The Use of Bisphosphonates in the Treatment of Osteoporosis
The Use of Bisphosphonates in the Treatment of Osteoporosis
Purpose of Review: The bisphosphonates alendronate and risedronate, given orally once weekly, are the cornerstone of treatment of postmenopausal osteoporosis, as well as of male and secondary osteoporosis. They reduce significantly the risk of vertebral and nonvertebral fractures; their effects appear early, within 6-12 months, and appear to be sustained. Several questions remain unanswered, however. In addition, data on a new bisphosphonate became available in 2004.
Recent Findings: The optimal duration of treatment has not been clearly established. Long-term data with alendronate are now available, indicating a persistence of alendronate effects on bone mineral density and bone turnover markers several years after stopping treatment given for 5 years. Whether these effects translate into sustained reduction of fractures needs to be further analyzed. Because of their efficacy, bisphosphonate use has been explored in other forms of osteoporosis, such as after androgen deprivation therapy for prostatic cancer. The challenge of long-term compliance with treatment of osteoporosis has triggered the use of intermittent bisphosphonate. The effects of intermittent oral and intravenous ibandronate on bone mineral density, bone turnover, and fractures have been recently reported.
Summary: The mechanism by which bisphosphonates improve bone strength is not yet fully understood but probably involves complex effects on different components of bone strength, such as microarchitecture.
Among various treatments used in the management of postmenopausal osteoporosis, the two bisphosphonates alendronate and risedronate, available worldwide, play a prominent role. Both have been shown to reduce the risk of vertebral fracture by approximately 50% and to reduce the risk of nonvertebral fracture, including the hip, by 20-50% according to patient characteristics. The efficacy of these two bisphosphonates on bone mineral density (BMD) at the spine and hip as well as on biochemical markers of bone turnover has been shown consistently in postmenopausal women across various ages and severity of the disease. A pooled analysis of data from three randomized double-blind, placebo-controlled, 3-year fracture-endpoint trials performed over 3 years was done to determine the efficacy of risedronate in reducing vertebral fracture risk in women aged 80 and older, with osteoporosis. After 1 year, the risk of new vertebral fractures in the risedronate group was 80% lower than with placebo (P < 0.01) and the reduction was 44% after 3 years (P = 0.003). The incidence of nonvertebral fractures was slightly but not significantly reduced with risedronate, probably because of limited statistical power. Importantly, the safety profile was comparable to that of placebo, although patient age ranged from 80-98 years. Most antiresorptive therapy reduced the risk of fracture within 1 year. This is also true with bisphosphonates. In 2442 postmenopausal osteoporotic women from two pooled trials, risedronate was found to reduce significantly the risk of clinical vertebral fractures within 6 months. In a post-hoc analysis of women with osteoporosis women with and without vertebral fractures who had low BMD (lumbar spine T-score <-2.5) taken from four randomized placebo-controlled trials, risedronate was found to reduce significantly the risk of major nonvertebral fractures by 6-12 months.
The convenience of bisphosphonate dosing has been markedly improved by the once-weekly regimen, as compared with daily dosing. As previously shown for alendronate, the equivalence of risedronate 35 mg once a week vs 5 mg daily over 2 years has been recently shown, with similar increase in BMD at the spine and hip and similar reduction in bone turnover markers, without safety issues. An important step in obtaining acceptance and full reimbursement of the bisphosphonates is to demonstrate their cost effectiveness in the management of osteoporosis. A health economic study performed in Sweden has shown that alendronate is, indeed, cost effective for treating women with osteoporosis as defined by prevalent vertebral fractures or a low BMD (T-score <-2.5) regardless of age. Using a similar Markov model that was adapted to fit a cohort of Swedish men, and assuming a similar fracture risk reduction in men as compared with women over 10 years for a treatment duration period of 5 years, the same group concluded that treating a 71-year-old man with osteoporosis (prior vertebral fracture and low BMD) was cost effective, i.e., associated with the cost of 14 843 Euros per quality-adjusted life year gained. Using a similar model, risedronate was found to be cost effective in the United Kingdom in elderly women with osteoporosis and low BMD. Treatment was cost effective in women from age 65 years with and without a previous vertebral fracture, as well as in women whose BMD T-score was at the threshold of osteoporosis and who also had an additional risk factor for fracture (e.g., smoking, oral glucocorticoid use). Thus, bisphosphonates appear as a first-line treatment of both men and postmenopausal women with osteoporosis.
Abstract
Purpose of Review: The bisphosphonates alendronate and risedronate, given orally once weekly, are the cornerstone of treatment of postmenopausal osteoporosis, as well as of male and secondary osteoporosis. They reduce significantly the risk of vertebral and nonvertebral fractures; their effects appear early, within 6-12 months, and appear to be sustained. Several questions remain unanswered, however. In addition, data on a new bisphosphonate became available in 2004.
Recent Findings: The optimal duration of treatment has not been clearly established. Long-term data with alendronate are now available, indicating a persistence of alendronate effects on bone mineral density and bone turnover markers several years after stopping treatment given for 5 years. Whether these effects translate into sustained reduction of fractures needs to be further analyzed. Because of their efficacy, bisphosphonate use has been explored in other forms of osteoporosis, such as after androgen deprivation therapy for prostatic cancer. The challenge of long-term compliance with treatment of osteoporosis has triggered the use of intermittent bisphosphonate. The effects of intermittent oral and intravenous ibandronate on bone mineral density, bone turnover, and fractures have been recently reported.
Summary: The mechanism by which bisphosphonates improve bone strength is not yet fully understood but probably involves complex effects on different components of bone strength, such as microarchitecture.
Introduction
Among various treatments used in the management of postmenopausal osteoporosis, the two bisphosphonates alendronate and risedronate, available worldwide, play a prominent role. Both have been shown to reduce the risk of vertebral fracture by approximately 50% and to reduce the risk of nonvertebral fracture, including the hip, by 20-50% according to patient characteristics. The efficacy of these two bisphosphonates on bone mineral density (BMD) at the spine and hip as well as on biochemical markers of bone turnover has been shown consistently in postmenopausal women across various ages and severity of the disease. A pooled analysis of data from three randomized double-blind, placebo-controlled, 3-year fracture-endpoint trials performed over 3 years was done to determine the efficacy of risedronate in reducing vertebral fracture risk in women aged 80 and older, with osteoporosis. After 1 year, the risk of new vertebral fractures in the risedronate group was 80% lower than with placebo (P < 0.01) and the reduction was 44% after 3 years (P = 0.003). The incidence of nonvertebral fractures was slightly but not significantly reduced with risedronate, probably because of limited statistical power. Importantly, the safety profile was comparable to that of placebo, although patient age ranged from 80-98 years. Most antiresorptive therapy reduced the risk of fracture within 1 year. This is also true with bisphosphonates. In 2442 postmenopausal osteoporotic women from two pooled trials, risedronate was found to reduce significantly the risk of clinical vertebral fractures within 6 months. In a post-hoc analysis of women with osteoporosis women with and without vertebral fractures who had low BMD (lumbar spine T-score <-2.5) taken from four randomized placebo-controlled trials, risedronate was found to reduce significantly the risk of major nonvertebral fractures by 6-12 months.
The convenience of bisphosphonate dosing has been markedly improved by the once-weekly regimen, as compared with daily dosing. As previously shown for alendronate, the equivalence of risedronate 35 mg once a week vs 5 mg daily over 2 years has been recently shown, with similar increase in BMD at the spine and hip and similar reduction in bone turnover markers, without safety issues. An important step in obtaining acceptance and full reimbursement of the bisphosphonates is to demonstrate their cost effectiveness in the management of osteoporosis. A health economic study performed in Sweden has shown that alendronate is, indeed, cost effective for treating women with osteoporosis as defined by prevalent vertebral fractures or a low BMD (T-score <-2.5) regardless of age. Using a similar Markov model that was adapted to fit a cohort of Swedish men, and assuming a similar fracture risk reduction in men as compared with women over 10 years for a treatment duration period of 5 years, the same group concluded that treating a 71-year-old man with osteoporosis (prior vertebral fracture and low BMD) was cost effective, i.e., associated with the cost of 14 843 Euros per quality-adjusted life year gained. Using a similar model, risedronate was found to be cost effective in the United Kingdom in elderly women with osteoporosis and low BMD. Treatment was cost effective in women from age 65 years with and without a previous vertebral fracture, as well as in women whose BMD T-score was at the threshold of osteoporosis and who also had an additional risk factor for fracture (e.g., smoking, oral glucocorticoid use). Thus, bisphosphonates appear as a first-line treatment of both men and postmenopausal women with osteoporosis.
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