Calcium plus Vitamin D for Postmenopausal Women — Bone Appétit?
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《新英格兰医药杂志》
There are many therapies that reduce the risk of fracture in people with osteoporosis. Calcium and vitamin D are the most widely used therapies for osteoporosis, even though their efficacy in terms of the prevention of fracture is uncertain. In fact, calcium supplements are the biggest seller in the multibillion-dollar dietary-supplement industry; annual sales in the United States in 2004 have been estimated to be as high as $993 million.1
The effect of calcium supplementation on bone mineral density has been the subject of many studies. In general, calcium has a small beneficial effect on bone mineral density, but it may be less effective in preventing bone loss in women who have recently undergone menopause and at sites rich in trabecular bone.2,3 The effect of calcium on the risk of fracture is less clear.2,4 When administered in doses of 400 to 800 IU per day, vitamin D by itself probably has little effect on bone mineral density, except among subjects who have a deficiency of vitamin D.5 Some studies have indicated that, when given with calcium, supplementation of at least 700 IU of vitamin D daily reduces the risk of fracture6,7,8; however, other studies have not shown this finding.5,9,10 The inconsistency of these results suggests that any benefit of calcium plus vitamin D on bone mineral density or the risk of fracture is, at best, small and may vary from group to group.
In this issue of the Journal, Jackson et al. report results from the Women's Health Initiative (WHI) calcium plus vitamin D trial.11 The investigators of this trial randomly assigned more than 36,000 postmenopausal women between the ages of 50 and 79 to receive 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 twice daily (for a total daily intake of 1000 mg of elemental calcium and 400 IU of vitamin D) or matching placebos for an average of seven years. Annualized rates of hip, total, and site-specific fractures were compared between the groups. Personal use of calcium and vitamin D was permitted, as was the use of bisphosphonates or calcitonin. In addition, more than half of the participants were receiving hormone-replacement therapy on entry, many as part of the active hormone-replacement treatment program of the WHI. Calcium with vitamin D supplementation increased total-hip bone mineral density by 1 percent as compared with placebo. According to an intention-to-treat analysis, there was no significant effect of calcium with vitamin D supplementation on any of the fracture end points. Calcium with vitamin D supplementation increased the risk of renal calculi by 17 percent. When data were excluded at the time a woman's adherence to therapy fell below 80 percent, the risk of hip fractures was significantly reduced (hazard ratio, 0.71; 95 percent confidence interval, 0.52 to 0.97).
The WHI was designed with the hope that it would provide clear answers to several important public health issues, including the efficacy of calcium and vitamin D for the prevention of fractures. Has the WHI calcium with vitamin D trial succeeded in this regard? Unfortunately, although the trial was well conducted, the results of the current study leave many questions unanswered. Although the primary intention-to-treat analysis failed to show any beneficial effect of calcium with vitamin D supplementation on the rates of fractures, a subgroup analysis of women who largely adhered to the protocol suggested that calcium with vitamin D supplementation reduces the risk of hip fracture.
However, there were several aspects of the study design and characteristics of the study population that may have reduced the chances of detecting a benefit of calcium with vitamin D therapy. First, the subjects were not selected on the basis of low bone mineral density or risk factors for fragility fractures. In some ways, this is a strength of the study, since it asks whether the findings apply to all postmenopausal women. It is plausible, however, that calcium with vitamin D supplementation would be more effective in a population of women with osteoporosis. Second, 64 percent of women in the placebo group had a daily calcium intake from diet and supplements of at least 800 mg at baseline, and 42 percent had a daily vitamin D intake of at least 400 IU. It seems likely that calcium with vitamin D supplementation would be more effective in women with a low intake of calcium and of vitamin D, although analysis of subgroups stratified according to intake levels did not reveal such an effect. There was, however, a trend suggesting that there was a reduction in the risk of hip fracture among women who did not use personal (i.e., non–study-medication) calcium supplements. Third, the dose of vitamin D — 400 IU per day — may not have been sufficient, since trials that have demonstrated benefits of calcium with vitamin D supplementation have administered at least 700 IU per day.8 Fourth, more than half of all participants in both groups were currently receiving hormone-replacement therapy. Because hormone-replacement therapy is a fairly potent antiresorptive regimen and significantly reduced the risk of hip, vertebral, and other fractures associated with osteoporosis in a similar group of women,12 one might expect the use of hormone-replacement therapy to diminish the chance of detecting an additional benefit of reduced fractures with calcium with vitamin D supplementation.
It comes as a surprise that there was a nonsignificant trend of a beneficial effect of calcium with vitamin D supplementation in current users of hormone-replacement therapy. Nonetheless, because of the risks associated with the use of hormone-replacement therapy that were demonstrated in the WHI randomized trial comparing hormone-replacement therapy with placebo,13 the use of hormone-replacement therapy among postmenopausal women has declined dramatically. Thus, the widespread use of hormone-replacement therapy in the current study limits the ability to generalize the results. Finally, the WHI calcium plus vitamin D trial was designed with 85 percent power to detect an 18 percent reduction in hip fractures, with the assumption of an annual rate of 33.6 fractures per 10,000 persons in the placebo group. The observed rate of hip fractures in the placebo group was about half the predicted rate. Thus, the study may have lacked sufficient power to detect a reduction in the rate of hip fractures. There were, however, 374 incident hip fractures — nearly four times as many as the number that occurred in the WHI Hormone Therapy trial, in which a significant reduction in the rate of hip fractures was observed among women in the group receiving hormone-replacement therapy.13 Moreover, with more than 1100 fractures of the lower arm or wrist and more than 4200 total fractures, the current study was well powered to detect a benefit of calcium with vitamin D supplementation for these end points. Thus, with these limitations in mind, we must conclude that calcium with vitamin D supplementation is not an effective means of preventing fractures in this population.
Many people may be disappointed with these results. Studies are generally designed in the hope that the results will be positive. Still, the findings from this trial have important public health implications. The results add to the existing body of evidence that calcium with vitamin D supplementation by itself is insufficient therapy to prevent fractures in postmenopausal women, though it may be beneficial in selected subgroups, such as women over the age of 60 or those with a low intake of calcium and vitamin D. With the widespread marketing of calcium and vitamin D, many women believe that they are completely protected against the development of osteoporosis if they are taking these supplements. This study should help correct this important misconception and allow more women to receive optimal therapy for bone health.
The WHI calcium plus vitamin D trial also raises the important question of whether calcium with vitamin D supplementation should be recommended routinely for postmenopausal women. Although there was an increased risk of kidney stones, the possible benefits of calcium with vitamin D supplementation for the risk of fracture cannot be totally ignored. It seems reasonable to recommend that women consume the recommended daily levels of calcium and vitamin D through diet, supplements, or both. But one message is clear: calcium with vitamin D supplementation by itself is not enough to ensure optimal bone health. Clinicians and patients should be aware that even if a woman is receiving adequate calcium with vitamin D supplementation, she may still be at risk for fracture, particularly if she has low bone mineral density or other clinical risk factors. Additional therapy with agents that have been proved to reduce the risk of fracture in women with osteoporosis, such as antiresorptive medications or teriparatide, may be indicated. Calcium with vitamin D supplementation is akin to the ante for a poker game: it is where everyone starts. If the clinical data suggest that the risk of fracture is significant, however, a woman probably needs something more.
Supported by a grant (K24 DK02759) from the National Institutes of Health.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston.
References
Supplement business report. San Diego, Calif.: Nutrition Business Journal, 2005:203.
Shea B, Wells G, Cranney A, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis. Endocr Rev 2002;23:552-559.
Dawson-Hughes BD, Dallal GE, Krall EA, Sadowski L, Sahyoun N, Tannenbaum S. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 1990;323:878-883.
Cumming RG, Nevitt MC. Calcium for prevention of osteoporotic fractures in postmenopausal women. J Bone Miner Res 1997;12:1321-1329.
Papadimitropoulos E, Wells G, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VIII. Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23:560-569.
Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327:1637-1642.
Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337:670-676.
Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293:2257-2264.
Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003-1003.
Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365:1621-1628.
Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.
Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003;290:1729-1738.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.(Joel S. Finkelstein, M.D.)
The effect of calcium supplementation on bone mineral density has been the subject of many studies. In general, calcium has a small beneficial effect on bone mineral density, but it may be less effective in preventing bone loss in women who have recently undergone menopause and at sites rich in trabecular bone.2,3 The effect of calcium on the risk of fracture is less clear.2,4 When administered in doses of 400 to 800 IU per day, vitamin D by itself probably has little effect on bone mineral density, except among subjects who have a deficiency of vitamin D.5 Some studies have indicated that, when given with calcium, supplementation of at least 700 IU of vitamin D daily reduces the risk of fracture6,7,8; however, other studies have not shown this finding.5,9,10 The inconsistency of these results suggests that any benefit of calcium plus vitamin D on bone mineral density or the risk of fracture is, at best, small and may vary from group to group.
In this issue of the Journal, Jackson et al. report results from the Women's Health Initiative (WHI) calcium plus vitamin D trial.11 The investigators of this trial randomly assigned more than 36,000 postmenopausal women between the ages of 50 and 79 to receive 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 twice daily (for a total daily intake of 1000 mg of elemental calcium and 400 IU of vitamin D) or matching placebos for an average of seven years. Annualized rates of hip, total, and site-specific fractures were compared between the groups. Personal use of calcium and vitamin D was permitted, as was the use of bisphosphonates or calcitonin. In addition, more than half of the participants were receiving hormone-replacement therapy on entry, many as part of the active hormone-replacement treatment program of the WHI. Calcium with vitamin D supplementation increased total-hip bone mineral density by 1 percent as compared with placebo. According to an intention-to-treat analysis, there was no significant effect of calcium with vitamin D supplementation on any of the fracture end points. Calcium with vitamin D supplementation increased the risk of renal calculi by 17 percent. When data were excluded at the time a woman's adherence to therapy fell below 80 percent, the risk of hip fractures was significantly reduced (hazard ratio, 0.71; 95 percent confidence interval, 0.52 to 0.97).
The WHI was designed with the hope that it would provide clear answers to several important public health issues, including the efficacy of calcium and vitamin D for the prevention of fractures. Has the WHI calcium with vitamin D trial succeeded in this regard? Unfortunately, although the trial was well conducted, the results of the current study leave many questions unanswered. Although the primary intention-to-treat analysis failed to show any beneficial effect of calcium with vitamin D supplementation on the rates of fractures, a subgroup analysis of women who largely adhered to the protocol suggested that calcium with vitamin D supplementation reduces the risk of hip fracture.
However, there were several aspects of the study design and characteristics of the study population that may have reduced the chances of detecting a benefit of calcium with vitamin D therapy. First, the subjects were not selected on the basis of low bone mineral density or risk factors for fragility fractures. In some ways, this is a strength of the study, since it asks whether the findings apply to all postmenopausal women. It is plausible, however, that calcium with vitamin D supplementation would be more effective in a population of women with osteoporosis. Second, 64 percent of women in the placebo group had a daily calcium intake from diet and supplements of at least 800 mg at baseline, and 42 percent had a daily vitamin D intake of at least 400 IU. It seems likely that calcium with vitamin D supplementation would be more effective in women with a low intake of calcium and of vitamin D, although analysis of subgroups stratified according to intake levels did not reveal such an effect. There was, however, a trend suggesting that there was a reduction in the risk of hip fracture among women who did not use personal (i.e., non–study-medication) calcium supplements. Third, the dose of vitamin D — 400 IU per day — may not have been sufficient, since trials that have demonstrated benefits of calcium with vitamin D supplementation have administered at least 700 IU per day.8 Fourth, more than half of all participants in both groups were currently receiving hormone-replacement therapy. Because hormone-replacement therapy is a fairly potent antiresorptive regimen and significantly reduced the risk of hip, vertebral, and other fractures associated with osteoporosis in a similar group of women,12 one might expect the use of hormone-replacement therapy to diminish the chance of detecting an additional benefit of reduced fractures with calcium with vitamin D supplementation.
It comes as a surprise that there was a nonsignificant trend of a beneficial effect of calcium with vitamin D supplementation in current users of hormone-replacement therapy. Nonetheless, because of the risks associated with the use of hormone-replacement therapy that were demonstrated in the WHI randomized trial comparing hormone-replacement therapy with placebo,13 the use of hormone-replacement therapy among postmenopausal women has declined dramatically. Thus, the widespread use of hormone-replacement therapy in the current study limits the ability to generalize the results. Finally, the WHI calcium plus vitamin D trial was designed with 85 percent power to detect an 18 percent reduction in hip fractures, with the assumption of an annual rate of 33.6 fractures per 10,000 persons in the placebo group. The observed rate of hip fractures in the placebo group was about half the predicted rate. Thus, the study may have lacked sufficient power to detect a reduction in the rate of hip fractures. There were, however, 374 incident hip fractures — nearly four times as many as the number that occurred in the WHI Hormone Therapy trial, in which a significant reduction in the rate of hip fractures was observed among women in the group receiving hormone-replacement therapy.13 Moreover, with more than 1100 fractures of the lower arm or wrist and more than 4200 total fractures, the current study was well powered to detect a benefit of calcium with vitamin D supplementation for these end points. Thus, with these limitations in mind, we must conclude that calcium with vitamin D supplementation is not an effective means of preventing fractures in this population.
Many people may be disappointed with these results. Studies are generally designed in the hope that the results will be positive. Still, the findings from this trial have important public health implications. The results add to the existing body of evidence that calcium with vitamin D supplementation by itself is insufficient therapy to prevent fractures in postmenopausal women, though it may be beneficial in selected subgroups, such as women over the age of 60 or those with a low intake of calcium and vitamin D. With the widespread marketing of calcium and vitamin D, many women believe that they are completely protected against the development of osteoporosis if they are taking these supplements. This study should help correct this important misconception and allow more women to receive optimal therapy for bone health.
The WHI calcium plus vitamin D trial also raises the important question of whether calcium with vitamin D supplementation should be recommended routinely for postmenopausal women. Although there was an increased risk of kidney stones, the possible benefits of calcium with vitamin D supplementation for the risk of fracture cannot be totally ignored. It seems reasonable to recommend that women consume the recommended daily levels of calcium and vitamin D through diet, supplements, or both. But one message is clear: calcium with vitamin D supplementation by itself is not enough to ensure optimal bone health. Clinicians and patients should be aware that even if a woman is receiving adequate calcium with vitamin D supplementation, she may still be at risk for fracture, particularly if she has low bone mineral density or other clinical risk factors. Additional therapy with agents that have been proved to reduce the risk of fracture in women with osteoporosis, such as antiresorptive medications or teriparatide, may be indicated. Calcium with vitamin D supplementation is akin to the ante for a poker game: it is where everyone starts. If the clinical data suggest that the risk of fracture is significant, however, a woman probably needs something more.
Supported by a grant (K24 DK02759) from the National Institutes of Health.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston.
References
Supplement business report. San Diego, Calif.: Nutrition Business Journal, 2005:203.
Shea B, Wells G, Cranney A, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis. Endocr Rev 2002;23:552-559.
Dawson-Hughes BD, Dallal GE, Krall EA, Sadowski L, Sahyoun N, Tannenbaum S. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 1990;323:878-883.
Cumming RG, Nevitt MC. Calcium for prevention of osteoporotic fractures in postmenopausal women. J Bone Miner Res 1997;12:1321-1329.
Papadimitropoulos E, Wells G, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VIII. Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23:560-569.
Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327:1637-1642.
Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337:670-676.
Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293:2257-2264.
Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003-1003.
Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365:1621-1628.
Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.
Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003;290:1729-1738.
Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.(Joel S. Finkelstein, M.D.)