WOMEN’S HEALTH
A Randomized, Double-Blind, PlaceboControlled Study to Evaluate the Effects of Alendronate on Bone Mineral Density and Bone Remodelling in Perimenopausal Women With Low Bone Mineral Density Aliya Khan, MD, FRCPC, FACP, FACE,1,2 Sacha Dubois, MPH,3,4,5 Amina A. Khan,2 M. Zohair Rahman, BSc,2 O. Ahmed Khan, MD,2 Hamid T. Syed,2 Christine Derzko, MD, FRCSC6 Department of Medicine, McMaster University, Hamilton ON
1
Bone Research and Education Centre, Oakville ON
2
Department of Health and Behavioural Sciences, Lakehead University, Thunder Bay ON
3
Human Sciences Division, Northern Ontario School of Medicine, Thunder Bay ON
4
Research Department, St. Joseph’s Care Group, Thunder Bay ON
5
Departments of Obstetrics and Gynaecology and Internal Medicine (Endocrinology), University of Toronto, Toronto ON
6
Abstract Background: Perimenopausal women can experience rapid bone loss at skeletal sites with both cortical and cancellous bone, increasing the prevalence of osteoporosis following menopause. Methods: We conducted a 12-month randomized placebo-controlled trial evaluating the effects of alendronate 70 mg with 2800 IU cholecalciferol administered once per week for 12 months in comparison with placebo and cholecalciferol. The primary end-point was the percentage change in the lumbar spine bone mineral density (BMD) from baseline to 12 months. Secondary end-points were the change in BMD at the femoral neck and changes in biochemical markers of bone turnover. Results: Forty-five women were recruited to participate in the study. Five subjects withdrew from the study before randomization for unrelated reasons. Forty subjects were randomly allocated to the alendronate and placebo groups. The mean lumbar spine BMD in women treated with alendronate increased by 3.66% (mean paired difference, d = 0.032; ± 0.008 SE) at 12 months, compared with a reduction of 3.33% (d = −0.030; ± 0.008 SE) in the control group (P < 0.001). In the femoral neck, the mean
Key Words: Perimenopause, alendronate, bisphosphonate, osteoporosis, fracture risk Competing Interests: none declared. Received on January 19, 2014 Accepted on June 20, 2014
976 l NOVEMBER JOGC NOVEMBRE 2014
BMD in the alendronate group increased by 2.07% (d = 0.014; ± 0.009 SE) at 12 months, compared with a reduction of 1.87% (d = −0.014; ± 0.008 SE) in the control group (P = 0.046). There were no differences in BMD between the alendronate and placebo groups at the total hip sites after 12 months. At 12 months, both bone-specific alkaline phosphatase and urinary N-telopeptide were significantly reduced, by 37.79% (d = −9.90; ± 1.92 SE) and 27.21% (d = −11.68; ± 4.80 SE) respectively, in the alendronate group; in the control group, these levels increased (P < 0.001). Conclusion: Weekly treatment with alendronate 70 mg and cholecalciferol 2800 IU increases BMD and decreases bone turnover in perimenopausal women.
Résumé Contexte : Les femmes périménopausées peuvent connaître une perte osseuse rapide aux points du squelette qui comptent des os tant corticaux que spongieux, ce qui accroît la prévalence de l’ostéoporose à la suite de la ménopause. Méthodes : Nous avons mené un essai comparatif randomisé avec placebo (d’une durée de 12 mois) qui cherchait à évaluer les effets de l’administration de 70 mg d’alendronate et de 2 800 UI de cholécalciférol (une fois par semaine, pendant 12 mois), par comparaison avec l’administration d’un placebo et de cholécalciférol. Le critère d’évaluation principal était la modification (en pourcentage, entre la valeur de départ et la valeur à 12 mois) de la densité minérale osseuse (DMO) de la colonne lombaire. Parmi les critères d’évaluation secondaires, on trouvait la modification de la DMO du col fémoral et les modifications des marqueurs biochimiques du renouvellement des cellules osseuses.
Effects of Alendronate on Bone Mineral Density and Bone Remodelling in Perimenopausal Women With Low Bone Mineral Density
J Obstet Gynaecol Can 2014;36(11):976–982
is approximately twice that of premenopausal women; this leads to bone loss and micro-architectural deterioration and eventually to decreasing bone strength and an increasing risk of fragility fracture. By reducing bone remodelling, nitrogen-containing bisphosphonates are effective in significantly decreasing the risk of vertebral, non-vertebral, and hip fracture in postmenopausal women.5 Alendronate, a nitrogencontaining aminobisphosphonate, has been shown to increase BMD effectively at the hip, the spine, and at total body skeletal sites.6,7 Alendronate reduces the risk of vertebral, hip, and forearm fractures by approximately 50% in postmenopausal women.8 Long-term aminobisphosphonate therapy may increase the risk of potential side-effects, including osteonecrosis of the jaw9 and atypical femoral fracture.10 As aminobisphosphonates have long-term retention in the skeleton, it may be possible to prevent the rapid decline in bone density observed in the transmenopause with a short course of aminobisphosphonate therapy during this time. We report the results of a 12-month, randomized, doubleblind, placebo-controlled study evaluating alendronate in the prevention of bone loss in perimenopausal women.
INTRODUCTION
The trial was registered as an investigator-initiated study under the Merck Clinical Research program.
Résultats : Nous avons sollicité la participation de 45 femmes à l’étude. Cinq participantes se sont désistées avant la randomisation pour des raisons n’ayant rien à voir avec l’étude. Quarante femmes ont été affectées au hasard à un groupe devant recevoir de l’alendronate ou à un groupe devant recevoir un placebo. Chez les femmes traitées à l’alendronate, la DMO moyenne de la colonne lombaire a connu une hausse de l’ordre de 3,66 % (différence moyenne appariée, d = 0,032; ± 0,008 ET) à 12 mois, par comparaison avec une baisse de l’ordre de 3,33 % (d = −0,030; ± 0,008 ET) au sein du groupe témoin (P 177 μmol/L); subjects consuming excess alcohol, defined as more than four of the following per day: 30 mL of distilled spirits, 340 mL NOVEMBER JOGC NOVEMBRE 2014 l 977
Women’s Health
of beer, or 120 mL of wine; and subjects with a history of allergy or intolerance to bisphosphonates. Subjects with esophageal abnormalities that delayed esophageal emptying, such as stricture or achalasia, were excluded. Subjects with hypocalcemia (corrected serum calcium
A Randomized, Double-Blind, PlaceboControlled Study to Evaluate the Effects of Alendronate on Bone Mineral Density and Bone Remodelling in Perimenopausal Women With Low Bone Mineral Density Aliya Khan, MD, FRCPC, FACP, FACE,1,2 Sacha Dubois, MPH,3,4,5 Amina A. Khan,2 M. Zohair Rahman, BSc,2 O. Ahmed Khan, MD,2 Hamid T. Syed,2 Christine Derzko, MD, FRCSC6 Department of Medicine, McMaster University, Hamilton ON
1
Bone Research and Education Centre, Oakville ON
2
Department of Health and Behavioural Sciences, Lakehead University, Thunder Bay ON
3
Human Sciences Division, Northern Ontario School of Medicine, Thunder Bay ON
4
Research Department, St. Joseph’s Care Group, Thunder Bay ON
5
Departments of Obstetrics and Gynaecology and Internal Medicine (Endocrinology), University of Toronto, Toronto ON
6
Abstract Background: Perimenopausal women can experience rapid bone loss at skeletal sites with both cortical and cancellous bone, increasing the prevalence of osteoporosis following menopause. Methods: We conducted a 12-month randomized placebo-controlled trial evaluating the effects of alendronate 70 mg with 2800 IU cholecalciferol administered once per week for 12 months in comparison with placebo and cholecalciferol. The primary end-point was the percentage change in the lumbar spine bone mineral density (BMD) from baseline to 12 months. Secondary end-points were the change in BMD at the femoral neck and changes in biochemical markers of bone turnover. Results: Forty-five women were recruited to participate in the study. Five subjects withdrew from the study before randomization for unrelated reasons. Forty subjects were randomly allocated to the alendronate and placebo groups. The mean lumbar spine BMD in women treated with alendronate increased by 3.66% (mean paired difference, d = 0.032; ± 0.008 SE) at 12 months, compared with a reduction of 3.33% (d = −0.030; ± 0.008 SE) in the control group (P < 0.001). In the femoral neck, the mean
Key Words: Perimenopause, alendronate, bisphosphonate, osteoporosis, fracture risk Competing Interests: none declared. Received on January 19, 2014 Accepted on June 20, 2014
976 l NOVEMBER JOGC NOVEMBRE 2014
BMD in the alendronate group increased by 2.07% (d = 0.014; ± 0.009 SE) at 12 months, compared with a reduction of 1.87% (d = −0.014; ± 0.008 SE) in the control group (P = 0.046). There were no differences in BMD between the alendronate and placebo groups at the total hip sites after 12 months. At 12 months, both bone-specific alkaline phosphatase and urinary N-telopeptide were significantly reduced, by 37.79% (d = −9.90; ± 1.92 SE) and 27.21% (d = −11.68; ± 4.80 SE) respectively, in the alendronate group; in the control group, these levels increased (P < 0.001). Conclusion: Weekly treatment with alendronate 70 mg and cholecalciferol 2800 IU increases BMD and decreases bone turnover in perimenopausal women.
Résumé Contexte : Les femmes périménopausées peuvent connaître une perte osseuse rapide aux points du squelette qui comptent des os tant corticaux que spongieux, ce qui accroît la prévalence de l’ostéoporose à la suite de la ménopause. Méthodes : Nous avons mené un essai comparatif randomisé avec placebo (d’une durée de 12 mois) qui cherchait à évaluer les effets de l’administration de 70 mg d’alendronate et de 2 800 UI de cholécalciférol (une fois par semaine, pendant 12 mois), par comparaison avec l’administration d’un placebo et de cholécalciférol. Le critère d’évaluation principal était la modification (en pourcentage, entre la valeur de départ et la valeur à 12 mois) de la densité minérale osseuse (DMO) de la colonne lombaire. Parmi les critères d’évaluation secondaires, on trouvait la modification de la DMO du col fémoral et les modifications des marqueurs biochimiques du renouvellement des cellules osseuses.
Effects of Alendronate on Bone Mineral Density and Bone Remodelling in Perimenopausal Women With Low Bone Mineral Density
J Obstet Gynaecol Can 2014;36(11):976–982
is approximately twice that of premenopausal women; this leads to bone loss and micro-architectural deterioration and eventually to decreasing bone strength and an increasing risk of fragility fracture. By reducing bone remodelling, nitrogen-containing bisphosphonates are effective in significantly decreasing the risk of vertebral, non-vertebral, and hip fracture in postmenopausal women.5 Alendronate, a nitrogencontaining aminobisphosphonate, has been shown to increase BMD effectively at the hip, the spine, and at total body skeletal sites.6,7 Alendronate reduces the risk of vertebral, hip, and forearm fractures by approximately 50% in postmenopausal women.8 Long-term aminobisphosphonate therapy may increase the risk of potential side-effects, including osteonecrosis of the jaw9 and atypical femoral fracture.10 As aminobisphosphonates have long-term retention in the skeleton, it may be possible to prevent the rapid decline in bone density observed in the transmenopause with a short course of aminobisphosphonate therapy during this time. We report the results of a 12-month, randomized, doubleblind, placebo-controlled study evaluating alendronate in the prevention of bone loss in perimenopausal women.
INTRODUCTION
The trial was registered as an investigator-initiated study under the Merck Clinical Research program.
Résultats : Nous avons sollicité la participation de 45 femmes à l’étude. Cinq participantes se sont désistées avant la randomisation pour des raisons n’ayant rien à voir avec l’étude. Quarante femmes ont été affectées au hasard à un groupe devant recevoir de l’alendronate ou à un groupe devant recevoir un placebo. Chez les femmes traitées à l’alendronate, la DMO moyenne de la colonne lombaire a connu une hausse de l’ordre de 3,66 % (différence moyenne appariée, d = 0,032; ± 0,008 ET) à 12 mois, par comparaison avec une baisse de l’ordre de 3,33 % (d = −0,030; ± 0,008 ET) au sein du groupe témoin (P 177 μmol/L); subjects consuming excess alcohol, defined as more than four of the following per day: 30 mL of distilled spirits, 340 mL NOVEMBER JOGC NOVEMBRE 2014 l 977
Women’s Health
of beer, or 120 mL of wine; and subjects with a history of allergy or intolerance to bisphosphonates. Subjects with esophageal abnormalities that delayed esophageal emptying, such as stricture or achalasia, were excluded. Subjects with hypocalcemia (corrected serum calcium
