JBMR
COMMENTARY
The Calcium Supplement Controversy: Now What? Douglas C Bauer Departments of Medicine and Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA
F
or decades there has been a consistent public health message about the use of calcium supplements in healthy adults: they prevent fracture and have no serious side effects. Although there is disagreement about the populations that are most likely to benefit and the magnitude of antifracture benefits, the best evidence pooled from multiple placebo‐controlled trials suggests that supplementation with calcium plus vitamin D reduces fracture risk about 12%.(1) Some populations, such as the institutionalized elderly and those with inadequate dietary intake, may benefit from supplements to a greater degree than independent‐living individuals with adequate calcium intake. The potential nonskeletal benefits of calcium supplementation remain controversial.(2) In addition to mild and often self‐limited gastrointestinal intolerance, the most important confirmed side effect of supplementation is a 17% increase in nephrolithiasis.(3) The calcium supplement landscape, however, has changed considerably since the publication of two meta‐analyses by Bolland and colleagues in 2010(4) and 2011,(5) concluding that calcium supplements increase the risk of both coronary and cerebrovascular events. The first meta‐analysis pooled 15 placebo‐controlled trials of calcium supplements without vitamin D and found a statistically significant 31% increased risk of myocardial infarction (p ¼ 0.04) and a nonsignificant 20% increased risk of stroke (p ¼ 0.11) among calcium‐treated individuals.(4) The study received considerable attention in the lay press, but was also criticized for excluding calcium plus vitamin D trials, inconsistent validation of cardiovascular endpoints, and the lack of a dose‐response. In fact, analyses stratified on baseline calcium intake revealed significant supplement‐related increases in myocardial infarction among those with higher pretreatment dietary calcium intake (above the median of 805 mg/d) but not among those with lower pretreatment calcium intake (interaction p ¼ 0.01). A follow‐up meta‐analysis by Bolland and colleagues5 addressed at least some of these criticisms by including calcium plus vitamin D trials, and the results were similar: after pooling eight placebo‐controlled trials, randomization to calcium alone or calcium plus vitamin D was associated with a statistically significant 24% increase in myocardial infarction (p ¼ 0.004) and a nonsignificant 15% increase in stroke (p ¼ 0.06). Although Bolland and colleagues included the Women’s Health Initiative (WHI) Calcium Plus Vitamin D Supplementation Trial, which rigorously adjudicated thousands of cardiovascular outcomes
and had previously reported no increase in vascular events among the calcium plus D group,(6) in their second meta‐analysis Bolland and colleagues(5) excluded the 46% of WHI participants taking personal calcium supplements at baseline. The rationale offered for excluding women taking personal calcium supplements was that it allowed a pure comparison of supplement use versus no supplement use. Unfortunately, analysis of a subset of trial participants does not preserve the full benefits of initial randomization,(7) and those taking and not taking personal supplements at baseline might have differed in subtle but important ways. Given the size of the WHI trial and the overall null effect on cardiovascular endpoints, it is not surprising that two other meta‐analyses of the same topic which included all of the WHI trial participants found no increase in cardiovascular risk with supplementation.(8,9) If calcium supplements do increase the risk of cardiovascular events, the mechanism is not known. Calcium supplements, but not dietary calcium, transiently increase serum calcium,(10) which might lead to arrhythmias in susceptible individuals, but evidence linking calcium supplements to mechanisms that clearly cause vascular disease, such as accelerated atherosclerosis, intimal plaque instability, or altered coagulation, are lacking. In addition, several studies of coronary artery calcium, a surrogate vascular measurement that is able to identify subclinical atherosclerosis and is associated with future vascular events,(11) have found no relationship to calcium supplement use. For example, neither the prospective Framingham Heart Study(12) nor the WHI trial(13) found a relationship between use of calcium supplements and coronary calcium score. In this regard, a high‐quality ancillary study of the Calcium Intake Fracture Outcomes Study (CAIFOS) reported in this issue of the Journal of Bone and Mineral Research by Lewis and colleagues(14) is of interest. CAIFOS was a 5‐year placebo‐ controlled trial of calcium carbonate (1.2 gm per day of elemental calcium) that enrolled nearly 1500 older women with a mean baseline calcium intake of 970 mg/day, and previously reported a nonsignificant reduction in fracture risk (relative risk [RR] ¼ 0.86; 95% confidence interval [CI], 0.87–1.12)(15) and no significant effect on atherosclerotic events or death (RR ¼ 0.94; 95% CI, 0.69–1.28).(16) The current report by Lewis and colleagues14 details the effects of 3 years of calcium supplements on two accepted surrogate measurements of cardiovascular risk: carotid artery intimal medial thickness and the presence or absence of
Address correspondence to: Douglas C Bauer, MD, UCSF School of Medicine, Departments of Medicine Epidemiology & Biostatistics, 185 Berry Street, Suite 5700, San Francisco, CA 94143, USA. E‐mail: [email protected] This is a Commentary on Lewis et al. (J Bone Miner Res. 2014;29:534–541. DOI: 10.1002/jbmr.2117). Journal of Bone and Mineral Research, Vol. 29, No. 3, March 2014, pp 531–533 DOI: 10.1002/jbmr.2184 © 2014 American Society for Bone and Mineral Research
531
atherosclerotic carotid plaque, both assessed by B‐mode ultrasonography.(17) The reported intention‐to‐treat results are solidly null: there were no significant differences in either of the two measurements among calcium‐treated or placebo‐treated women. Results were similar in a per protocol analysis among women who were at least 80% compliant. Although reassuring, the study did not collect carotid measurements prior to randomization and did not assess coronary atherosclerosis directly. Nonetheless, the Lewis and colleagues14 study strongly suggests that up to 3 years of daily calcium supplementation in older women does not have an adverse effect on carotid atherosclerosis. Thus, at this point we are left with a clinical conundrum: post hoc analyses of some, but not all, placebo‐controlled trials have found that randomization to calcium or calcium plus vitamin D increases the risk of cardiovascular events, and no obvious biologic mechanism exists to account for such an adverse effect. Observational data are also inconsistent.(18) What could explain these apparently discordant results? One potential explanation for the inconsistent relationship between calcium supplement use and cardiovascular events is that the association is real but is obscured in some studies by a threshold effect; ie, even low doses of supplemental calcium increase vascular risk and higher doses do not further increase risk. This explanation appears to be favored by Bolland and colleagues(5) because they use it as the primary rational for excluding WHI participants taking personal calcium supplements in their second meta‐analysis of calcium trials with and without vitamin D, but this line of reasoning is not compelling without a credible mechanism or at least some supportive data from surrogate outcomes such as coronary artery calcium or intimal medial thickness. Importantly, WHI investigators recently reanalyzed the WHI trial and extended cohort data and have concluded that calcium supplementation had no effects on the risk of myocardial infarction, coronary heart disease, or stroke.(19) Another potential but increasingly unlikely explanation for the inconsistent association between calcium supplement use and vascular events is that vitamin D may reduce coronary heart disease, and therefore the cardiovascular harms of calcium supplements are negated when administered with vitamin D from any source. Although a number of observational studies have suggested a beneficial cardiovascular effect of vitamin D supplementation, the most rigorous review recently summarized for the U.S. Preventive Services Task Force concludes that there is little quality evidence that vitamin D is cardioprotective.(2) A final potential and increasingly likely explanation for the inconsistent relationship between calcium supplementation and cardiovascular disease is that there is no true association and the apparent relationship has resulted from chance or bias. The probability that an observed relationship between calcium supplement use and vascular events is due to chance alone is quantified by the p value, and in the first Bolland and colleagues4 meta‐analysis the p values were 0.04 for myocardial infarction and 0.11 for stroke, making chance a reasonable explanation for the observed findings. Bias as a potential explanation for positive results is often more difficult to detect, assess, and quantify than chance, even in controlled trials, particularly if there is differential ascertainment of endpoints by treatment group, selective publication or pooling of results, or post hoc analysis of subgroups identified after randomization. Is there a way forward? Clearly the issue needs to be resolved because both calcium supplement use and cardiovascular disease are very common in the elderly and even a weak causal
532
BAUER
relationship would have a substantial public health impact and require a change to clinical practice. Although time‐consuming and expensive, large pragmatic trials with multiple clinical endpoints and objective collection and adjudication of cardiovascular events will be needed to definitively answer the question. Concerns that it would be impractical or unethical to randomize older adults to calcium plus vitamin D supplements or placebo are unfounded because there appears to be true clinical equipoise. Additional studies, both observational and randomized, of potential mechanisms are needed, particularly those related to the effects of transient hypercalcemia as well as novel imaging and other biomarkers for atherosclerosis. In summary, adequate calcium intake remains an important bone health concern in older adults and clarification of the population‐specific antifracture benefits and cardiovascular safety of calcium supplements are important clinical and public health questions. Currently, we know that calcium supplements modestly increase the risk of nephrolithiasis and may cause mild gastrointestinal symptoms, but the evidence supporting a causal relationship between supplementation and cardiovascular events remains inconsistent and inconclusive. Indiscriminate discontinuation of calcium supplements is not necessary, but until additional data are available clinicians should promote adequate dietary calcium as a means to achieve the daily intake recommended by the Institute of Medicine,(20) and reserve supplements for those who are unable or unwilling to achieve adequate dietary intake. Reassuringly, randomized trials have confirmed that clinician‐based efforts to increase dietary calcium are feasible and often successful.(21)
Disclosures The author states that he has no conflicts of interest.
References 1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta‐analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(12):827–38. 2. Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. Forthcoming. Epub. 2013 Nov 12. DOI:10.7326/0003‐4819‐159‐12‐201312170‐ 00729 3. Wallace RB, Wactawski‐Wende J, O’Sullivan MJ, et al. Urinary tract stone occurrence in the Women’s Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr. 2011;94(1):270–7. 4. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction,cardiovascular events: meta‐analysis. BMJ. 2010;341:c3691. 5. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta‐analysis. BMJ. 2011;342:d2040. 6. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115(7):846–54. 7. Moye LA, Random research. Circulation. 2001;103(25):3150–3. 8. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315–23. 9. Lewis J, Rejnmark L, Ivey K, Prentice RL, Prince R. The cardiovascular safety of calcium supplementation with or without vitamin D in
Journal of Bone and Mineral Research
elderly women: a collaborative meta‐analysis of published and unpublished trial level evidence from randomised controlled trials. J Bone Miner Res. 2013;28(Suppl 1):[Presented orally at the 35th Annual Meeting American Society for Bone and Mineral Research (ASBMR); 2013 Oct 4; Baltimore, MD, USA; Oral Presentations, Presentation Number: 1002]. Available from: http://www.asbmr.org/education/ AbstractDetail?aid ¼ cb39c171‐4131‐43df‐aa5b‐c8ba3ddb6bf8. 10. Reid IR, Bolland MJ, Grey A. Effect of calcium supplementation on hip fractures. Osteoporos Int. 2008;19(8):1119–23. 11. Youssef G, Kalia N, Darabian S, Budoff MJ. Coronary calcium: new insights, recent data, and clinical role. Curr Cardiol Rep. 2013;15(1): 325. 12. Samelson EJ, Booth SL, Fox CS, et al. Calcium intake is not associated with increased coronary artery calcification: the Framingham Study. Am J Clin Nutr. 2012;96(6):1274–180. 13. Manson JE, Allison MA, Carr JJ, et al. Calcium/vitamin D supplementation and coronary artery calcification in the Women’s Health Initiative. Menopause. 2010;17(4):683–91. 14. Lewis JR, Zhu K, Thompson PL, Prince RL. The effects of 3 years of calcium supplementation on common carotid artery intimal medial thickness and carotid atherosclerosis in older women: an ancillary study of the CAIFOS randomized controlled trial. J Bone Miner Res. 2014;29(3):534–541.
Journal of Bone and Mineral Research
15. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5‐year, double‐blind, placebo‐controlled trial in elderly women. Arch Intern Med. 2006;166(8):869–75. 16. Lewis JR, Calver J, Zhu K, Flicker L, Prince RL. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5‐year RCT and a 4.5‐year follow‐up. J Bone Miner Res. 2011;26(1):35–41. 17. Den Ruijter HM, Peters SA, Anderson TJ, et al. Common carotid intima‐media thickness measurements in cardiovascular risk prediction: a meta‐analysis. JAMA. 2012;308(8):796–803. 18. Bauer DC, Clinical practice. Calcium supplements and fracture prevention. N Engl J Med. 2013;369(16):1537–43. 19. Prentice RL, Pettinger MB, Jackson RD, et al. Health risks and benefits from calcium and vitamin D supplementation: Women’s Health Initiative clinical trial and cohort study. Osteoporos Int. 2013;24(2): 567–80. 20. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press; 2011. 21. Wong SY, Lau EM, Lau WW, Lynn HS. Is dietary counselling effective in increasing dietary calcium, protein and energy intake in patients with osteoporotic fractures? A randomized controlled clinical trial. J Hum Nutr Diet. 2004;17(4):359–64.
THE CALCIUM SUPPLEMENT CONTROVERSY
533
COMMENTARY
The Calcium Supplement Controversy: Now What? Douglas C Bauer Departments of Medicine and Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA
F
or decades there has been a consistent public health message about the use of calcium supplements in healthy adults: they prevent fracture and have no serious side effects. Although there is disagreement about the populations that are most likely to benefit and the magnitude of antifracture benefits, the best evidence pooled from multiple placebo‐controlled trials suggests that supplementation with calcium plus vitamin D reduces fracture risk about 12%.(1) Some populations, such as the institutionalized elderly and those with inadequate dietary intake, may benefit from supplements to a greater degree than independent‐living individuals with adequate calcium intake. The potential nonskeletal benefits of calcium supplementation remain controversial.(2) In addition to mild and often self‐limited gastrointestinal intolerance, the most important confirmed side effect of supplementation is a 17% increase in nephrolithiasis.(3) The calcium supplement landscape, however, has changed considerably since the publication of two meta‐analyses by Bolland and colleagues in 2010(4) and 2011,(5) concluding that calcium supplements increase the risk of both coronary and cerebrovascular events. The first meta‐analysis pooled 15 placebo‐controlled trials of calcium supplements without vitamin D and found a statistically significant 31% increased risk of myocardial infarction (p ¼ 0.04) and a nonsignificant 20% increased risk of stroke (p ¼ 0.11) among calcium‐treated individuals.(4) The study received considerable attention in the lay press, but was also criticized for excluding calcium plus vitamin D trials, inconsistent validation of cardiovascular endpoints, and the lack of a dose‐response. In fact, analyses stratified on baseline calcium intake revealed significant supplement‐related increases in myocardial infarction among those with higher pretreatment dietary calcium intake (above the median of 805 mg/d) but not among those with lower pretreatment calcium intake (interaction p ¼ 0.01). A follow‐up meta‐analysis by Bolland and colleagues5 addressed at least some of these criticisms by including calcium plus vitamin D trials, and the results were similar: after pooling eight placebo‐controlled trials, randomization to calcium alone or calcium plus vitamin D was associated with a statistically significant 24% increase in myocardial infarction (p ¼ 0.004) and a nonsignificant 15% increase in stroke (p ¼ 0.06). Although Bolland and colleagues included the Women’s Health Initiative (WHI) Calcium Plus Vitamin D Supplementation Trial, which rigorously adjudicated thousands of cardiovascular outcomes
and had previously reported no increase in vascular events among the calcium plus D group,(6) in their second meta‐analysis Bolland and colleagues(5) excluded the 46% of WHI participants taking personal calcium supplements at baseline. The rationale offered for excluding women taking personal calcium supplements was that it allowed a pure comparison of supplement use versus no supplement use. Unfortunately, analysis of a subset of trial participants does not preserve the full benefits of initial randomization,(7) and those taking and not taking personal supplements at baseline might have differed in subtle but important ways. Given the size of the WHI trial and the overall null effect on cardiovascular endpoints, it is not surprising that two other meta‐analyses of the same topic which included all of the WHI trial participants found no increase in cardiovascular risk with supplementation.(8,9) If calcium supplements do increase the risk of cardiovascular events, the mechanism is not known. Calcium supplements, but not dietary calcium, transiently increase serum calcium,(10) which might lead to arrhythmias in susceptible individuals, but evidence linking calcium supplements to mechanisms that clearly cause vascular disease, such as accelerated atherosclerosis, intimal plaque instability, or altered coagulation, are lacking. In addition, several studies of coronary artery calcium, a surrogate vascular measurement that is able to identify subclinical atherosclerosis and is associated with future vascular events,(11) have found no relationship to calcium supplement use. For example, neither the prospective Framingham Heart Study(12) nor the WHI trial(13) found a relationship between use of calcium supplements and coronary calcium score. In this regard, a high‐quality ancillary study of the Calcium Intake Fracture Outcomes Study (CAIFOS) reported in this issue of the Journal of Bone and Mineral Research by Lewis and colleagues(14) is of interest. CAIFOS was a 5‐year placebo‐ controlled trial of calcium carbonate (1.2 gm per day of elemental calcium) that enrolled nearly 1500 older women with a mean baseline calcium intake of 970 mg/day, and previously reported a nonsignificant reduction in fracture risk (relative risk [RR] ¼ 0.86; 95% confidence interval [CI], 0.87–1.12)(15) and no significant effect on atherosclerotic events or death (RR ¼ 0.94; 95% CI, 0.69–1.28).(16) The current report by Lewis and colleagues14 details the effects of 3 years of calcium supplements on two accepted surrogate measurements of cardiovascular risk: carotid artery intimal medial thickness and the presence or absence of
Address correspondence to: Douglas C Bauer, MD, UCSF School of Medicine, Departments of Medicine Epidemiology & Biostatistics, 185 Berry Street, Suite 5700, San Francisco, CA 94143, USA. E‐mail: [email protected] This is a Commentary on Lewis et al. (J Bone Miner Res. 2014;29:534–541. DOI: 10.1002/jbmr.2117). Journal of Bone and Mineral Research, Vol. 29, No. 3, March 2014, pp 531–533 DOI: 10.1002/jbmr.2184 © 2014 American Society for Bone and Mineral Research
531
atherosclerotic carotid plaque, both assessed by B‐mode ultrasonography.(17) The reported intention‐to‐treat results are solidly null: there were no significant differences in either of the two measurements among calcium‐treated or placebo‐treated women. Results were similar in a per protocol analysis among women who were at least 80% compliant. Although reassuring, the study did not collect carotid measurements prior to randomization and did not assess coronary atherosclerosis directly. Nonetheless, the Lewis and colleagues14 study strongly suggests that up to 3 years of daily calcium supplementation in older women does not have an adverse effect on carotid atherosclerosis. Thus, at this point we are left with a clinical conundrum: post hoc analyses of some, but not all, placebo‐controlled trials have found that randomization to calcium or calcium plus vitamin D increases the risk of cardiovascular events, and no obvious biologic mechanism exists to account for such an adverse effect. Observational data are also inconsistent.(18) What could explain these apparently discordant results? One potential explanation for the inconsistent relationship between calcium supplement use and cardiovascular events is that the association is real but is obscured in some studies by a threshold effect; ie, even low doses of supplemental calcium increase vascular risk and higher doses do not further increase risk. This explanation appears to be favored by Bolland and colleagues(5) because they use it as the primary rational for excluding WHI participants taking personal calcium supplements in their second meta‐analysis of calcium trials with and without vitamin D, but this line of reasoning is not compelling without a credible mechanism or at least some supportive data from surrogate outcomes such as coronary artery calcium or intimal medial thickness. Importantly, WHI investigators recently reanalyzed the WHI trial and extended cohort data and have concluded that calcium supplementation had no effects on the risk of myocardial infarction, coronary heart disease, or stroke.(19) Another potential but increasingly unlikely explanation for the inconsistent association between calcium supplement use and vascular events is that vitamin D may reduce coronary heart disease, and therefore the cardiovascular harms of calcium supplements are negated when administered with vitamin D from any source. Although a number of observational studies have suggested a beneficial cardiovascular effect of vitamin D supplementation, the most rigorous review recently summarized for the U.S. Preventive Services Task Force concludes that there is little quality evidence that vitamin D is cardioprotective.(2) A final potential and increasingly likely explanation for the inconsistent relationship between calcium supplementation and cardiovascular disease is that there is no true association and the apparent relationship has resulted from chance or bias. The probability that an observed relationship between calcium supplement use and vascular events is due to chance alone is quantified by the p value, and in the first Bolland and colleagues4 meta‐analysis the p values were 0.04 for myocardial infarction and 0.11 for stroke, making chance a reasonable explanation for the observed findings. Bias as a potential explanation for positive results is often more difficult to detect, assess, and quantify than chance, even in controlled trials, particularly if there is differential ascertainment of endpoints by treatment group, selective publication or pooling of results, or post hoc analysis of subgroups identified after randomization. Is there a way forward? Clearly the issue needs to be resolved because both calcium supplement use and cardiovascular disease are very common in the elderly and even a weak causal
532
BAUER
relationship would have a substantial public health impact and require a change to clinical practice. Although time‐consuming and expensive, large pragmatic trials with multiple clinical endpoints and objective collection and adjudication of cardiovascular events will be needed to definitively answer the question. Concerns that it would be impractical or unethical to randomize older adults to calcium plus vitamin D supplements or placebo are unfounded because there appears to be true clinical equipoise. Additional studies, both observational and randomized, of potential mechanisms are needed, particularly those related to the effects of transient hypercalcemia as well as novel imaging and other biomarkers for atherosclerosis. In summary, adequate calcium intake remains an important bone health concern in older adults and clarification of the population‐specific antifracture benefits and cardiovascular safety of calcium supplements are important clinical and public health questions. Currently, we know that calcium supplements modestly increase the risk of nephrolithiasis and may cause mild gastrointestinal symptoms, but the evidence supporting a causal relationship between supplementation and cardiovascular events remains inconsistent and inconclusive. Indiscriminate discontinuation of calcium supplements is not necessary, but until additional data are available clinicians should promote adequate dietary calcium as a means to achieve the daily intake recommended by the Institute of Medicine,(20) and reserve supplements for those who are unable or unwilling to achieve adequate dietary intake. Reassuringly, randomized trials have confirmed that clinician‐based efforts to increase dietary calcium are feasible and often successful.(21)
Disclosures The author states that he has no conflicts of interest.
References 1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta‐analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(12):827–38. 2. Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. Forthcoming. Epub. 2013 Nov 12. DOI:10.7326/0003‐4819‐159‐12‐201312170‐ 00729 3. Wallace RB, Wactawski‐Wende J, O’Sullivan MJ, et al. Urinary tract stone occurrence in the Women’s Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr. 2011;94(1):270–7. 4. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction,cardiovascular events: meta‐analysis. BMJ. 2010;341:c3691. 5. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta‐analysis. BMJ. 2011;342:d2040. 6. Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115(7):846–54. 7. Moye LA, Random research. Circulation. 2001;103(25):3150–3. 8. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315–23. 9. Lewis J, Rejnmark L, Ivey K, Prentice RL, Prince R. The cardiovascular safety of calcium supplementation with or without vitamin D in
Journal of Bone and Mineral Research
elderly women: a collaborative meta‐analysis of published and unpublished trial level evidence from randomised controlled trials. J Bone Miner Res. 2013;28(Suppl 1):[Presented orally at the 35th Annual Meeting American Society for Bone and Mineral Research (ASBMR); 2013 Oct 4; Baltimore, MD, USA; Oral Presentations, Presentation Number: 1002]. Available from: http://www.asbmr.org/education/ AbstractDetail?aid ¼ cb39c171‐4131‐43df‐aa5b‐c8ba3ddb6bf8. 10. Reid IR, Bolland MJ, Grey A. Effect of calcium supplementation on hip fractures. Osteoporos Int. 2008;19(8):1119–23. 11. Youssef G, Kalia N, Darabian S, Budoff MJ. Coronary calcium: new insights, recent data, and clinical role. Curr Cardiol Rep. 2013;15(1): 325. 12. Samelson EJ, Booth SL, Fox CS, et al. Calcium intake is not associated with increased coronary artery calcification: the Framingham Study. Am J Clin Nutr. 2012;96(6):1274–180. 13. Manson JE, Allison MA, Carr JJ, et al. Calcium/vitamin D supplementation and coronary artery calcification in the Women’s Health Initiative. Menopause. 2010;17(4):683–91. 14. Lewis JR, Zhu K, Thompson PL, Prince RL. The effects of 3 years of calcium supplementation on common carotid artery intimal medial thickness and carotid atherosclerosis in older women: an ancillary study of the CAIFOS randomized controlled trial. J Bone Miner Res. 2014;29(3):534–541.
Journal of Bone and Mineral Research
15. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5‐year, double‐blind, placebo‐controlled trial in elderly women. Arch Intern Med. 2006;166(8):869–75. 16. Lewis JR, Calver J, Zhu K, Flicker L, Prince RL. Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5‐year RCT and a 4.5‐year follow‐up. J Bone Miner Res. 2011;26(1):35–41. 17. Den Ruijter HM, Peters SA, Anderson TJ, et al. Common carotid intima‐media thickness measurements in cardiovascular risk prediction: a meta‐analysis. JAMA. 2012;308(8):796–803. 18. Bauer DC, Clinical practice. Calcium supplements and fracture prevention. N Engl J Med. 2013;369(16):1537–43. 19. Prentice RL, Pettinger MB, Jackson RD, et al. Health risks and benefits from calcium and vitamin D supplementation: Women’s Health Initiative clinical trial and cohort study. Osteoporos Int. 2013;24(2): 567–80. 20. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press; 2011. 21. Wong SY, Lau EM, Lau WW, Lynn HS. Is dietary counselling effective in increasing dietary calcium, protein and energy intake in patients with osteoporotic fractures? A randomized controlled clinical trial. J Hum Nutr Diet. 2004;17(4):359–64.
THE CALCIUM SUPPLEMENT CONTROVERSY
533
