NEWS & VIEWS Controversy—cardiovascular effects of calcium supplementation Ian R. Reid
Of late, clinical trial data, meta-analyses and observational studies have caused concern that the use of calcium supplements might increase the risk of myocardial infarction and stroke. A new meta-analysis suggests that there is no problem with calcium supplements, but as the analysis includes controversial data omitted from previous analyses, the debate will continue. Reid, I. R. Nat. Rev. Endocrinol. 10, 641–642 (2014); published online 19 August 2014; doi:10.1038/nrendo.2014.146
The use of calcium supplements to prevent osteoporosis continues to be the subject of considerable controversy with respect to both their efficacy and safety. If used alone, calcium supplements seem to increase the risk of hip fracture; if used in combination with vitamin D, they only reduce the risk of these fractures in institutionalized individu‑ als who have very low levels of vitamin D.1 With regard to the safety of calcium supple‑ ments, at least three other concerns exist. The Women’s Health Initiative (WHI) study showed that the use of calcium sup‑ plements in combination with vitamin D increased the risk of renal calculi by 17%, causing more calculi than the number of fractures prevented.2 Gastrointestinal adverse effects have been recognized as an unfortunate complication of the use of calcium supplements for many years. A 2012 study reported a 2‑fold increased risk of admission to hospital with an acute gastrointestinal emergency in a group of patients randomized to receive calcium supplements; again, these supplements caused more hospital admissions than frac‑ tures prevented.3 The balance of these issues alone suggests that calcium supplements, with or without vitamin D, do not have a net beneficial effect. However, a third safety issue, myocardial infarction (and possibly stroke), has dominated this discussion lately. These adverse events first came to light in the Auckland Calcium Study and were con‑ firmed in two subsequent meta-analyses of studies assessing the effects of calcium monotherapy.4,5 The question of whether or not the use of calcium supplements in
‘‘
…there is probably no net benefit from the use of calcium supplements, independent of cardiovascular effects…
’’
combination with vitamin D also has an adverse effect on cardiovascular outcomes is more controversial. The answer might be found in the WHI study, depending on how the data are analysed, as this is by far the largest trial in this area conducted to date.5,6 The issue of the cardiovascular safety of calcium supplements has now been revis‑ ited by Lewis and colleagues in a further meta-analysis.7 “Current evidence does not support the hypothesis that calcium sup‑ plementation with or without vitamin D increases coronary heart disease,” the authors conclude. Readers of this report 7 are likely to be puzzled as to why the authors reached such different conclusions from previous meta-analyses,4,6 as the new report does not explore the reasons for this dif‑ ference. A number of differences in the approach taken by Lewis and co-workers7 account for the apparently different out‑ comes reported. Firstly, the analysis was restricted to postmenopausal women, even though sensitivity analyses in the previous meta-analysis4 showed that sex does not influence the effect of calcium supplements on cardiovascular risk. Secondly, even though the question posed by the authors is whether or not calcium supplements have an effect on myocardial infarction, they chose a much broader cluster of cardiovascular diag‑ noses as the primary end point of their study
NATURE REVIEWS | ENDOCRINOLOGY
(including angina pectoris and chronic coro‑ nary heart disease), even though there has hitherto been no evidence that these entities are influenced by calcium supplementation. Thirdly, they have included two substantial cohorts omitted from the previous analyses.4 By far the largest study of the use of cal cium supplements in combination with vitamin D is the WHI study, and the wide spread self-administration of calc ium supplements in the study population has prev iously been shown to substantially influence the cardiovascular outcomes of that trial.6 Notwithstanding, Lewis and col‑ leagues chose to include all the participants from the WHI study, whereas the previous meta-analysis4,6 only included 16,000 (of the 36,000) participants who were calciumnaive at randomization. Furthermore, even though the stated aim of the study was to include only randomized controlled trials, Lewis et al. chose to include a large openlabel cluster-randomized trial.8 In this study, people living in different regions of the study city were invited to participate and were informed whether they would be ran‑ domized to intervention or control groups before they made their decision to partici‑ pate. This approach seems to have intro‑ duced bias in the recruitment phase of the study, as the consenting participants in the control group had significantly higher use of cardiovascular and other medications at the time of the study’s inception than the intervention group, suggesting an increased cardiovascular risk in the control group at
20
Ca 1
H 3
Li 11
Na 19
K
37
Rb 55
Cs NPG
CARDIOVASCULAR ENDOCRINOLOGY
87
Fr
4
Be 12
Mg 20
21
Ca
Sc
38
39
Sr 56
Y
57–71
22
Ti
40
Zr 72
23
V
41
Nb 73
24
Cr 42
Mo 74
25
Mn 43
Tc 75
26
Fe 44
Ru 76
Ba
La–Lu
Hf
Ta
W
Re
Os
88
89–103
104
105
106
107
108
Ra
Ac–Lr
Rf
Db
Sg
Bh
Hs
VOLUME 10 | NOVEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS baseline. Thus, non-comparability of the treatment groups at baseline might have biased the study against identifying adverse effects resulting from the use of calcium sup‑ plements; a trial of this design should not be included in a meta-analysis of randomized controlled trials. With the broadening of trial end points and inclusion of low-quality studies, how do the analyses of Lewis et al.7 compare with the previous meta-analyses?4–6 For calcium supplements, with or without vitamin D, Lewis and colleagues found no effect on the incidence of total coronary heart disease, an end point not assessed in the previous meta-analysis.6 However, 82% of the weight in this analysis was derived from the WHI study and thus the analysis is essentially a republication of that study. Lewis et al.7 also reported no effect of calcium supplements on mortality, consistent with previous metaanalyses,4,5 but, again, more than half of the weight of this analysis was derived from the WHI study and the open-label clusterrandomized trial referred to above.8 For myocardial infarction Lewis and colleagues report that calcium supplements, with or without vitamin D, produce a risk ratio of 1.08 (95% CI 0.93–1.25), but three-quarters of the weight of this analysis is derived from the same two studies. The authors also present data on the effects of calcium supplementation alone, with a risk ratio for myocardial infarction of 1.37 (95% CI 0.98–1.92), confirming the adverse find‑ ings reported in previous meta-analyses.4,5 The marginal significance of this finding in comparison with that of a previous metaanalysis4 is attributable to the reduction in the number of study participants by onethird, as a result of excluding studies that included men. Thus, the only real differ‑ ence in findings relate to the analysis of the intervention with calcium supplements plus vitamin D, and simply reflect the effect of the 20,000 women in the WHI study already
NOVEMBER 2014 | VOLUME 10
taking calcium supplements and the almost 6,000 women in the problematic open-label cluster-randomized study.8 Which of these analyses should guide the use of calcium supplements? All the metaanalyses4–7 present data indicating that the use of calcium supplements alone increases the risk of myocardial infarction. It seems unlikely that the addition of a vitamin D supplement would substantially modify this finding, as vitamin D alone has no influence on cardiovascular risk.9 The reassurance that the analysis by Lewis and colleagues provides is probably misplaced and arises from the inclusion of large studies of poor design. This view is supported by the exten‑ sive literature on the adverse cardiovascular effects of calcium supplements in patients with renal failure, including patients with (pre-dialysis) glomerular filtration rates comparable to those seen in elderly patients with osteoporosis;10 the increased risk of myocardial infarction associated with the use of the calcimimetic agent strontium; and the increased cardiovascular risk asso‑ ciated with high–normal serum levels of cal cium.6 However, much of this discussion is academic, as there is probably no net bene fit from the use of calcium supplements, independent of their cardiovascular effects, as their low efficacy is more than counter‑ balanced by their adverse effects on renal calculi and gastrointestinal disorders. Thus, the controversy over the cardiov ascular safety of calcium supplements is not the critical issue, but merely another reason for directing patients at risk of osteoporotic fractures towards other safer interventions that are proven to reduce fractures. Such safe and effective interventions are now freely available and so the need for calcium supplements has largely disappeared. Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. [email protected]
Acknowledgements The author’s work is supported by the Health Research Council of New Zealand (grant 12/1110). Competing interests The author has received speaker honoraria from Sanofi. 1.
Reid, I. R. & Bolland, M. J. Calcium risk–benefit updated—new WHI analyses. Maturitas 77, 1–3 (2014). 2. Jackson, R. D. et al. Calcium plus vitamin D supplementation and the risk of fractures. N. Engl. J. Med. 354, 669–683 (2006). 3. Lewis, J. R., Zhu, K. & Prince, R. L. Adverse events from calcium supplementation: relationship to errors in myocardial infarction self-reporting in randomized controlled trials of calcium supplementation. J. Bone Miner. Res. 27, 719–722 (2012). 4. Bolland, M. J. et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341, c3691 (2010). 5. Mao, P.‑J. et al. Effect of calcium or vitamin D supplementation on vascular outcomes: a meta-analysis of randomized controlled trials. Int. J. Cardiol. 169, 106–111 (2013). 6. Bolland, M. J., Grey, A., Avenell, A., Gamble, G. D. & Reid, I. R. 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 342, d2040 (2011). 7. Lewis, J. R. et al. The effects of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: a collaborative metaanalysis of randomized controlled trials. J. Bone Miner. Res. http://dx.doi.org/10.1002/ jbmr.2311. 8. Larsen, E. R., Mosekilde, L. & Foldspang, A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3‑year intervention study. J. Bone Miner. Res. 19, 370–378 (2004). 9. Bolland, M. J., Grey, A., Gamble, G. D. & Reid, I. R. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential metaanalysis. Lancet Diabetes Endocrinol. 2, 307–320 (2014). 10. Jamal, S. A. et al. Effect of calcium-based versus non‑calcium‑based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 382, 1268–1277 (2013).
www.nature.com/nrendo © 2014 Macmillan Publishers Limited. All rights reserved
Of late, clinical trial data, meta-analyses and observational studies have caused concern that the use of calcium supplements might increase the risk of myocardial infarction and stroke. A new meta-analysis suggests that there is no problem with calcium supplements, but as the analysis includes controversial data omitted from previous analyses, the debate will continue. Reid, I. R. Nat. Rev. Endocrinol. 10, 641–642 (2014); published online 19 August 2014; doi:10.1038/nrendo.2014.146
The use of calcium supplements to prevent osteoporosis continues to be the subject of considerable controversy with respect to both their efficacy and safety. If used alone, calcium supplements seem to increase the risk of hip fracture; if used in combination with vitamin D, they only reduce the risk of these fractures in institutionalized individu‑ als who have very low levels of vitamin D.1 With regard to the safety of calcium supple‑ ments, at least three other concerns exist. The Women’s Health Initiative (WHI) study showed that the use of calcium sup‑ plements in combination with vitamin D increased the risk of renal calculi by 17%, causing more calculi than the number of fractures prevented.2 Gastrointestinal adverse effects have been recognized as an unfortunate complication of the use of calcium supplements for many years. A 2012 study reported a 2‑fold increased risk of admission to hospital with an acute gastrointestinal emergency in a group of patients randomized to receive calcium supplements; again, these supplements caused more hospital admissions than frac‑ tures prevented.3 The balance of these issues alone suggests that calcium supplements, with or without vitamin D, do not have a net beneficial effect. However, a third safety issue, myocardial infarction (and possibly stroke), has dominated this discussion lately. These adverse events first came to light in the Auckland Calcium Study and were con‑ firmed in two subsequent meta-analyses of studies assessing the effects of calcium monotherapy.4,5 The question of whether or not the use of calcium supplements in
‘‘
…there is probably no net benefit from the use of calcium supplements, independent of cardiovascular effects…
’’
combination with vitamin D also has an adverse effect on cardiovascular outcomes is more controversial. The answer might be found in the WHI study, depending on how the data are analysed, as this is by far the largest trial in this area conducted to date.5,6 The issue of the cardiovascular safety of calcium supplements has now been revis‑ ited by Lewis and colleagues in a further meta-analysis.7 “Current evidence does not support the hypothesis that calcium sup‑ plementation with or without vitamin D increases coronary heart disease,” the authors conclude. Readers of this report 7 are likely to be puzzled as to why the authors reached such different conclusions from previous meta-analyses,4,6 as the new report does not explore the reasons for this dif‑ ference. A number of differences in the approach taken by Lewis and co-workers7 account for the apparently different out‑ comes reported. Firstly, the analysis was restricted to postmenopausal women, even though sensitivity analyses in the previous meta-analysis4 showed that sex does not influence the effect of calcium supplements on cardiovascular risk. Secondly, even though the question posed by the authors is whether or not calcium supplements have an effect on myocardial infarction, they chose a much broader cluster of cardiovascular diag‑ noses as the primary end point of their study
NATURE REVIEWS | ENDOCRINOLOGY
(including angina pectoris and chronic coro‑ nary heart disease), even though there has hitherto been no evidence that these entities are influenced by calcium supplementation. Thirdly, they have included two substantial cohorts omitted from the previous analyses.4 By far the largest study of the use of cal cium supplements in combination with vitamin D is the WHI study, and the wide spread self-administration of calc ium supplements in the study population has prev iously been shown to substantially influence the cardiovascular outcomes of that trial.6 Notwithstanding, Lewis and col‑ leagues chose to include all the participants from the WHI study, whereas the previous meta-analysis4,6 only included 16,000 (of the 36,000) participants who were calciumnaive at randomization. Furthermore, even though the stated aim of the study was to include only randomized controlled trials, Lewis et al. chose to include a large openlabel cluster-randomized trial.8 In this study, people living in different regions of the study city were invited to participate and were informed whether they would be ran‑ domized to intervention or control groups before they made their decision to partici‑ pate. This approach seems to have intro‑ duced bias in the recruitment phase of the study, as the consenting participants in the control group had significantly higher use of cardiovascular and other medications at the time of the study’s inception than the intervention group, suggesting an increased cardiovascular risk in the control group at
20
Ca 1
H 3
Li 11
Na 19
K
37
Rb 55
Cs NPG
CARDIOVASCULAR ENDOCRINOLOGY
87
Fr
4
Be 12
Mg 20
21
Ca
Sc
38
39
Sr 56
Y
57–71
22
Ti
40
Zr 72
23
V
41
Nb 73
24
Cr 42
Mo 74
25
Mn 43
Tc 75
26
Fe 44
Ru 76
Ba
La–Lu
Hf
Ta
W
Re
Os
88
89–103
104
105
106
107
108
Ra
Ac–Lr
Rf
Db
Sg
Bh
Hs
VOLUME 10 | NOVEMBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS baseline. Thus, non-comparability of the treatment groups at baseline might have biased the study against identifying adverse effects resulting from the use of calcium sup‑ plements; a trial of this design should not be included in a meta-analysis of randomized controlled trials. With the broadening of trial end points and inclusion of low-quality studies, how do the analyses of Lewis et al.7 compare with the previous meta-analyses?4–6 For calcium supplements, with or without vitamin D, Lewis and colleagues found no effect on the incidence of total coronary heart disease, an end point not assessed in the previous meta-analysis.6 However, 82% of the weight in this analysis was derived from the WHI study and thus the analysis is essentially a republication of that study. Lewis et al.7 also reported no effect of calcium supplements on mortality, consistent with previous metaanalyses,4,5 but, again, more than half of the weight of this analysis was derived from the WHI study and the open-label clusterrandomized trial referred to above.8 For myocardial infarction Lewis and colleagues report that calcium supplements, with or without vitamin D, produce a risk ratio of 1.08 (95% CI 0.93–1.25), but three-quarters of the weight of this analysis is derived from the same two studies. The authors also present data on the effects of calcium supplementation alone, with a risk ratio for myocardial infarction of 1.37 (95% CI 0.98–1.92), confirming the adverse find‑ ings reported in previous meta-analyses.4,5 The marginal significance of this finding in comparison with that of a previous metaanalysis4 is attributable to the reduction in the number of study participants by onethird, as a result of excluding studies that included men. Thus, the only real differ‑ ence in findings relate to the analysis of the intervention with calcium supplements plus vitamin D, and simply reflect the effect of the 20,000 women in the WHI study already
NOVEMBER 2014 | VOLUME 10
taking calcium supplements and the almost 6,000 women in the problematic open-label cluster-randomized study.8 Which of these analyses should guide the use of calcium supplements? All the metaanalyses4–7 present data indicating that the use of calcium supplements alone increases the risk of myocardial infarction. It seems unlikely that the addition of a vitamin D supplement would substantially modify this finding, as vitamin D alone has no influence on cardiovascular risk.9 The reassurance that the analysis by Lewis and colleagues provides is probably misplaced and arises from the inclusion of large studies of poor design. This view is supported by the exten‑ sive literature on the adverse cardiovascular effects of calcium supplements in patients with renal failure, including patients with (pre-dialysis) glomerular filtration rates comparable to those seen in elderly patients with osteoporosis;10 the increased risk of myocardial infarction associated with the use of the calcimimetic agent strontium; and the increased cardiovascular risk asso‑ ciated with high–normal serum levels of cal cium.6 However, much of this discussion is academic, as there is probably no net bene fit from the use of calcium supplements, independent of their cardiovascular effects, as their low efficacy is more than counter‑ balanced by their adverse effects on renal calculi and gastrointestinal disorders. Thus, the controversy over the cardiov ascular safety of calcium supplements is not the critical issue, but merely another reason for directing patients at risk of osteoporotic fractures towards other safer interventions that are proven to reduce fractures. Such safe and effective interventions are now freely available and so the need for calcium supplements has largely disappeared. Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. [email protected]
Acknowledgements The author’s work is supported by the Health Research Council of New Zealand (grant 12/1110). Competing interests The author has received speaker honoraria from Sanofi. 1.
Reid, I. R. & Bolland, M. J. Calcium risk–benefit updated—new WHI analyses. Maturitas 77, 1–3 (2014). 2. Jackson, R. D. et al. Calcium plus vitamin D supplementation and the risk of fractures. N. Engl. J. Med. 354, 669–683 (2006). 3. Lewis, J. R., Zhu, K. & Prince, R. L. Adverse events from calcium supplementation: relationship to errors in myocardial infarction self-reporting in randomized controlled trials of calcium supplementation. J. Bone Miner. Res. 27, 719–722 (2012). 4. Bolland, M. J. et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341, c3691 (2010). 5. Mao, P.‑J. et al. Effect of calcium or vitamin D supplementation on vascular outcomes: a meta-analysis of randomized controlled trials. Int. J. Cardiol. 169, 106–111 (2013). 6. Bolland, M. J., Grey, A., Avenell, A., Gamble, G. D. & Reid, I. R. 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 342, d2040 (2011). 7. Lewis, J. R. et al. The effects of calcium supplementation on verified coronary heart disease hospitalization and death in postmenopausal women: a collaborative metaanalysis of randomized controlled trials. J. Bone Miner. Res. http://dx.doi.org/10.1002/ jbmr.2311. 8. Larsen, E. R., Mosekilde, L. & Foldspang, A. Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3‑year intervention study. J. Bone Miner. Res. 19, 370–378 (2004). 9. Bolland, M. J., Grey, A., Gamble, G. D. & Reid, I. R. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential metaanalysis. Lancet Diabetes Endocrinol. 2, 307–320 (2014). 10. Jamal, S. A. et al. Effect of calcium-based versus non‑calcium‑based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 382, 1268–1277 (2013).
www.nature.com/nrendo © 2014 Macmillan Publishers Limited. All rights reserved
