- Email: [email protected]
Risedronate prevented new vertebral and nonvertebral fractures in postmenopausal women with osteoporosis
MEN OPA U S E
Risedronate prevented new vertebral and nonvertebral fractures in postmenopausal women with osteoporosis Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 1999; 282:1344d1352
OBJECTIVE To determine the efficacy of risedronate in the prevention of vertebral and non-vertebral fractures in postmenopausal women with osteoporosis and a previous vertebral fracture. DESIGN Multicentre, randomized, triple-blind, three-arm, placebo-controlled trial. Allocation was performed using a computer-generated, blocked randomization schedule and coded medications, stratified by centre and the number of vertebral fractures. Duration of the study was 3 years. SETTING 110 centres in North America. SUBJECTS 2458 women, aged 485 (mean 69) years, who were at least 5 years postmenopause and who had osteoporosis, defined as two or more radiographically visible vertebral fractures or one fracture plus low bone mineral density (t score4!2.0). Follow-up radiographs were available for 75–85% of women. INTERVENTION 817 women were randomized to receive oral risedronate 2.5 mg daily, 821 to receive risedronate 5 mg daily, and 820 to receive placebo. All women also received calcium 1000 mg daily. MAIN OUTCOME MEASURES Incident vertebral fractures, bone mineral density, and non-vertebral fractures.
MAIN RESULTS At one year, the percentages of women with new vertebral fractures (based on survival analysis) were 6.4% with placebo, 3.8% with risedronate 2.5 mg (relative risk (RR) 0.5, 95% CI 0.3–0.9) and 2.4% with risedronate 5 mg (RR 0.4, CI 0.2–0.6). There was no significant difference between dose groups (P"0.16*), but the 2.5 mg risedronate arm was discontinued after 1 year because of evidence of low efficacy from other trials. At 3 years, the percentages of women with new vertebral fractures were 16.3% with placebo and 11.3% with risedronate 5 mg (RR 0.6, CI 0.4–0.8, number needed to treat to prevent vertebral fracture in one woman is 20*). Compared to placebo, bone mineral density in the femoral neck, femoral trochanter and lumbar spine increased, at 3 years, by 3–4% with risedronate 5 mg (P(0.05). The incidence of non-vertebral fractures was 8.4% in the placebo group and 5.2% in the risedronate 5 mg group (RR 0.6, CI 0.4–0.9). In the risedronate 5 mg and placebo groups, the withdrawal rates (40 and 45%, respectively) and the proportions of women with upper gastrointestinal tract complaints (30 and 27%, respectively) were similar. CONCLUSION Risedronate 5 mg reduced the risk of new vertebral and non-vertebral fractures and increased bone mineral density in postmenopausal women with osteoporosis and previous fractures. * Calculated from data in article.
Risedronate prevented new vertebral fractures in postmenopausal women with osteoporosis Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 2000; 11:83d91
OBJECTIVE To determine the efficacy of risedronate in the prevention of vertebral and non-vertebral fractures in postmenopausal women with osteoporosis and a previous vertebral fracture.
INTERVENTION 408 women were randomized to receive oral risedronate 2.5 mg daily, 407 to receive risedronate 5 mg daily, and 407 to receive placebo. All women also received calcium 1000 mg daily.
DESIGN Multicentre, randomized, triple-blind, three-arm, placebo-controlled trial. Allocation was performed using a computer-generated, blocked randomization schedule and coded medications, stratified by centre and the number of vertebral fractures. Duration of the study was 3 years.
MAIN OUTCOME MEASURES Incident vertebral fractures, bone mineral density, and non-vertebral fractures.
SETTING Eighty centres in Europe and Australia. SUBJECTS 1222 women, aged 485 (mean 71) years, who were at least 5 years postmenopause and who had osteoporosis, defined as two or more radiographically visible vertebral fractures. Follow-up radiographs were available for 81–85% of women. 106
Evidence-based Obstetrics and Gynecology (2000) 2, 106d107 doi:10.1054/ebog.2000.0191, available online at http://www.idealibrary.com on
MAIN RESULTS At one year, the percentages of women with new vertebral fractures (based on survival analysis) were 13.0% with placebo, 7.1% with risedronate 2.5 mg (relative risk [RR] 0.5, 95% CI 0.3–0.8) and 5.6% with risedronate 5 mg (RR 0.4, CI 0.2–0.7). There was no significant difference between dose groups (P"0.41*), but the 2.5 mg risedronate arm was discontinued after 2 years because of evidence of low efficacy from other trials. At 3 years, the percentages of women with new vertebral fractures ^ 2000 Harcourt Publishers Ltd
were 29.0% with placebo and 18.1% with risedronate 5 mg (RR 0.5, CI 0.4–0.7, number needed to treat to prevent vertebral fracture in 1 woman is 10). Compared to placebo, bone mineral density in the femoral neck, femoral trochanter and lumbar spine increased, at 3 years, by 3–6% with risedronate 5 mg (P(0.001). The incidence of non-vertebral fractures was 16.0% in the placebo group and 10.9% in the risedronate 5 mg group (RR 0.7, CI 0.4–1.0). The withdrawal rate was slightly higher in the placebo group (46%) than
in the risedronate 5 mg group (38%) and the proportions of women with upper gastrointestinal tract complaints (27 and 26%, respectively) were similar.
Commentary
Harris and Reginster studies, respectively. The investigators also examined the risk of new vertebral fractures after 1 year of risedronate therapy; compared with placebo, treatment with risedronate 5 mg/day reduced the incidence of vertebral fractures by 65 and 61%, in the two studies, respectively. No significant difference in adverse events was seen between the risedronate and placebo groups. These studies are also notable for what they tell us about osteoporotic vertebral fractures. The placebo group in the Reginster study had more advanced osteoporosis at baseline (greater number of prevalent vertebral fractures and lower lumbar spine bone mineral density) than their counterparts in the Harris study. This difference corresponded to a higher incidence of new vertebral fractures in the Reginster study (13% over 1 year and 29% over 3 years), compared with the Harris study (6.4 and 16%, respectively), a finding that emphasizes that vertebral fracture risk increases in relation to the number of existing vertebral fractures. In conclusion, these clinical trials demonstrated that oral risedronate therapy (at the recommended dose of 5 mg/day), given over 3 years, was well tolerated and reduced the incidences of both vertebral and non-vertebral fractures in women with established postmenopausal osteoporosis. Furthermore, these studies are the first to show a rapid and clinically important reduction in the incidence of vertebral fractures (both clinical and subclinical) with 1 year of therapy.
Osteoporosis is a major health concern, affecting a growing number of individuals worldwide. The disorder is characterized by low bone mass and bone fragility, resulting in an increased risk of fracture. Indeed, vertebral fractures have been synonymous with the diagnosis of osteoporosis since its earliest characterization as a metabolic bone disease. The prevention of fractures is the primary goal of osteoporosis treatment. Several antiresorptive agents have been used successfully for the treatment of postmenopausal osteoporosis, including calcium and vitamin D,1 estrogen,2 raloxifene,3 calcitonin,4 and the bisphosphonates.5d7 Bisphosphonates have become accepted as the most potent inhibitors of bone resorption available clinically and are the mainstay in the treatment of osteoporosis. The two most rigorously studied bisphosphonate therapies are alendronate5d7 and risedronate. Both drugs have been found to increase bone mineral density and reduce vertebral and non-vertebral fractures. However, there has not yet been a head-to-head comparison of the relative efficacy of these two drugs in the same patient population and it is invalid to compare their effects across studies. The two present studies were both large, 3-year, multicentred, randomized, controlled trials, that evaluated the efficacy of risedronate in the treatment of postmenopausal osteoporosis. The first study, by Harris et al, was conducted in North America and the second study, by Reginster et al, was performed in Europe and Australia. The primary purpose of the trials was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures. A total of 2458 postmenopausal women with at least two vertebral fractures (or one vertebral fracture and a lumbar spine bone mineral density t-score of !2.0 or lower) participated in the Harris study, whereas the Reginster study involved 1226 postmenopausal women who had experienced at least two osteoporotic vertebral fractures. At study entry, in both trials, vertebral fractures were determined by visual inspection of the X-ray films. The subjects were randomly assigned to treatment with placebo or risedronate 2.5 or 5 mg/day. The 2.5 mg/day group was discontinued before the completion of the studies, because of new data showing better results and a similar safety profile with the 5 mg/day dose. All women received 1000 mg/day of calcium, with a vitamin D supplement if baseline levels of the vitamin were low. Quantitative (15% loss in vertebral height) and semi-quantitative assessments were used to identify both prevalent and incident vertebral fractures for the purpose of the efficacy determination. Women were not excluded on the basis of previous or active gastrointestinal illness or because of concomitant use of aspirin or non-steroidal anti-inflammatory agents. While the dropout rates in the studies were high, the rates were no higher than what the authors had anticipated and there was no evident difference between the treatment groups in the proportion of subjects discontinuing treatment or in the reasons for withdrawal. Following 3 years of treatment, the results indicated that, when compared to placebo, risedronate 5 mg/day reduced the incidence of vertebral fractures by 41% ( P"0.003) and 49% (P(0.001) and non-vertebral fractures by 39% ( P"0.02) and 33% ( P"0.06) in the
^ 2000 Harcourt Publishers Ltd
CONCLUSION Risedronate 5 mg reduced the risk of new vertebral fractures and increased bone mineral density in postmenopausal women with osteoporosis and previous fractures. *Calculated from data in article.
George Ioannidis, MSc Alexandra Papaioannou, MD Jonathan D. Adachi, MD McMaster University, Hamilton Ontario, Canada
Literature cited 1. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327:1637d1647 2. Lufkin EG, Heinz W, Wahner W, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Int Med 1992; 117:1d9 3. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999; 282:637d645 4. Chesnut CH III, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevention of recurrence of osteoporotic fractures study. Am J Med 2000; 109:267d276 5. Black DM, Cummings SR, Karph DB, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348:1535d1541 6. Cummings SR, Black BM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA 1998; 280:2077d2082 7. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled randomized trial of the effect of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Osteoporos Int 1999; 9:461d468
Evidence-based Obstetrics and Gynecology (2000) 2, 106d107
107
Risedronate prevented new vertebral and nonvertebral fractures in postmenopausal women with osteoporosis Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 1999; 282:1344d1352
OBJECTIVE To determine the efficacy of risedronate in the prevention of vertebral and non-vertebral fractures in postmenopausal women with osteoporosis and a previous vertebral fracture. DESIGN Multicentre, randomized, triple-blind, three-arm, placebo-controlled trial. Allocation was performed using a computer-generated, blocked randomization schedule and coded medications, stratified by centre and the number of vertebral fractures. Duration of the study was 3 years. SETTING 110 centres in North America. SUBJECTS 2458 women, aged 485 (mean 69) years, who were at least 5 years postmenopause and who had osteoporosis, defined as two or more radiographically visible vertebral fractures or one fracture plus low bone mineral density (t score4!2.0). Follow-up radiographs were available for 75–85% of women. INTERVENTION 817 women were randomized to receive oral risedronate 2.5 mg daily, 821 to receive risedronate 5 mg daily, and 820 to receive placebo. All women also received calcium 1000 mg daily. MAIN OUTCOME MEASURES Incident vertebral fractures, bone mineral density, and non-vertebral fractures.
MAIN RESULTS At one year, the percentages of women with new vertebral fractures (based on survival analysis) were 6.4% with placebo, 3.8% with risedronate 2.5 mg (relative risk (RR) 0.5, 95% CI 0.3–0.9) and 2.4% with risedronate 5 mg (RR 0.4, CI 0.2–0.6). There was no significant difference between dose groups (P"0.16*), but the 2.5 mg risedronate arm was discontinued after 1 year because of evidence of low efficacy from other trials. At 3 years, the percentages of women with new vertebral fractures were 16.3% with placebo and 11.3% with risedronate 5 mg (RR 0.6, CI 0.4–0.8, number needed to treat to prevent vertebral fracture in one woman is 20*). Compared to placebo, bone mineral density in the femoral neck, femoral trochanter and lumbar spine increased, at 3 years, by 3–4% with risedronate 5 mg (P(0.05). The incidence of non-vertebral fractures was 8.4% in the placebo group and 5.2% in the risedronate 5 mg group (RR 0.6, CI 0.4–0.9). In the risedronate 5 mg and placebo groups, the withdrawal rates (40 and 45%, respectively) and the proportions of women with upper gastrointestinal tract complaints (30 and 27%, respectively) were similar. CONCLUSION Risedronate 5 mg reduced the risk of new vertebral and non-vertebral fractures and increased bone mineral density in postmenopausal women with osteoporosis and previous fractures. * Calculated from data in article.
Risedronate prevented new vertebral fractures in postmenopausal women with osteoporosis Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 2000; 11:83d91
OBJECTIVE To determine the efficacy of risedronate in the prevention of vertebral and non-vertebral fractures in postmenopausal women with osteoporosis and a previous vertebral fracture.
INTERVENTION 408 women were randomized to receive oral risedronate 2.5 mg daily, 407 to receive risedronate 5 mg daily, and 407 to receive placebo. All women also received calcium 1000 mg daily.
DESIGN Multicentre, randomized, triple-blind, three-arm, placebo-controlled trial. Allocation was performed using a computer-generated, blocked randomization schedule and coded medications, stratified by centre and the number of vertebral fractures. Duration of the study was 3 years.
MAIN OUTCOME MEASURES Incident vertebral fractures, bone mineral density, and non-vertebral fractures.
SETTING Eighty centres in Europe and Australia. SUBJECTS 1222 women, aged 485 (mean 71) years, who were at least 5 years postmenopause and who had osteoporosis, defined as two or more radiographically visible vertebral fractures. Follow-up radiographs were available for 81–85% of women. 106
Evidence-based Obstetrics and Gynecology (2000) 2, 106d107 doi:10.1054/ebog.2000.0191, available online at http://www.idealibrary.com on
MAIN RESULTS At one year, the percentages of women with new vertebral fractures (based on survival analysis) were 13.0% with placebo, 7.1% with risedronate 2.5 mg (relative risk [RR] 0.5, 95% CI 0.3–0.8) and 5.6% with risedronate 5 mg (RR 0.4, CI 0.2–0.7). There was no significant difference between dose groups (P"0.41*), but the 2.5 mg risedronate arm was discontinued after 2 years because of evidence of low efficacy from other trials. At 3 years, the percentages of women with new vertebral fractures ^ 2000 Harcourt Publishers Ltd
were 29.0% with placebo and 18.1% with risedronate 5 mg (RR 0.5, CI 0.4–0.7, number needed to treat to prevent vertebral fracture in 1 woman is 10). Compared to placebo, bone mineral density in the femoral neck, femoral trochanter and lumbar spine increased, at 3 years, by 3–6% with risedronate 5 mg (P(0.001). The incidence of non-vertebral fractures was 16.0% in the placebo group and 10.9% in the risedronate 5 mg group (RR 0.7, CI 0.4–1.0). The withdrawal rate was slightly higher in the placebo group (46%) than
in the risedronate 5 mg group (38%) and the proportions of women with upper gastrointestinal tract complaints (27 and 26%, respectively) were similar.
Commentary
Harris and Reginster studies, respectively. The investigators also examined the risk of new vertebral fractures after 1 year of risedronate therapy; compared with placebo, treatment with risedronate 5 mg/day reduced the incidence of vertebral fractures by 65 and 61%, in the two studies, respectively. No significant difference in adverse events was seen between the risedronate and placebo groups. These studies are also notable for what they tell us about osteoporotic vertebral fractures. The placebo group in the Reginster study had more advanced osteoporosis at baseline (greater number of prevalent vertebral fractures and lower lumbar spine bone mineral density) than their counterparts in the Harris study. This difference corresponded to a higher incidence of new vertebral fractures in the Reginster study (13% over 1 year and 29% over 3 years), compared with the Harris study (6.4 and 16%, respectively), a finding that emphasizes that vertebral fracture risk increases in relation to the number of existing vertebral fractures. In conclusion, these clinical trials demonstrated that oral risedronate therapy (at the recommended dose of 5 mg/day), given over 3 years, was well tolerated and reduced the incidences of both vertebral and non-vertebral fractures in women with established postmenopausal osteoporosis. Furthermore, these studies are the first to show a rapid and clinically important reduction in the incidence of vertebral fractures (both clinical and subclinical) with 1 year of therapy.
Osteoporosis is a major health concern, affecting a growing number of individuals worldwide. The disorder is characterized by low bone mass and bone fragility, resulting in an increased risk of fracture. Indeed, vertebral fractures have been synonymous with the diagnosis of osteoporosis since its earliest characterization as a metabolic bone disease. The prevention of fractures is the primary goal of osteoporosis treatment. Several antiresorptive agents have been used successfully for the treatment of postmenopausal osteoporosis, including calcium and vitamin D,1 estrogen,2 raloxifene,3 calcitonin,4 and the bisphosphonates.5d7 Bisphosphonates have become accepted as the most potent inhibitors of bone resorption available clinically and are the mainstay in the treatment of osteoporosis. The two most rigorously studied bisphosphonate therapies are alendronate5d7 and risedronate. Both drugs have been found to increase bone mineral density and reduce vertebral and non-vertebral fractures. However, there has not yet been a head-to-head comparison of the relative efficacy of these two drugs in the same patient population and it is invalid to compare their effects across studies. The two present studies were both large, 3-year, multicentred, randomized, controlled trials, that evaluated the efficacy of risedronate in the treatment of postmenopausal osteoporosis. The first study, by Harris et al, was conducted in North America and the second study, by Reginster et al, was performed in Europe and Australia. The primary purpose of the trials was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures. A total of 2458 postmenopausal women with at least two vertebral fractures (or one vertebral fracture and a lumbar spine bone mineral density t-score of !2.0 or lower) participated in the Harris study, whereas the Reginster study involved 1226 postmenopausal women who had experienced at least two osteoporotic vertebral fractures. At study entry, in both trials, vertebral fractures were determined by visual inspection of the X-ray films. The subjects were randomly assigned to treatment with placebo or risedronate 2.5 or 5 mg/day. The 2.5 mg/day group was discontinued before the completion of the studies, because of new data showing better results and a similar safety profile with the 5 mg/day dose. All women received 1000 mg/day of calcium, with a vitamin D supplement if baseline levels of the vitamin were low. Quantitative (15% loss in vertebral height) and semi-quantitative assessments were used to identify both prevalent and incident vertebral fractures for the purpose of the efficacy determination. Women were not excluded on the basis of previous or active gastrointestinal illness or because of concomitant use of aspirin or non-steroidal anti-inflammatory agents. While the dropout rates in the studies were high, the rates were no higher than what the authors had anticipated and there was no evident difference between the treatment groups in the proportion of subjects discontinuing treatment or in the reasons for withdrawal. Following 3 years of treatment, the results indicated that, when compared to placebo, risedronate 5 mg/day reduced the incidence of vertebral fractures by 41% ( P"0.003) and 49% (P(0.001) and non-vertebral fractures by 39% ( P"0.02) and 33% ( P"0.06) in the
^ 2000 Harcourt Publishers Ltd
CONCLUSION Risedronate 5 mg reduced the risk of new vertebral fractures and increased bone mineral density in postmenopausal women with osteoporosis and previous fractures. *Calculated from data in article.
George Ioannidis, MSc Alexandra Papaioannou, MD Jonathan D. Adachi, MD McMaster University, Hamilton Ontario, Canada
Literature cited 1. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327:1637d1647 2. Lufkin EG, Heinz W, Wahner W, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Int Med 1992; 117:1d9 3. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999; 282:637d645 4. Chesnut CH III, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevention of recurrence of osteoporotic fractures study. Am J Med 2000; 109:267d276 5. Black DM, Cummings SR, Karph DB, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348:1535d1541 6. Cummings SR, Black BM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA 1998; 280:2077d2082 7. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled randomized trial of the effect of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Osteoporos Int 1999; 9:461d468
Evidence-based Obstetrics and Gynecology (2000) 2, 106d107
107