Calcium plus Vitamin D3 Supplementation and Colorectal Cancer in Women
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《新英格兰医药杂志》
The effect of vitamin and mineral supplementation and diet on the risk of colorectal cancer is an active area of research. In this issue of the Journal, Wactawski-Wende et al.1 report the results of a Women's Health Initiative (WHI) trial to test the hypothesis that postmenopausal women randomly assigned to receive 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily would have a lower risk of hip fracture and, secondarily, a lower risk of any type of fracture and colorectal cancer than women receiving placebo. The calcium plus vitamin D study involved 36,282 women from 40 WHI centers across the United States. Only women who had already been enrolled for one year in another component of a WHI trial — dietary modification involving a low-fat diet high in fruits and vegetables, postmenopausal hormone therapy, both interventions, or placebo or usual diet — were eligible if they also met other eligibility criteria. The one-year delay was intended to avoid placing an undue burden on the participants.2,3 An intention-to-treat analysis showed that after an average of seven years of follow-up, the rates of invasive colorectal cancer and the tumor characteristics were similar among the 18,176 women assigned to receive calcium with vitamin D supplementation and the 18,106 women assigned to the placebo group.1 How do these results fit into the contextual puzzle of the relation between total calcium and vitamin D intakes and the risk of colorectal cancer?
The WHI trial had three overlapping components: a dietary-modification group, a hormone-therapy group, and a calcium with vitamin D component added a year after the first two elements. By design, participants in one group were members of another; for example, in the calcium with vitamin D trial, 69 percent of the women had been enrolled in the Dietary Modification trial, 54 percent had been enrolled in the Hormone Therapy trial, and 14 percent had been enrolled in both trials.1 Since the mean age of the women was 62 years at entry into the calcium with vitamin D trial, the women were just reaching the high-risk age for colorectal cancer when the trial ended. Thus, the study may have been stopped too early to detect the effects of calcium plus vitamin D supplementation on incident colorectal cancer, with its estimated latency period of 10 to 20 years.
The enrollment of women in three overlapping trials maximized the participation and size of the WHI trial but created a complex approach with potential confounders for biologic interpretation. For example, bone density is improved by increased intakes of dairy foods, fruit, and vegetables rich in vitamin C, vitamin K, and potassium and other minerals that enhance calcium absorption.4 After the occurrence of additional cases of colorectal cancer among the participants, future analyses could examine whether dietary patterns in combination with supplementation modified the risk of colorectal cancer.
As compared with age-matched peers in the Third National Health and Nutrition Examination Survey, women in the calcium with vitamin D trial were better educated, were less likely to smoke cigarettes, were more likely to drink alcohol weekly, had higher average calcium intakes (by 130 mg per day), and had higher body-mass indexes.2 The characteristics of the participants reflect those of healthy volunteers in some trials. However, the participants were at lower risk for colorectal cancer than men and women who received a diagnosis of an adenomatous polyp before enrollment in trials reporting that calcium supplementation reduced the risk of recurrent polyps.5,6,7 More men than women were enrolled in the polyp-recurrence trials, and the supplement dose used was higher than the dose in the calcium with vitamin D trial.5,6,7 The rates of colorectal cancer increase with age, but the age trajectory is later for women than for men.8 Thus, the lower-risk profile of the WHI participants, their later age trajectory for colorectal cancer, and their earlier age at enrollment may have reduced the incidence of colorectal cancer and the study's power to detect any effects of calcium plus vitamin D supplementation on the risk of colorectal cancer.
Observational epidemiologic research on the effect of dietary intakes of calcium on the risk of colorectal cancer reveal inconsistent, weak inverse associations: there was a significant inverse relation with distal-colon cancer alone in the Nurses' Health Study, but no association in the Women's Health Study.9,10 Few epidemiologic studies have been published on the association of vitamin D supplementation with the risk of colorectal cancer, with most findings not reaching significance.10 In contrast, studies in animals indicate that supplementation with calcium and vitamin D reduces the risk of colorectal cancer.11
Given that colorectal cancer was a secondary end point in the WHI calcium with vitamin D trial and that the dose of calcium plus vitamin D was lower than the dose in polyp-recurrence trials, there is a need for a study in which colorectal cancer is the primary outcome among women who receive calcium with vitamin D supplements. Yet, before we consider initiating another trial, we should avail ourselves of several other opportunities. One is to examine the association between total calcium with vitamin D intake and the risk of colorectal cancer in the observational cohort from the WHI trial.12 In a nested case–control study in the calcium with vitamin D trial population, there was a significant inverse association between lower serum 25-hydroxyvitamin D levels and a higher risk of colorectal cancer,1 similar to the findings in the Nurses' Health Study,13 another study involving women. Another opportunity is to compare changes in plasma levels of 25-hydroxyvitamin D and osteocalcin in postmenopausal women with osteopenia (stratified according to the severity of osteopenia, treatment such as alendronate or risedronate, and the use of supplements) with those in women without osteopenia who are eligible to receive calcium with vitamin D supplements.
A controlled feeding study could be designed to provide and keep track of all foods eaten by participants and to monitor their weight, physical activity, and exposure to ultraviolet light. Another study might examine the effects of various doses of calcium with vitamin D supplements in healthy postmenopausal women who follow a low-fat diet high in fruits and vegetables as compared with women who follow their usual diet. These studies could contribute data on the kinetics and the optimal doses of calcium plus vitamin D supplements in postmenopausal women with and in those without osteopenia. Such data could provide information to bridge the knowledge gap from the current study to the next step, a pooled study evaluating the sex-specific risk of colorectal cancer or, perhaps, a colorectal-cancer trial. Thus, the conclusion of Wactawski-Wende et al. about the role of calcium plus vitamin D supplementation in the prevention of colorectal cancer needs to be interpreted in the light of the complexities of the WHI study and the probability that the doses of these substances may have been too low to achieve the desired effect.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Cancer Prevention and Population Sciences, University of Texas M.D. Anderson Cancer Center, Houston.
References
Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696.
Jackson RD, LaCroix AZ, Cauley JA, McGowan J. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003;13:Suppl:S98-S106.
Hays J, Hunt JR, Hubbell A, et al. The Women's Health Initiative recruitment methods and results. Ann Epidemiol 2003;13:Suppl:S18-S77.
Nieves JW. Osteoporosis: the role of micronutrients. Am J Clin Nutr 2005;81:Suppl:1232S-1239S.
Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999;340:101-107.
Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. Lancet 2000;356:1300-1306.
Hofstad B, Almendingen K, Vatn M, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998;59:148-156.
Hawk ET, Limburg PJ, Viner JL. Epidemiology and prevention of colorectal cancer. Surg Clin North Am 2002;82:905-941.
Martinez ME. Primary prevention of colorectal cancer: lifestyle, nutrition, exercise. Recent Results Cancer Res 2005;166:177-211.
Lin J, Zhang SM, Cook NR, Manson JE, Lee IM, Buring JE. Intakes of calcium and vitamin D and risk of colorectal cancer in women. Am J Epidemiol 2005;161:755-764.
Newmark HL, Wargovich MJ, Bruce WR. Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst 1984;72:1323-1325.
Prentice RI, Langer R, Stefanick MI, et al. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemiol 2005;162:404-414.
Feskanich D, Ma J, Fuchs CS, et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2004;13:1502-1508.(Michele R. Forman, Ph.D.,)
The WHI trial had three overlapping components: a dietary-modification group, a hormone-therapy group, and a calcium with vitamin D component added a year after the first two elements. By design, participants in one group were members of another; for example, in the calcium with vitamin D trial, 69 percent of the women had been enrolled in the Dietary Modification trial, 54 percent had been enrolled in the Hormone Therapy trial, and 14 percent had been enrolled in both trials.1 Since the mean age of the women was 62 years at entry into the calcium with vitamin D trial, the women were just reaching the high-risk age for colorectal cancer when the trial ended. Thus, the study may have been stopped too early to detect the effects of calcium plus vitamin D supplementation on incident colorectal cancer, with its estimated latency period of 10 to 20 years.
The enrollment of women in three overlapping trials maximized the participation and size of the WHI trial but created a complex approach with potential confounders for biologic interpretation. For example, bone density is improved by increased intakes of dairy foods, fruit, and vegetables rich in vitamin C, vitamin K, and potassium and other minerals that enhance calcium absorption.4 After the occurrence of additional cases of colorectal cancer among the participants, future analyses could examine whether dietary patterns in combination with supplementation modified the risk of colorectal cancer.
As compared with age-matched peers in the Third National Health and Nutrition Examination Survey, women in the calcium with vitamin D trial were better educated, were less likely to smoke cigarettes, were more likely to drink alcohol weekly, had higher average calcium intakes (by 130 mg per day), and had higher body-mass indexes.2 The characteristics of the participants reflect those of healthy volunteers in some trials. However, the participants were at lower risk for colorectal cancer than men and women who received a diagnosis of an adenomatous polyp before enrollment in trials reporting that calcium supplementation reduced the risk of recurrent polyps.5,6,7 More men than women were enrolled in the polyp-recurrence trials, and the supplement dose used was higher than the dose in the calcium with vitamin D trial.5,6,7 The rates of colorectal cancer increase with age, but the age trajectory is later for women than for men.8 Thus, the lower-risk profile of the WHI participants, their later age trajectory for colorectal cancer, and their earlier age at enrollment may have reduced the incidence of colorectal cancer and the study's power to detect any effects of calcium plus vitamin D supplementation on the risk of colorectal cancer.
Observational epidemiologic research on the effect of dietary intakes of calcium on the risk of colorectal cancer reveal inconsistent, weak inverse associations: there was a significant inverse relation with distal-colon cancer alone in the Nurses' Health Study, but no association in the Women's Health Study.9,10 Few epidemiologic studies have been published on the association of vitamin D supplementation with the risk of colorectal cancer, with most findings not reaching significance.10 In contrast, studies in animals indicate that supplementation with calcium and vitamin D reduces the risk of colorectal cancer.11
Given that colorectal cancer was a secondary end point in the WHI calcium with vitamin D trial and that the dose of calcium plus vitamin D was lower than the dose in polyp-recurrence trials, there is a need for a study in which colorectal cancer is the primary outcome among women who receive calcium with vitamin D supplements. Yet, before we consider initiating another trial, we should avail ourselves of several other opportunities. One is to examine the association between total calcium with vitamin D intake and the risk of colorectal cancer in the observational cohort from the WHI trial.12 In a nested case–control study in the calcium with vitamin D trial population, there was a significant inverse association between lower serum 25-hydroxyvitamin D levels and a higher risk of colorectal cancer,1 similar to the findings in the Nurses' Health Study,13 another study involving women. Another opportunity is to compare changes in plasma levels of 25-hydroxyvitamin D and osteocalcin in postmenopausal women with osteopenia (stratified according to the severity of osteopenia, treatment such as alendronate or risedronate, and the use of supplements) with those in women without osteopenia who are eligible to receive calcium with vitamin D supplements.
A controlled feeding study could be designed to provide and keep track of all foods eaten by participants and to monitor their weight, physical activity, and exposure to ultraviolet light. Another study might examine the effects of various doses of calcium with vitamin D supplements in healthy postmenopausal women who follow a low-fat diet high in fruits and vegetables as compared with women who follow their usual diet. These studies could contribute data on the kinetics and the optimal doses of calcium plus vitamin D supplements in postmenopausal women with and in those without osteopenia. Such data could provide information to bridge the knowledge gap from the current study to the next step, a pooled study evaluating the sex-specific risk of colorectal cancer or, perhaps, a colorectal-cancer trial. Thus, the conclusion of Wactawski-Wende et al. about the role of calcium plus vitamin D supplementation in the prevention of colorectal cancer needs to be interpreted in the light of the complexities of the WHI study and the probability that the doses of these substances may have been too low to achieve the desired effect.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Cancer Prevention and Population Sciences, University of Texas M.D. Anderson Cancer Center, Houston.
References
Wactawski-Wende J, Kotchen JM, Anderson GL, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-696.
Jackson RD, LaCroix AZ, Cauley JA, McGowan J. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003;13:Suppl:S98-S106.
Hays J, Hunt JR, Hubbell A, et al. The Women's Health Initiative recruitment methods and results. Ann Epidemiol 2003;13:Suppl:S18-S77.
Nieves JW. Osteoporosis: the role of micronutrients. Am J Clin Nutr 2005;81:Suppl:1232S-1239S.
Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. N Engl J Med 1999;340:101-107.
Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. Lancet 2000;356:1300-1306.
Hofstad B, Almendingen K, Vatn M, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998;59:148-156.
Hawk ET, Limburg PJ, Viner JL. Epidemiology and prevention of colorectal cancer. Surg Clin North Am 2002;82:905-941.
Martinez ME. Primary prevention of colorectal cancer: lifestyle, nutrition, exercise. Recent Results Cancer Res 2005;166:177-211.
Lin J, Zhang SM, Cook NR, Manson JE, Lee IM, Buring JE. Intakes of calcium and vitamin D and risk of colorectal cancer in women. Am J Epidemiol 2005;161:755-764.
Newmark HL, Wargovich MJ, Bruce WR. Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst 1984;72:1323-1325.
Prentice RI, Langer R, Stefanick MI, et al. Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women's Health Initiative clinical trial. Am J Epidemiol 2005;162:404-414.
Feskanich D, Ma J, Fuchs CS, et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2004;13:1502-1508.(Michele R. Forman, Ph.D.,)