Best Practice & Research Clinical Rheumatology 27 (2013) 805–820
Contents lists available at ScienceDirect
Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh
8
Prevention of incident fractures in patients with prevalent fragility fractures: Current and future approaches Natasha M. Appelman-Dijkstra, Socrates E. Papapoulos* Center of Bone Quality, Leiden University Medical Centre, Leiden, The Netherlands
a b s t r a c t Keywords: Fractures Osteoporosis Bisphosphonates Denosumab SERMs PTH Strontium ranelate Cathepsin K Sclerostin
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. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Osteoporotic fractures are common, their incidence increases with age and causes significant morbidity, deterioration of the quality of life and increased mortality [1]. Furthermore, the presence of
* Corresponding author. Center of Bone Quality (C7Q), Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands. Tel.: þ31 71 5262490; fax: þ31 71 5248136. E-mail address: [email protected] (S.E. Papapoulos). 1521-6942/$ – see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.berh.2014.01.010
806
N.M. Appelman-Dijkstra, S.E. Papapoulos / Best Practice & Research Clinical Rheumatology 27 (2013) 805–820
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 [2,3]. 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 [4–6]. 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 [7,8]. 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 [9]. 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 [10,11]. 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 [12]. 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 [13]. 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 [14]. 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 [15,16]. 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 [17]. 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 [15]. 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 [18,19]. However, based on risk/benefit analysis, intranasal calcitonin and tibolone are no longer considered in the treatment of postmenopausal
N.M. Appelman-Dijkstra, S.E. Papapoulos / Best Practice & Research Clinical Rheumatology 27 (2013) 805–820
807
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 [20]. 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 [21]. 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 [22]. 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 [23]. 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
Contents lists available at ScienceDirect
Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh
8
Prevention of incident fractures in patients with prevalent fragility fractures: Current and future approaches Natasha M. Appelman-Dijkstra, Socrates E. Papapoulos* Center of Bone Quality, Leiden University Medical Centre, Leiden, The Netherlands
a b s t r a c t Keywords: Fractures Osteoporosis Bisphosphonates Denosumab SERMs PTH Strontium ranelate Cathepsin K Sclerostin
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. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Osteoporotic fractures are common, their incidence increases with age and causes significant morbidity, deterioration of the quality of life and increased mortality [1]. Furthermore, the presence of
* Corresponding author. Center of Bone Quality (C7Q), Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands. Tel.: þ31 71 5262490; fax: þ31 71 5248136. E-mail address: [email protected] (S.E. Papapoulos). 1521-6942/$ – see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.berh.2014.01.010
806
N.M. Appelman-Dijkstra, S.E. Papapoulos / Best Practice & Research Clinical Rheumatology 27 (2013) 805–820
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 [2,3]. 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 [4–6]. 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 [7,8]. 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 [9]. 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 [10,11]. 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 [12]. 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 [13]. 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 [14]. 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 [15,16]. 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 [17]. 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 [15]. 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 [18,19]. However, based on risk/benefit analysis, intranasal calcitonin and tibolone are no longer considered in the treatment of postmenopausal
N.M. Appelman-Dijkstra, S.E. Papapoulos / Best Practice & Research Clinical Rheumatology 27 (2013) 805–820
807
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 [20]. 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 [21]. 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 [22]. 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 [23]. 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
