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Estrogen alone or with calcitriol improved bone density to a similar extent in elderly women with normal bone density
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Estrogen alone or with calcitriol improved bone density to a similar extent in elderly women with normal bone density Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metabol 2001; 86: 3618 ^3628.
OBJECTIVE To compare the e¡ectiveness of estrogen, calcitriol (vitamin D), and estrogen plus calcitriol in preventing bone loss in elderly women with normal bone density. DESIGN Randomized, double-blind, placebocontrolled trial. Allocation was by a randomization scheme prepared by an outside group, strati¢ed by hysterectomy status. Duration of the study was 3 years. SETTING University hospital in the USA. SUBJECTS Four hundred and eighty-nine women, aged 65^77 (mean 71) years, who responded to a mailed invitation and had femoral neck bone density within the normal range for their age (mean T-score 1.8), no severe chronic illness, and no estrogen treatment in the previous 6 months. Mean daily intake of calcium was 742 mg and of dietary vitamin D was 141 IU. 85% of women completed the study. INTERVENTION One hundred and twenty-one women were randomized to receive conjugated estrogen 0.625 mg daily (plus medroxyprogesterone acetate 2.5 mg daily for women with a uterus), 123 women to receive calcitriol 0.25 mg twice daily, 122 women to receive both treatments, and 123 women to receive placebos. Bone mineral density (BMD) was assessed every 6 months. MAIN OUTCOME MEASURES Change in bone density at the femoral neck and spine, compared to placebo. MAIN RESULTS After 3 years, the mean (7SD) percent change in BMD at the femoral neck was 0.574.9 in the placebo group, 0.174.3 in the
46
Evidence-based Obstetrics and Gynecology (2002) 4, 46 ^ 47 doi:10.1054/ebog.5, available online at http://www.idealibrary.com.on
calcitriol group (p=0.57), 3.075.5 in the estrogen group (po0.0001), and 3.875.0 in the estrogen + calcitriol group (po0.0001), by intention-to-treat. The mean percent change in BMD at the spine was 0.974.8 in the placebo group, 1.774.8 in the calcitriol group (p=0.01), 4.476.4 in the estrogen group (po0.0001), and 4.976.0 in the estrogen + calcitriol group (po0.0001). Signi¢cant improvements in BMD, compared to placebo, were also seen at the trochanter, total hip, total body, and radius for the two estrogen groups and at the radius for the calcitriol group. At all sites, the estrogen and estrogen + calcitriol groups were not signi¢cantly di¡erent. Compliance with the study medication for the duration of the study was highest in the placebo (78%) and calcitriol (70%) groups, and lower in the estrogen groups (62 and 65%). When only compliant women were considered, the changes in BMD at the femoral neck and spine were similar to the above ¢gures in the placebo and calcitriol groups, but increased by 1^2 percentage points in the estrogen groups. The proportion of women with non-vertebral fractures during the study was 11% with placebo, 5% with calcitriol, 12% with estrogen, and 8% with estrogen + calcitriol (NS). Common side-e¡ects were vaginal bleeding in the estrogen groups and hypercalciuria in the calcitriol groups.
CONCLUSION In elderly women with normal bone mineral density for their age, treatment with estrogen alone or estrogen plus calcitriol resulted in similar improvements in BMD over 3 years. Treatment with calcitriol alone increased BMD in the spine, but not the femoral neck.
1361-259X/02/$ - see front matter & 2002 Published by Elsevier Science Ltd.
Commentary Adequate concentrations of vitamin D are important in maintaining bone health via its action on intestinal absorption of calcium.Calcitriol (1,25 dihydroxy vitamin D), the biologically active form of vitamin D, directly acts to stimulate osteoblasts and osteoclasts, thus participating in bone remodeling. Age-related reductions in sunlight-induced skin formation of vitamin D and reductions in vitamin D and calcium absorption may contribute to declining bone density with age.1 As many as 30% of patients suffering a hip fracture show histological evidence of osteomalacia (vitamin D deficiency). In the absence of adequate sunlight, physiologic doses of vitamin D (ergocalciferol) are 500 IU for those 50 ^70 years of age, 600 IU for those 70 and older, and 800 IU for the homebound or institutionalized. A few previous clinical trials have demonstrated that superphysiologic doses of calcitriol reduce bone loss and decrease fracture rates in older men and women.2,3 Whether this represents treatment of sub-clinical osteomalacia in the population studied or a pharmacological effect is unclear. This is an important distinction because high doses of vitamin D can lead to hypercalcemia, which can be clinically significant. The present study evaluated the effect of calcitriol alone, continuous combined hormone replacement therapy alone (HRT), or both treatments on bone mineral density (BMD). Study subjects were carefully selected, thoroughly evaluated and described, and properly randomized.The majority of these 489 older menopausal women did not have any evidence of vitamin D insufficiency. Bone density was normal for age, although 42% of the women met criteria for osteopenia (T-score of 1.5 to 2.4) and 19% met criteria for osteoporosis (T-score 2.5 or less).Women with conditions that might predispose to hypercalcemia were excluded. Dietary calcium was restricted to 500 ^1000 mg daily and calcium supplements were not given; thus, calcium intake was below the recommended dose of1000 ^1200 mg of elemental calcium daily. Subjects were carefully monitored for side-e¡ects, including hypercalcuria and hypercalcemia. The calcitriol alone, HRTalone, and HRT plus calcitriol groups all demonstrated significant increases in BMD at the spine, com-
pared with placebo. The magnitude of the effect with calcitriol alone was much less than in the HRT groups. In an intention-totreat analysis (the most appropriate statistical treatment of the data), there was no difference between the HRT alone and the HRT plus calcitriol groups. The minimal effect on BMD of these relatively high doses of calcitriol contrasts with incidences of hypercalcuria of 15% in the HRT plus calcitriol group and 26% in the calcitriol alone group. Hypercalcemia was also observed in 12% of subjects in the calcitriol alone group.These high rates occurred despite the apparent dietary calcium restriction in the study subjects. The results of this study suggest that treating older menopausal women, who are not vitamin D deficient, with this relatively high dose of calcitriol provides minimal benefit for BMD and runs the risk of inducing hypercalcemia and hypercalciuria. At present, clinicians should continue to recommend that menopausal women consume1200 mg of elemental calcium daily and appropriate doses of vitamin D as ergocalciferol. Pharmacotherapy with HRT (including the continuous combined regimen used in this study), bisphosphonates, selective estrogen receptor modulators, or calcitonin remains appropriate for women with established osteoporosis. Mary B. Laya, MD, MPH and Heidi Powell, MD University of Washington, Seattle WA, USA
Literature cited 1. Blumsohn A, Eastell R. Age related factors. In: Riggs B, Melton L (eds) Osteoporosis: Etiology, Diagnosis and Management. Philadelphia: Lippincott-Raven,1995: 11^182. 2. Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 1992; 326: 357^362. 3. Gallagher JC, Goldgar D.Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A randomized controlled study. Ann Intern Med 1990; 113: 649^ 655.
Evidence-based Obstetrics and Gynecology (2002) 4, 46 ^ 47
47
Estrogen alone or with calcitriol improved bone density to a similar extent in elderly women with normal bone density Gallagher JC, Fowler SE, Detter JR, Sherman SS. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metabol 2001; 86: 3618 ^3628.
OBJECTIVE To compare the e¡ectiveness of estrogen, calcitriol (vitamin D), and estrogen plus calcitriol in preventing bone loss in elderly women with normal bone density. DESIGN Randomized, double-blind, placebocontrolled trial. Allocation was by a randomization scheme prepared by an outside group, strati¢ed by hysterectomy status. Duration of the study was 3 years. SETTING University hospital in the USA. SUBJECTS Four hundred and eighty-nine women, aged 65^77 (mean 71) years, who responded to a mailed invitation and had femoral neck bone density within the normal range for their age (mean T-score 1.8), no severe chronic illness, and no estrogen treatment in the previous 6 months. Mean daily intake of calcium was 742 mg and of dietary vitamin D was 141 IU. 85% of women completed the study. INTERVENTION One hundred and twenty-one women were randomized to receive conjugated estrogen 0.625 mg daily (plus medroxyprogesterone acetate 2.5 mg daily for women with a uterus), 123 women to receive calcitriol 0.25 mg twice daily, 122 women to receive both treatments, and 123 women to receive placebos. Bone mineral density (BMD) was assessed every 6 months. MAIN OUTCOME MEASURES Change in bone density at the femoral neck and spine, compared to placebo. MAIN RESULTS After 3 years, the mean (7SD) percent change in BMD at the femoral neck was 0.574.9 in the placebo group, 0.174.3 in the
46
Evidence-based Obstetrics and Gynecology (2002) 4, 46 ^ 47 doi:10.1054/ebog.5, available online at http://www.idealibrary.com.on
calcitriol group (p=0.57), 3.075.5 in the estrogen group (po0.0001), and 3.875.0 in the estrogen + calcitriol group (po0.0001), by intention-to-treat. The mean percent change in BMD at the spine was 0.974.8 in the placebo group, 1.774.8 in the calcitriol group (p=0.01), 4.476.4 in the estrogen group (po0.0001), and 4.976.0 in the estrogen + calcitriol group (po0.0001). Signi¢cant improvements in BMD, compared to placebo, were also seen at the trochanter, total hip, total body, and radius for the two estrogen groups and at the radius for the calcitriol group. At all sites, the estrogen and estrogen + calcitriol groups were not signi¢cantly di¡erent. Compliance with the study medication for the duration of the study was highest in the placebo (78%) and calcitriol (70%) groups, and lower in the estrogen groups (62 and 65%). When only compliant women were considered, the changes in BMD at the femoral neck and spine were similar to the above ¢gures in the placebo and calcitriol groups, but increased by 1^2 percentage points in the estrogen groups. The proportion of women with non-vertebral fractures during the study was 11% with placebo, 5% with calcitriol, 12% with estrogen, and 8% with estrogen + calcitriol (NS). Common side-e¡ects were vaginal bleeding in the estrogen groups and hypercalciuria in the calcitriol groups.
CONCLUSION In elderly women with normal bone mineral density for their age, treatment with estrogen alone or estrogen plus calcitriol resulted in similar improvements in BMD over 3 years. Treatment with calcitriol alone increased BMD in the spine, but not the femoral neck.
1361-259X/02/$ - see front matter & 2002 Published by Elsevier Science Ltd.
Commentary Adequate concentrations of vitamin D are important in maintaining bone health via its action on intestinal absorption of calcium.Calcitriol (1,25 dihydroxy vitamin D), the biologically active form of vitamin D, directly acts to stimulate osteoblasts and osteoclasts, thus participating in bone remodeling. Age-related reductions in sunlight-induced skin formation of vitamin D and reductions in vitamin D and calcium absorption may contribute to declining bone density with age.1 As many as 30% of patients suffering a hip fracture show histological evidence of osteomalacia (vitamin D deficiency). In the absence of adequate sunlight, physiologic doses of vitamin D (ergocalciferol) are 500 IU for those 50 ^70 years of age, 600 IU for those 70 and older, and 800 IU for the homebound or institutionalized. A few previous clinical trials have demonstrated that superphysiologic doses of calcitriol reduce bone loss and decrease fracture rates in older men and women.2,3 Whether this represents treatment of sub-clinical osteomalacia in the population studied or a pharmacological effect is unclear. This is an important distinction because high doses of vitamin D can lead to hypercalcemia, which can be clinically significant. The present study evaluated the effect of calcitriol alone, continuous combined hormone replacement therapy alone (HRT), or both treatments on bone mineral density (BMD). Study subjects were carefully selected, thoroughly evaluated and described, and properly randomized.The majority of these 489 older menopausal women did not have any evidence of vitamin D insufficiency. Bone density was normal for age, although 42% of the women met criteria for osteopenia (T-score of 1.5 to 2.4) and 19% met criteria for osteoporosis (T-score 2.5 or less).Women with conditions that might predispose to hypercalcemia were excluded. Dietary calcium was restricted to 500 ^1000 mg daily and calcium supplements were not given; thus, calcium intake was below the recommended dose of1000 ^1200 mg of elemental calcium daily. Subjects were carefully monitored for side-e¡ects, including hypercalcuria and hypercalcemia. The calcitriol alone, HRTalone, and HRT plus calcitriol groups all demonstrated significant increases in BMD at the spine, com-
pared with placebo. The magnitude of the effect with calcitriol alone was much less than in the HRT groups. In an intention-totreat analysis (the most appropriate statistical treatment of the data), there was no difference between the HRT alone and the HRT plus calcitriol groups. The minimal effect on BMD of these relatively high doses of calcitriol contrasts with incidences of hypercalcuria of 15% in the HRT plus calcitriol group and 26% in the calcitriol alone group. Hypercalcemia was also observed in 12% of subjects in the calcitriol alone group.These high rates occurred despite the apparent dietary calcium restriction in the study subjects. The results of this study suggest that treating older menopausal women, who are not vitamin D deficient, with this relatively high dose of calcitriol provides minimal benefit for BMD and runs the risk of inducing hypercalcemia and hypercalciuria. At present, clinicians should continue to recommend that menopausal women consume1200 mg of elemental calcium daily and appropriate doses of vitamin D as ergocalciferol. Pharmacotherapy with HRT (including the continuous combined regimen used in this study), bisphosphonates, selective estrogen receptor modulators, or calcitonin remains appropriate for women with established osteoporosis. Mary B. Laya, MD, MPH and Heidi Powell, MD University of Washington, Seattle WA, USA
Literature cited 1. Blumsohn A, Eastell R. Age related factors. In: Riggs B, Melton L (eds) Osteoporosis: Etiology, Diagnosis and Management. Philadelphia: Lippincott-Raven,1995: 11^182. 2. Tilyard MW, Spears GF, Thomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 1992; 326: 357^362. 3. Gallagher JC, Goldgar D.Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A randomized controlled study. Ann Intern Med 1990; 113: 649^ 655.
Evidence-based Obstetrics and Gynecology (2002) 4, 46 ^ 47
47