonin and tibolone are no longer considered in the treatment of postmenopausal osteoporosis, while hormone therapy is not a first treatment option anymore. These agents are, therefore, not included in our analysis. In addition, the use and prescription of strontium ranelate have been restricted by the European Regulatory Authority to patients with severe osteoporosis at high risk of fractures and to physicians experienced in the treatment of osteoporosis, respectively .
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Selection of patients for inclusion in randomised controlled trials (RCTs) of the efficacy of treatments on the incidence of fractures is generally based on the level of BMD in patients with or without vertebral fractures. In only one clinical trial, patients were selected on the basis of a prevalent nonvertebral fracture (hip) and no BMD criteria . Therefore, in order to address the question formulated in the Introduction, we searched the literature for additional pre-planned or post-hoc analyses of RCTs of the efficacy of interventions in patients with prevalent vertebral or nonvertebral fractures. The evidence provided by post-hoc analyses is weaker than that of RCTs and pre-planned analyses of RCTs and should be considered exploratory rather than confirmatory. We performed a Medline, Cochrane and EMBASE search using the keywords bisphosphonates, alendronate, clodronate, minodronate, pamidronate, risedronate, zoledronic acid, SERMs, denosumab (DMAb), teriparatide, parathyroid hormone, strontium ranelate, fractures, osteoporosis. We restricted our search to randomised trials. In the following paragraphs, we review the results of the efficacy of these agents in reducing the risk of new fractures in patients with prevalent fragility fractures.
Bisphosphonates
Bisphosphonates are the most frequently used pharmacological interventions in the treatment of osteoporosis. These compounds have a beneficial effect on bone strength by decreasing the rate of bone remodelling, maintaining or improving trabecular and cortical architecture and by increasing bone mineral density . The primary pharmacological action of bisphosphonates is the reduction of bone resorption. Because of the coupling of bone resorption with bone formation, the latter will also decrease with bisphosphonate treatment. This occurs, however, at a slower rate, so that 3–6 months after the start of treatment, a new steady state between bone resorption and bone formation is achieved at a lower rate of bone turnover, which is kept constant during the whole duration of treatment, as shown in clinical trials up to 10 years .
Alendronate
The efficacy of alendronate in reducing the risk of fractures was examined in the Fracture Intervention Trial (FIT). Postmenopausal women with femoral BMD t -score <−1.6 and at least one prevalent vertebral fracture were assigned to placebo ( n = 1005) or alendronate ( n = 1022) for 3 years . The dose of alendronate was initially 5 mg/d and was increased to 10 mg/d after 2 years because other studies suggested that this dose had greater effects than 5 mg on BMD and bone markers with similar tolerability. Spine radiographs were obtained after 2 and 3 years. Alendronate reduced the incidence of new vertebral fractures by 47% (relative hazard (RH) 0.53; 95% confidence interval (CI) 0.41–0.68), of any clinical fracture by 28% (RH 0.72; 95% CI 0.58–0.90) and of nonvertebral fractures by 20% (RH 0.80; 95% CI 0.63–1.01), a non-significant reduction. However, alendronate reduced significantly the risk of hip fractures by 51% (RH 0.49; 95% CI 0.23–0.99) and those of the wrist by 48% (RH 0.52; 95% CI 0.31–0.87). In this, as well in other RCTs with alendronate, no specific subgroup analysis of the efficacy of this bisphosphonate in patients with a history of nonvertebral fractures has been reported.
Ibandronate
The iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) examined the efficacy of ibandronate on the risk of vertebral fractures in women with lumbar spine BMD t -score <−2.0 in at least one vertebra (L1–L4) and one to four prevalent vertebral fractures . Patients were randomised to placebo ( n = 975) or ibandronate 2.5 mg/d ( n = 977) for 3 years. A third group ( n = 977) received ibandronate intermittently (20 mg every other day for 12 doses every 3 months). Spine radiographs were taken annually. Compared to placebo, both daily and intermittent ibandronate reduced significantly the risk of new vertebral fractures by 62% (relative risk (RR) 95% CI 41–75) and 50% (RR 95% CI 26–66), respectively, after 3 years. In the BONE study, daily and intermittent ibandronate had no significant effect on the risk of nonvertebral fractures. Post-hoc analysis showed that daily ibandronate reduced significantly the incidence of nonvertebral fractures in a high-risk population (femoral neck BMD < −3.0) by 69%. The 2.5 mg daily dose of ibandronate was not registered for the treatment of osteoporosis. Instead, two different dosing regimens have been approved (150 mg orally once monthly and 3 mg intravenously once in 3 months). These two regimens provide substantially higher total annual doses than the daily regimen and were reported to significantly decrease the incidence of nonvertebral fractures by 38% (hazard ratio (HR) 0.62; 95% CI 0.39–0.97), compared to the 2.5 mg daily dose, in a pooled analysis of individual patient data . We did not identify a subgroup analysis of the efficacy of ibandronate in patients with a history of nonvertebral fractures.
Risedronate
Vertebral Efficacy with Risedronate Therapy (VERT) was the pivotal trial that examined the efficacy of risedronate on the risk of vertebral fractures. In VERT North America (NA), women with two or more prevalent vertebral fractures or one prevalent vertebral fracture and low lumbar spine BMD were assigned to placebo ( n = 820) or risedronate 5 mg/d ( n = 821); in a third group that received risedronate 2.5 mg/d, treatment was discontinued after the first year because data from other trials indicated that this dose was less effective than the 5-mg dose . Spine radiographs were taken after 1, 2 and 3 years. Compared to placebo, risedronate reduced the incidence of vertebral fractures by 41% (95% CI 18–58) after 3 years. VERT Multinational (VERT-MN) included women with two or more prevalent vertebral fractures (mean 4) who were assigned to placebo ( n = 407) or risedronate 5 mg/d ( n = 407); a third group that received risedronate 2.5 mg/d was discontinued after 2 years. Risedronate reduced the risk of vertebral fractures by 49% (RR 0.51; 95% CI 0.36–0.73) after 3 years .
In the VERT-NA study, risedronate 5 mg/d reduced significantly the cumulative incidence of nonvertebral osteoporotic fractures by 39% (95% CI 6–61), while in the VERT-MN a 33% (RR 0.67; 95% CI 0.44–1.04) decrease was not statistically significant. The Hip Intervention Program (HIP) study was designed to assess the effect of risedronate on the risk of hip fractures and included 9331 patients, 5445 women 70–79 years old with osteoporosis (femoral neck BMD t -score <−4.0 or <−3.0 plus a non-skeletal risk factor for hip fracture), and 3886 women ≥80 years old with at least one non-skeletal risk factor for hip fracture or low BMD . The women were randomly assigned to receive treatment with risedronate 2.5 and 5.0 mg/d or placebo for 3 years. In this study, the combined effect of the two risedronate doses against placebo was estimated. In a post-hoc analysis of women with osteoporosis defined by BMD who had, in addition, prevalent vertebral fractures, risedronate reduced the risk of nonvertebral osteoporotic fractures by 30% (RR 0.70; 95% CI 0.5–0.9) and that of hip fractures by 60% (RR 0.40; 95% CI 0.2–0.8). We did not identify a subgroup analysis of the efficacy of risedronate in patients with a history of nonvertebral fractures.
Zoledronate
The efficacy of zoledronate in reducing the risk of osteoporotic fractures was examined in the HORIZON clinical trial . Postmenopausal women with osteoporosis (femoral neck BMD t -score ≤−2.5 with or without prevalent vertebral fractures or t -score ≤−1.5 with at least one moderate or two mild vertebral fractures) were randomised to receive a single 15-min infusion of zoledronate 5 mg ( n = 3889) or placebo ( n = 3876) at baseline, at 12 months and at 24 months. Spine radiographs were taken annually. Compared to placebo, zoledronate reduced the incidence of vertebral fractures by 70% (RR 0.30; 95% CI 0.24–0.38) and that of hip fractures by 41% (HR 0.59; 95% CI 0.42–0.83) after 3 years. The risk of nonvertebral fractures was also significantly reduced by 25% (HR 0.75; 95% CI 0.64–0.87).
In a pre-planned analysis of women with prevalent vertebral fractures included in the HORIZON clinical trial, the efficacy of zoledronate in reducing the incidence of new vertebral, nonvertebral and hip fractures was significant and similar in women with osteoporosis (BMD t -score < −2.5) and osteopenia (BMD t -score <−1.5 and >−2.5); relative risk reductions of the incidence of new vertebral fractures were 71.5% and 65.9%, respectively, of nonvertebral fractures 23.6% and 32.6%, respectively and of hip fractures 41.2% and 76%, respectively .
Particularly significant was the HORIZON – Recurrent Fracture Trial (RFT) study in which 2127 patients were randomised to receive yearly intravenous infusions of zoledronate 5 mg or placebo within 90 days of surgical repair of a hip fracture . After a median follow-up of 1.9 years, zoledronate decreased the risk of any clinical fracture by 35% (HR 0.65; 95% CI 0.50–0.84), of nonvertebral fractures by 27% (HR 0.73; 95% CI 0.55–0.98), of hip fractures by 30% (HR 0.70; 0.41–1.19) and of vertebral fractures by 46% (HR 0.54; 0.32–0.92). Importantly, only 41% of patients had a BMD t -score <−2.5; 35.3% had osteopenia, while in 11.4% BMD was normal; in 12.1% of patients, BMD data were not available. In addition, zoledronate treatment reduced significantly all-cause mortality by 28% (RR 0.72; 95% CI 0.56–0.93); this effect was unrelated to the reduction of the incidence of new fractures. Notably, epidemiological studies also reported survival benefits in patients treated with oral bisphosphonates .
Other bisphosphonates
The bisphosphonates discussed have been approved for the treatment of osteoporosis worldwide. However, RCTs of other bisphosphonates, approved in some countries, have also been performed. These include orally administered clodronate, minodronate and pamidronate which reduced significantly the incidence of incident vertebral fractures in patients with osteoporosis with prevalent vertebral fractures . In none of the studies with these bisphosphonates, results of their efficacy specifically in patients with a history of nonvertebral fractures were available.
Conclusion bisphosphonates
In patients with postmenopausal osteoporosis with prevalent vertebral fractures, and a wide range of BMD t -scores, bisphosphonates significantly decreased the incidence of new vertebral fractures ( Fig. 1 ). Particularly important were the results of the efficacy of alendronate and zoledronate in women with vertebral fractures and BMD t -scores <−1.6 and <−1.5, respectively, which justify the recommendation of guidelines to treat women with vertebral fractures independently of the level of BMD. In different studies with the same bisphosphonate (e.g., risedronate) or in the same study (zoledronate), treatment reduced the relative risk of fractures to the same extent, but induced greater reductions of the absolute risk of vertebral fractures in patients with a higher basal risk for fractures resulting in a substantially lower number needed to treat (NNT) ( Fig. 2 ). This consistent finding indicates, in addition, that bisphosphonate treatment of patients at higher fracture risk, as assessed by the presence of prevalent vertebral fractures, is more cost-effective, particularly for those bisphosphonates for which generic formulations are available. In patients with prevalent vertebral fractures, most bisphosphonates have also been shown to reduce the incidence of nonvertebral fractures including those of the hip ( Fig. 3 ). It should be mentioned, however, that the definition of nonvertebral fractures in studies with bisphosphonates as well as with other agents varied, which might have affected the outcome. From the design and report of RCTs of bisphosphonates, it has not been possible to assess their efficacy specifically in patients with a history of nonvertebral fractures, the only exception being the unique study of the efficacy of zoledronate in reducing the incidence of new fractures in women and men following the repair of a hip fracture.
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