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THE CLINICAL CLARITY BLOG
Calcium supplements, friend or foe?
SEPTEMBER 4, 2016 by DR MATTHEW D. LONG
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THE CLINICAL CLARITY BLOG
Calcium supplements, friend or foe?
SEPTEMBER 4, 2016 by DR MATTHEW D. LONG
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THE CLINICAL CLARITY BLOG
SEPTEMBER 4, 2016 by DR MATTHEW D. LONG
Sometimes conventional wisdom isn’t all that it’s cracked up to be. Just because something is well-accepted, seems logical and has never been challenged does not mean that it is actually true. A subject that has recently undergone such revisionist thinking is the appropriateness of calcium supplements to prevent or manage osteoporosis. Osteoporosis is obviously a significant public health challenge, and most medical professionals would agree that we haven’t come close to an effective solution, or even a comprehensive understanding of the mechanisms of this disease. However, there exists a number of strongly entrenched beliefs about osteoporosis that not only perpetuate the myths, but may actually undermine effective management and lead to greater morbidity and mortality.
I can think of three widely held assumptions about osteoporosis that bear closer examination:
I can think of three widely held assumptions about osteoporosis that bear closer examination:
Osteoporosis is a calcium deficiency problem.
Calcium supplements are beneficial for preventing and managing osteoporosis.
Calcium supplements are natural, and therefore safe.
To address the first question, we should start by saying that calcium is of vital importance to the maintenance of bone health. Not only is it required for effective skeletal mineralisation, it is essential to muscle contraction and nerve physiology (1). With calcium playing such a fundamental role in the makeup of bone it seems reasonable to assume that a disorder of demineralisation might be helped by increasing available calcium through supplementation. This view is indeed popular. According to Michaelsson et al (2), "Supplemental use of calcium has become common, and more than 60% of middle aged and older women in the United States are regular users of calcium supplements."
For a long time the view that calcium supplementation is a reasonable course of action to support bone health has been relatively unchallenged. Tai (3) states that,
For a long time the view that calcium supplementation is a reasonable course of action to support bone health has been relatively unchallenged. Tai (3) states that,
"Maintaining a calcium intake of at least 1000 - 1200 mg/ day has long been recommended for older individuals to treat and prevent osteoporosis. Calcium supplements are commonly taken to achieve such intakes, which are considerably higher than the average intake of calcium in the diet in older people in Western countries, around 700-900 mg/day. Recently, concerns have emerged about the risk-benefit profile of calcium supplements."
But is the amount of calcium that we take in through our diet every day actually correlated with circulating calcium levels? Does a greater daily intake mean that there will be more calcium available in the bloodstream to then be incorporated into bone? This is a fundamental question that we need to understand if we are going to make scientifically sound management decisions. Interestingly enough, according to Michaelsson, "Calcium levels in serum are under tight homeostatic control, and calcium intake is not normally correlated with calcium serum levels." This is why people living in countries with significantly lower average daily intakes of ~ 300 mg/day (such as Asia and Africa) can maintain viable bone density, while those in Europe with a high intake of dairy products can take in 4 to 5 times as much calcium and not suffer any side effects, such as renal calculi (4). Although there is certainly a transient increase in serum calcium after taking a supplement, the average circulating level is otherwise determined by tightly regulated physiological processes.
So it does seem that simply bumping up our daily intake of calcium will have little bearing on the amount available for bone density regulation. Reid and colleagues (4) stated that,
So it does seem that simply bumping up our daily intake of calcium will have little bearing on the amount available for bone density regulation. Reid and colleagues (4) stated that,
"Concern regarding the safety of calcium supplements has led to recommendations that dietary calcium should be the primary source, and supplements reserved only for those who are unable to achieve an adequate dietary intake. The current recommendations for intakes of 1000 – 1200 mg day are not firmly based on evidence. The longitudinal bone densitometry studies reviewed here, together with the new data included in this review relating to total body calcium, suggest that intakes in women consuming only half these quantities are satisfactory and thus, they do not require additional supplementation. The continuing preoccupation with calcium nutrition has its origin in a period when calcium balance was the only technique available to assess dietary or other therapeutic effects on bone health. We now have persuasive evidence from direct measurements of changes in bone density that calcium balance does not reflect bone balance. Bone balance is determined by the relative activities of bone formation and bone resorption, both of which are cellular processes. The mineralization of newly formed bone utilizes calcium as a substrate, but there is no suggestion that provision of excess substrate has any positive effect on either bone formation or subsequent mineralization."
Indeed, the literature now suggests that the simplistic notion of osteoporosis as a calcium-deficiency problem is somewhat akin to the suggestion that headache is an aspirin-deficiency problem. Even if we limited our focus to the dietary aspects of bone health we would quickly realise that calcium is only one part of a very large food puzzle.
"The simplistic notion of osteoporosis as a calcium-deficiency problem is somewhat akin to the suggestion that headache is an aspirin-deficiency problem."
As Sahni (5) suggests, "To date, numerous studies have related additional nutrients with bone health, such as vitamins A, B, C, E, K; minerals (potassium, magnesium, silicon); and macronutrients (protein and fats). Studies have also gone beyond single nutrient associations and linked foods, food groups, and dietary patterns with bone health." As such, it looks like the prevention of osteoporosis is not just a simple matter of getting more calcium into the bloodstream. Then why have calcium supplements been used as a mainstay in osteoporosis management for so long? Surely there must be some benefit to taking them? Again, the science may disappoint you. Accordingly to Bolland and colleagues (6),
"Our analyses indicate that dietary calcium intake is not associated with risk of fracture, and there is no evidence currently that increasing dietary calcium intake prevents fractures. Calcium supplements have small inconsistent benefits on fracture reduction but probably have an unfavourable risk:benefit profile. There was no risk reduction in fracture at any site in pooled analyses of the randomised controlled trials of calcium supplements at lowest risk of bias, and there was evidence of publication bias in small-moderate sized trials. Collectively, these results suggest that clinicians, advocacy organisations, and health policymakers should not recommend increasing calcium intake for fracture prevention, either with calcium supplements or through dietary sources."
Tai stated that, "In a systematic review of calcium intake and fractures, we concluded that there was no evidence of an association between increased dietary calcium intake and lower risk of fracture." Furthermore, although some studies have shown a very small increase in bone mineral density in the first year after taking increased calcium (whether from dietary sources or through supplements), there is no further increase in bone density, or arrest of subsequent bone loss, in any year following (3). Overall, the most recent literature now confirms only a transient benefit, at best, for any sort of calcium supplementation and the focus has now shifted to the possible downsides of increasing calcium.
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Recently, the main concern was an apparent increased risk of cardiovascular disease in those taking supplements (7,8,9). According to Reid et al,
"...it seems sensible to maintain calcium intakes in the region of 500 – 1000 mg day in older individuals at risk of osteoporosis, but there seems to be little need for calcium supplements except in individuals with major malabsorption problems or substantial abnormalities of calcium metabolism. Because of their formulation, costs and probable safety issues, calcium supplements should be regarded as pharmaceutical agents rather than as part of a standard diet. As such, they do not meet the standard cost-benefit criteria for pharmaceutical use and are not cost-effective. If an individual’s fracture risk is sufficient to require pharmaceutical intervention, then safer and more effective measures are available which have been subjected to rigorous clinical trials and careful cost–benefit analyses. Calcium supplements have very little role to play in the prevention or treatment of osteoporosis."
Michaelsson wrote that, "In this study of women in the Swedish mammography cohort, a high calcium intake (>1400 mg per day) was associated with an increased risk of mortality, including death from cardiovascular disease. The increase was moderate with a high dietary calcium intake without supplement use, but the combination of a high diet calcium intake and calcium tablet use resulted in a more pronounced increase in mortality."
How might elevated dietary calcium lead to cardiovascular disease? It appears that elevated calcium leads to higher levels of circulating fibroblast growth factor, a known risk for both cardiovascular events and all cause mortality. Michaelsson explains that fibroblast growth factor acts to suppress the active form of vitamin D (calcitriol), which in turn leads to increased activity of the renin-angiotensin-aldosterone system and subsequently in promoting hypertension. It further drives the production of proinflammatory cytokines, which are involved in "pathogenesis of atherosclerosis, increased carotid artery intima media thickness, decreased endothelial function, hypertrophy of cardiac and vascular muscle cells and a possible increase in serum triglycerides. Finally, high serum calcium levels can increase the risk of cardiovascular mortality by induction of a hypercoagulable state."
Gallo (1) also found that an increase in serum calcium correlates with worsening lipid profile. But it is not only cardiovascular disease that may increase in the presence of elevated serum calcium.
Ironically, some studies have shown that high intake levels did not reduce fracture rate, and may even increase the rate of hip fractures. Warensjo et al (10) state, "High calcium doses slow bone turnover and also reduce the number of active bone remodelling sites. This situation can lead to a delay of bone repair caused by fatigue, and thus increase the risk of fractures independent of bone mineral density". Given that the whole point of taking calcium supplements is to prevent fracture, this is somewhat concerning.
As a final metaphorical nail in the calcium supplement coffin, a recent study by Kern et al (11) has raised the prospect that calcium supplementation may increase the risk of developing dementia in elderly women with established cerebrovascular disease. Their study, published in the journal Neurology, found that elderly women who had already experienced stroke, or who demonstrated ischaemic white matter lesions (WML) on brain MRI, were at higher risk of developing dementia than those who avoid supplementation. Given that this demographic (older women with CVD) is also highly likely to suffer osteoporosis, this possible association is a worry. The authors wrote, "Calcium supplementation might have direct toxic effects on vulnerable neurons, because the increased calcium levels may amplify ischemic cell death and worsen the outcome after cerebrovascular events." Furthermore,
How might elevated dietary calcium lead to cardiovascular disease? It appears that elevated calcium leads to higher levels of circulating fibroblast growth factor, a known risk for both cardiovascular events and all cause mortality. Michaelsson explains that fibroblast growth factor acts to suppress the active form of vitamin D (calcitriol), which in turn leads to increased activity of the renin-angiotensin-aldosterone system and subsequently in promoting hypertension. It further drives the production of proinflammatory cytokines, which are involved in "pathogenesis of atherosclerosis, increased carotid artery intima media thickness, decreased endothelial function, hypertrophy of cardiac and vascular muscle cells and a possible increase in serum triglycerides. Finally, high serum calcium levels can increase the risk of cardiovascular mortality by induction of a hypercoagulable state."
Gallo (1) also found that an increase in serum calcium correlates with worsening lipid profile. But it is not only cardiovascular disease that may increase in the presence of elevated serum calcium.
Ironically, some studies have shown that high intake levels did not reduce fracture rate, and may even increase the rate of hip fractures. Warensjo et al (10) state, "High calcium doses slow bone turnover and also reduce the number of active bone remodelling sites. This situation can lead to a delay of bone repair caused by fatigue, and thus increase the risk of fractures independent of bone mineral density". Given that the whole point of taking calcium supplements is to prevent fracture, this is somewhat concerning.
As a final metaphorical nail in the calcium supplement coffin, a recent study by Kern et al (11) has raised the prospect that calcium supplementation may increase the risk of developing dementia in elderly women with established cerebrovascular disease. Their study, published in the journal Neurology, found that elderly women who had already experienced stroke, or who demonstrated ischaemic white matter lesions (WML) on brain MRI, were at higher risk of developing dementia than those who avoid supplementation. Given that this demographic (older women with CVD) is also highly likely to suffer osteoporosis, this possible association is a worry. The authors wrote, "Calcium supplementation might have direct toxic effects on vulnerable neurons, because the increased calcium levels may amplify ischemic cell death and worsen the outcome after cerebrovascular events." Furthermore,
"Stroke and WMLs increase the risk for dementia. Herein, we add to this finding by showing that calcium supplementation further increases this risk. There may be several explanations for our results. Both WMLs and stroke are markers of generalized cerebrovascular disease with different types of vessel pathology, share common risk factors, and often co-occur. Histopathologically, WMLs are related to diffuse ischemic incomplete infarcts, presumably caused by hypoperfusion and ischemia, and stroke is related to ischemic infarcts, often surrounded by a penumbra of incomplete infarction. The mechanism of calcium supplements in the pathogenesis of dementia could be the steep increase in serum calcium levels caused by the supplements. Neurons located in areas of hypoperfusion might be especially vulnerable to the excitatory and excitotoxic effects of the calcium-level peaks caused by the supplementation. Calcium plays a central role in the mechanisms of cell death. In necrosis, the transmembrane influx of calcium ions activates proteases that are responsible for degrading critical proteins and disrupting membrane function. Studies in in-vitro models have shown that some surviving neurons undergo apoptosis several hours after the membrane potential is restored. Blocking calcium influx via NMDA receptors prevents both necrosis and apoptosis. This indicates the crucial role of calcium influx and intracellular calcium overload in the genesis of apoptosis and necrosis."
They further pointed out the difference between a dietary intake of calcium, and supplement use, stating,
"The steep increase in serum calcium levels after calcium supplementation might lead to increased coagulability, lipohyalinosis, or altered vascular flow and might be mediated through calcium receptors or changes in calcium-dependent hormone levels. Another explanation may be that calcium supplementation stimulates vascular calcification by abnormal extraosseous deposition in atherosclerotic plaques. Dietary calcium might be protective against vascular disease. The difference between dietary calcium and calcium intake by supplements could be explained by variations in corresponding changes in serum calcium concentration. Dietary intake does not increase the serum calcium levels to the same extent as supplements."
It does appear that the serum control of calcium is tightly regulated and, to a large extent, independent of daily calcium intake. But there is a meaningful spike following supplementation that might have adverse effects in susceptible individuals.
The literature does suggest that it is actually very difficult to become truly calcium deficient. However, if this were a possibility for specific individuals (such as in the elderly who are institutionalised) then food-based sources are far safer than supplementation. Obviously, we need to be careful in the way that we interpret all new data and the discussion about the role of calcium in human health is ongoing. But there does appear to be a growing chorus of concern about indiscriminate ingestion of calcium without consideration of the possible implications. Furthermore, as discussed in a recent Clinical Clarity Blog article about the role of the vestibular system in bone health (you can read it here), there are other possible avenues by which a chiropractor may offer benefit to patients with bone density challenges. There is increasing evidence that the vestibular system has considerable influence upon bone homeostasis through the sympathetic nervous system. Importantly for chiropractors, the vestibular apparatus projects to brainstem autonomic centres, and ultimately influences bone turnover (12). Although this is merely one factor in a very complex equation, it makes sense to me that we should encourage our patients to maximise their vestibular health (through both exercise and appropriate treatment) while de-emphasising the simplistic notion that calcium supplements are an inexpensive 'insurance' against osteoporosis.
The literature does suggest that it is actually very difficult to become truly calcium deficient. However, if this were a possibility for specific individuals (such as in the elderly who are institutionalised) then food-based sources are far safer than supplementation. Obviously, we need to be careful in the way that we interpret all new data and the discussion about the role of calcium in human health is ongoing. But there does appear to be a growing chorus of concern about indiscriminate ingestion of calcium without consideration of the possible implications. Furthermore, as discussed in a recent Clinical Clarity Blog article about the role of the vestibular system in bone health (you can read it here), there are other possible avenues by which a chiropractor may offer benefit to patients with bone density challenges. There is increasing evidence that the vestibular system has considerable influence upon bone homeostasis through the sympathetic nervous system. Importantly for chiropractors, the vestibular apparatus projects to brainstem autonomic centres, and ultimately influences bone turnover (12). Although this is merely one factor in a very complex equation, it makes sense to me that we should encourage our patients to maximise their vestibular health (through both exercise and appropriate treatment) while de-emphasising the simplistic notion that calcium supplements are an inexpensive 'insurance' against osteoporosis.
Something to think about...
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq)
Dr Matthew D. Long
BSc (Syd), M.Chiro (Macq)
References:
1. Gallo, L., Faniello, M. C., Canino, G., Tripolino, C., Gnasso, A., Cuda, G., et al. (2016). Serum Calcium Increase Correlates With Worsening of Lipid Profile. Medicine, 95(8), e2774–5. http://doi.org/10.1097/MD.0000000000002774
2. Michaelsson, K., Melhus, H., Warensjo Lemming, E., Wolk, A., & Byberg, L. (2013). Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ (Clinical Research Ed), 346(feb12 4), f228–f228. http://doi.org/10.1136/bmj.f228
3. Tai, V., Leung, W., Grey, A., Reid, I. R., & Bolland, M. J. (2015). Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ (Clinical Research Ed), 351, h4183. http://doi.org/10.1136/bmj.h4183
4. Reid, I. R., Bristow, S. M., & Bolland, M. J. (2015). Calcium supplements: benefits and risks. Journal of Internal Medicine, 278(4), 354–368. http://doi.org/10.1111/joim.12394
5. Sahni, S., Mangano, K. M., McLean, R. R., Hannan, M. T., & Kiel, D. P. (2015). Dietary Approaches for Bone Health: Lessons from the Framingham Osteoporosis Study. Current Osteoporosis Reports, 13(4), 245–255. http://doi.org/10.1007/s11914-015-0272-1
6. Bolland, M. J., Leung, W., Tai, V., Bastin, S., Gamble, G. D., Grey, A., & Reid, I. R. (2015). Calcium intake and risk of fracture: systematic review. BMJ (Clinical Research Ed), 351, h4580. http://doi.org/10.1136/bmj.h4580
7. Reid, I. R., Bolland, M. J., & Grey, A. (2010). Does calcium supplementation increase cardiovascular risk? Clinical Endocrinology, 73(6), 689–695. http://doi.org/10.1111/j.1365-2265.2010.03792.x
8. Bolland, M. J., Avenell, A., Baron, J. A., Grey, A., MacLennan, G. S., Gamble, G. D., & Reid, I. R. (2010). Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ (Clinical Research Ed), 341, c3691.
9. Bolland, M. J., Grey, A., & Reid, I. R. (2015). Should we prescribe calcium or vitamin D supplements to treat or prevent osteoporosis? Climacteric, 18(sup2), 22–31. http://doi.org/10.3109/13697137.2015.1098266
10. Warensjo, E., Byberg, L., Melhus, H., Gedeborg, R., Mallmin, H., Wolk, A., & Michaelsson, K. (2011). Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study. BMJ (Clinical Research Ed), 342(may24 1), d1473–d1473. http://doi.org/10.1136/bmj.d1473
11. Kern, J., Kern, S., Blennow, K., Zetterberg, H., Waern, M., Guo, X., et al. (2016). Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurology, 10.1212/WNL.0000000000003111. http://doi.org/10.1212/WNL.0000000000003111
12. Vignaux, G., Besnard, S., Denise, P., & Elefteriou, F. (2015). The Vestibular System: A Newly Identified Regulator of Bone Homeostasis Acting Through the Sympathetic Nervous System. Current Osteoporosis Reports, 13(4), 198–205. http://doi.org/10.1007/s11914-015-0271-2
1. Gallo, L., Faniello, M. C., Canino, G., Tripolino, C., Gnasso, A., Cuda, G., et al. (2016). Serum Calcium Increase Correlates With Worsening of Lipid Profile. Medicine, 95(8), e2774–5. http://doi.org/10.1097/MD.0000000000002774
2. Michaelsson, K., Melhus, H., Warensjo Lemming, E., Wolk, A., & Byberg, L. (2013). Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ (Clinical Research Ed), 346(feb12 4), f228–f228. http://doi.org/10.1136/bmj.f228
3. Tai, V., Leung, W., Grey, A., Reid, I. R., & Bolland, M. J. (2015). Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ (Clinical Research Ed), 351, h4183. http://doi.org/10.1136/bmj.h4183
4. Reid, I. R., Bristow, S. M., & Bolland, M. J. (2015). Calcium supplements: benefits and risks. Journal of Internal Medicine, 278(4), 354–368. http://doi.org/10.1111/joim.12394
5. Sahni, S., Mangano, K. M., McLean, R. R., Hannan, M. T., & Kiel, D. P. (2015). Dietary Approaches for Bone Health: Lessons from the Framingham Osteoporosis Study. Current Osteoporosis Reports, 13(4), 245–255. http://doi.org/10.1007/s11914-015-0272-1
6. Bolland, M. J., Leung, W., Tai, V., Bastin, S., Gamble, G. D., Grey, A., & Reid, I. R. (2015). Calcium intake and risk of fracture: systematic review. BMJ (Clinical Research Ed), 351, h4580. http://doi.org/10.1136/bmj.h4580
7. Reid, I. R., Bolland, M. J., & Grey, A. (2010). Does calcium supplementation increase cardiovascular risk? Clinical Endocrinology, 73(6), 689–695. http://doi.org/10.1111/j.1365-2265.2010.03792.x
8. Bolland, M. J., Avenell, A., Baron, J. A., Grey, A., MacLennan, G. S., Gamble, G. D., & Reid, I. R. (2010). Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ (Clinical Research Ed), 341, c3691.
9. Bolland, M. J., Grey, A., & Reid, I. R. (2015). Should we prescribe calcium or vitamin D supplements to treat or prevent osteoporosis? Climacteric, 18(sup2), 22–31. http://doi.org/10.3109/13697137.2015.1098266
10. Warensjo, E., Byberg, L., Melhus, H., Gedeborg, R., Mallmin, H., Wolk, A., & Michaelsson, K. (2011). Dietary calcium intake and risk of fracture and osteoporosis: prospective longitudinal cohort study. BMJ (Clinical Research Ed), 342(may24 1), d1473–d1473. http://doi.org/10.1136/bmj.d1473
11. Kern, J., Kern, S., Blennow, K., Zetterberg, H., Waern, M., Guo, X., et al. (2016). Calcium supplementation and risk of dementia in women with cerebrovascular disease. Neurology, 10.1212/WNL.0000000000003111. http://doi.org/10.1212/WNL.0000000000003111
12. Vignaux, G., Besnard, S., Denise, P., & Elefteriou, F. (2015). The Vestibular System: A Newly Identified Regulator of Bone Homeostasis Acting Through the Sympathetic Nervous System. Current Osteoporosis Reports, 13(4), 198–205. http://doi.org/10.1007/s11914-015-0271-2