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Is There a Link?1

Supplementation with calcium to support bone mineral density and reduce the risk of fractures is not controversial. Qualifications and refinements regarding calcium’s benefits to bone health and fracture reduction have been proposed with varying degrees of support, yet overall the consensus is one of benefit. In contrast to this consensus, there is considerable controversy regarding the unintended results of calcium supplementation. Concern arises primarily from trials in which calcium was supplemented alone without any of the co-factors and other nutrients found in bone and in dietary sources of calcium.

In 2010, a meta-analysis pooling the data from 15 calcium trials cast doubt on the wisdom of an approach built around supplementation with calcium alone. (Calcium sources were carbonate, citrate, lactogluconate or combinations thereof.) In this analysis of results involving 12,000 individuals, calcium supplementation was associated with a 30 percent elevation in the risk of heart attack.2 Subsequently, other studies have been published that appear to confirm a cardiovascular risk with calcium supplementation. Oddly, however, at least one such study did not find an increased risk in women, only in men.3 Prospective epidemiologic studies have examined the intake of dietary and supplemental calcium to uncover any association with CVD incidence or mortality in middle-aged and older adults (preponderantly menopausal and post-menopausal women) with inconsistent results.4

The Protective Role of Co-factors
To put the calcium-only trial results in perspective, the simple addition of vitamin D in the “Women’s Health Initiative calcium-vitamin D randomized controlled trial (2009)” was enough to prevent an increase in cardiovascular risk.5 36,282 postmenopausal women aged 51–82 years were assigned to 1,000 mg of elemental calcium and 400 IU of vitamin D3 daily or placebo with average followup of 7.0 years. A more recent re-analysis of the WHI data reconfirmed the protective effect of vitamin D co-supplementation.6 There was no increase in coronary events. The source of the difference between this trial and the results of the meta-analysis? Vitamin D plays a role in directing the course of calcium in the body. In appropriate amounts, vitamin D helps ensure that calcium makes its way to and is deposited in the hard tissues—the bones and teeth— rather than in the soft tissues, such as the arteries. Not surprisingly, recent research has demonstrated that adequate vitamin D intake and blood levels, on balance, are associated with better cardiovascular health. Most, albeit not all,7 large studies have found that baseline 25-OH vitamin D blood levels are predictive of both cardiovascular disease and overall mortality.8

Another theme that appears repeatedly in the literature reviewing this topic is that calcium from dietary sources is not associated with elevated cardiovascular risk.9 This finding makes a great deal of sense physiologically. It should be kept clearly in mind that bone not only does not consist only of calcium, it also does not consist only of minerals. Approximately 28 percent of bone consists of collagen and related proteins. With regard to minerals in bone, there are significant amounts of phosphorous and magnesium found in conjunction with calcium. These other minerals are important. In osteoporosis, the magnesium content of bone may be on the order of 0.5—0.6 percent, whereas in healthy bone the content generally is on the order of 1.2 to 1.8 percent (numbers are rounded). Moreover, it is likely that 60 percent or more of Americans are magnesium deficient.10 Greater magnesium intake, of course, is linked not just to better bones,11 but also to better blood pressure and superior cardiovascular health.12

The list of appropriate “chaperones” for calcium can be extended to include boron, vitamin K (especially as K2), and so forth. A number of these have been studied both through epidemiology and through classic clinical interventions. Vitamin K deficiency, for instance, is linked to reduced bone mineral density and increased the risk of fractures. The addition of supplemental K2 to treatments with either vitamin D or hormones has been shown to improve results. Moreover, as part of the “calcification paradox” in which osteoporosis is associated with increased rates of arterial calcification, vitamin K long has been known to exert opposite effects upon calcium deposition in the bones and the arteries. On balance, the evidence is that “[p]hytonadione and menaquinone may be effective for the prevention and treatment of osteoporosis and arterial calcification.”13

The point is that dietary sources of calcium consist of more than calcium and, as the meta-analysis in question itself notes, high dietary calcium intake is not associated with cardiovascular risk. Supplements that mimic dietary sources of calcium or are themselves dietary sources of calcium, such as ossein microcrystalline hydroxyapatite, have been shown to improve bone health.14,15 There is every reason to expect that a supplement that includes vitamins C, D3, K (various forms), magnesium, manganese, zinc, etc., all of which are heart-supportive and work in conjunction with calcium, itself is generally conducive to health.

Are Purified Calcium Sources a Source of Problems?
The forms of calcium used in supplements might be said to be the unacknowledged elephant in the room. In the 2010 meta-analysis, the calcium sources were carbonate, citrate, lactogluconate and/or combinations of these. The arguments for these sources range from cost (calcium carbonate, especially, being very cheap to produce) to purity to solubility.

Leaving aside the first two reasons, a primary driver of the development and marketing of calcium products has been the issue of solubility. This is unfortunate inasmuch as this has been known to be a red herring for more than two decades. There is a large amount of data that cast doubt upon the role of solubility of calcium supplements in subsequent calcium absorption. Indeed, there are many studies that compellingly reject any strong role for the degree of solubility of calcium supplements in determining absorption. As one researcher has put it, “calcium absorption does not seem to depend on the presence of gastric acid or on the degree of solubility of a given calcium salt.”16 Such findings have been replicated many times.

There are many aspects of calcium supplementation that defy facile generalizations. For instance, the mere increase in the mineral content of the bones sometimes is without real benefit in terms of preventing fractures. The effects of fluoride on bone mineral density, but lack of benefit and even an increase in fractures is a case in point.17,18 The same unexpected lack of benefit emerged from a meta-analysis of 15 randomized trials (n=47,365) in which calcium alone or with vitamin D was administered.19 Such findings have cast serious doubt on the prior facile equation of improved BMD and improved fracture risk. Whether calcium plus vitamin D resolves this issue is unclear, although there is evidence that the problem in this latter case is that the inconsistent results are a result of different vitamin D status and calcium intake at baseline, different doses and poor compliance in many of the trials. A Dutch review put the matter in perspective, to wit, “findings of community-based clinical trials with vitamin D and calcium supplementation in which compliance was moderate or less have often been negative, whereas studies in institutionalized patients in whom medication administration was supervised ensuring adequate compliance demonstrated significant benefits.”20 In other words, if both calcium and vitamin D are taken as directed, benefits are likely, but no benefits can be expected if the supplement is not taken as directed!

Calcium absorption normally is good. Indeed, the intestinal rate of absorption of calcium always declines rapidly as blood levels increase and therefore absorption is actually somewhat weak as a marker for the efficacy of a calcium product even under the best of circumstances. Unfortunately, higher rates of absorption do not appear to be well correlated to higher rates of improvement in bone health. Moreover, as with most compounds, rapid and excessive elevations of blood levels upset homeostasis and encourage rapid clearance or other countervailing mechanisms. Radically increased rates of calcium absorption leading to greatly elevated serum calcium levels may be one cause for the findings now being reported regarding calcium and cardiovascular disease. Overwhelming the body’s calcium uptake regulatory mechanisms with a calcium source that is dramatically more bioavailable than is the calcium even from the best calcium-rich foods should not be presumed to provide a benign advantage. Food-based sources of calcium and calcium supplements that act similarly to foods in both uptake and the inclusion of minerals and other nutrients found along with calcium in foods appear to be both safer and, according to the evidence, more effective.

Food calcium is sometimes referred to as “matrixbound” calcium. Calciums from milk and bone are different— they are tricalcium phosphate and hydroxyapatite (different types of calcium phosphates). Often it is claimed that matrix-bound calcium products—algal, eggshell, milk, bone, etc.—provide superior benefits. Perhaps they do, but it is not because of the nature of the calcium present. The benefits of matrix-bound calcium over other forms has more to do with the nature of the matrix than with the calcium.

  • • Algal and eggshell calciums contain additional trace elements21
  • • Bone-specific growth factors are found in eggshell and ossein (bone) matrices
  • • Milk calcium (if it uses the milk matrix and is not simply purified tricalcium phosphate) has a significant portion of colloidal phosphocaseinate that may prevent calcium precipitation and may prolong calcium residence time in the gut.22 Providing a sustained calcium dose has a stimulatory effect on passive diffusion.

To clarify the impact of matrix components other than calcium on bone health benefits, let’s take a closer look at the effects of bone-derived calcium on bone growth. Bonederived calcium is ossein-hydroxyapatite complex (OHC) also sometimes referred to as microcrystalline hydroxyapatite. This complex of hydroxyapatite calcium and protein (ossein) is isolated from bovine bone. Ossein is rich in proteins that stimulate bone growth: collagens, osteocalcin, and growth factors (IGF-I,II, TGF-B, bone morphogenic protein). This calcium source has been the subject of numerous studies (for a summary of 18 comparative OHC studies, see Castelo-Branco, C., et al., “Efficacy of osseinhydroxyapatite complex compared with calcium carbonate to prevent bone loss: a meta-analysis.” Menopause, 2009. 16(5): p. 984–91). When compared to calcium alone in the form of calcium carbonate, the ossein matrix provided an additional increase in BMD of at least 1 percent for total BMD and increases of up to 5 percent in vertebrae.

Clinical studies thus have uncovered an important clue with regard to the relation between calcium absorption and BMD, especially with regard to certain sites, such as the spine. If taken with meals, most forms of calcium yield similar absorption data and the differences between the best and the poorest performing sources can generally be overcome by taking just a bit more calcium. The 5 percent additional calcium found in the spinal vertebrae of women taking bone-derived calcium rather than calcium carbonate represents the actions of the other components found in the calcium source and not the impact of the calcium itself.

Non-calcium nutrients play many roles in bone health. The trace mineral boron, for instance, has a part in estrogen metabolism. Potassium has been shown to reduce calcium loss from the body. Magnesium, as is true of vitamin D and vitamin K2, helps to keep calcium in the bones, where it belongs, rather than in the lining of the arteries, where it does not. Zinc stimulates bone formation and reduces bone resorption. One or more of these nutrients always is found along side calcium in food sources and, likewise, in bone sources of calcium and in well-designed formulas. In contrast to food and other sources of calcium that are food-like, there is little or no reliable evidence that “purifying” calcium and making it more and more soluble improves upon bone benefits, yet it is becoming clear that overwhelming the body’s mechanisms for controlling calcium uptake can lead to negative effects, including upon the heart.

Conclusion
Bone health is a serious matter and it involves more than maintaining BMD or supplementing with calcium. The primary issue with calcium is not absorption, getting it into the body, but rather getting it to go where it is supposed to go and do what it is supposed to do. Most forms of calcium are similarly absorbed. Calcium forms are separated from one another in terms of benefits to a large extent by associated nutrients, including trace elements and activating factors. It is these factors that separate bone-derived or eggshell calcium from mere calcium carbonate. Similarly, nutrients such as silicon and vitamin K support calcium and vitamin D in part by influencing the factors associated with bone quality, not just bone quantity. Yes, calcium and BMD are important, but greater bone matrix health and reduced fracture risks are the true hallmarks of improved bone quality.

In other words, properly balanced and manufactured calcium supplements including co-factors and associated nutrients support bone heath, not risk factors. The majority of studies and reviews that have examined vitamin D usage in conjunction with calcium have found no relation to cardiovascular disease. Better yet, the preponderance of studies and reviews that have examined food as the source of calcium in the diet have found no relation to cardiovascular disease. The effects of dietary and supplemental calcium thus should be viewed as being controlled by the nature of the calcium ingested and by the adequacy of other nutrients that control how calcium is used and deposited in the body.

Endnotes:

  1. This is a longer version of an article that has been published previously.
  2. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010 Jul 29;341:c3691. doi: 10.1136/bmj.c3691.
  3. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study. JAMA Intern Med. 2013 Apr 22;173(8):639–46.
  4. Rautiainen S, Wang L, Manson JE, Sesso HD. The role of calcium in the prevention of cardiovascular disease a review of observational studies and randomized clinical trials. Curr Atheroscler Rep. 2013 Nov;15(11):362.
  5. LaCroix AZ, Kotchen J, Anderson G, Brzyski R, Cauley JA, Cummings SR, Gass M, Johnson KC, Ko M, Larson J, Manson JE, Stefanick ML, Wactawski-Wende J. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2009 May;64(5):559–67.
  6. Prentice RL, Pettinger MB, Jackson RD, Wactawski-Wende J, Lacroix AZ, Anderson GL, Chlebowski RT, Manson JE, Van Horn L, Vitolins MZ, Datta M, LeBlanc ES, Cauley JA, Rossouw JE. Health risks and benefits from calcium and vitamin D supplementation: Women’s Health Initiative clinical trial and cohort study. Osteoporos Int. 2013 Feb;24(2):567–80.
  7. 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 metaanalysis. BMJ. 2011 Apr 19;342:d2040.
  8. Heine GH, Nangaku M, Fliser D. Calcium and phosphate impact cardiovascular risk. Eur Heart J. 2013 Apr;34(15):1112–21.
  9. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart. 2012 Jun;98(12):920–5.
  10. http://www.mgwater.com/rod15.shtml
  11. Castiglioni S, Cazzaniga A, Albisetti W, Maier JA. Magnesium and osteoporosis: current state of knowledge and future research directions. Nutrients. 2013 Jul 31;5(8):3022–33.
  12. Eilat-Adar S, Sinai T, Yosefy C, Henkin Y. Nutritional recommendations for cardiovascular disease prevention. Nutrients. 2013 Sep 17;5(9):3646–83.
  13. Adams J, Pepping J. Vitamin K in the treatment and prevention of osteoporosis and arterial calcification. Am J Health Syst Pharm. 2005 Aug 1;62(15):1574–81
  14. Robert A. Disilvestro, Bethany Crawford, Wenyi Zhang and Sid Shastri. Effects of micronutrient supplementation plus resistance exercise training on bone metabolism markers in young adult woman. Journal of Nutritional & Environmental Medicine. February 2007;16(1): 26–32.
  15. Castelo-Branco C, Ciria-Recasens M, Cancelo-Hidalgo MJ, Palacios S, Haya-Palazuelos J, Carbonell-Abelló J, Blanch-Rubió J, Martínez-Zapata MJ, Manasanch J, Pérez-Edo L. Efficacy of ossein-hydroxyapatite complex compared with calcium carbonate to prevent bone loss: a meta-analysis. Menopause. 2009 Sep-Oct;16(5):984–91.
  16. Recker RR. Prevention of osteoporosis: calcium nutrition. Osteoporos Int. 1993;3 Suppl 1:163–5.
  17. Haguenauer D, Welch V, Shea B, Tugwell P, Adachi JD, Wells G. Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis. Osteoporos Int. 2000;11(9):727–38.
  18. Riggs BL, O’Fallon WM, Lane A, Hodgson SF, Wahner HW, Muhs J, Chao E, Melton LJ 3rd. Clinical trial of fluoride therapy in postmenopausal osteoporotic women: extended observations and additional analysis. J Bone Miner Res. 1994 Feb;9(2):265–75.
  19. Rabenda V, Bruyère O, Reginster JY. Relationship between bone mineral density changes and risk of fractures among patients receiving calcium with or without vitamin D supplementation: a meta-regression. Osteoporos Int. 2011 Mar;22(3):893–901.
  20. Lips P, Bouillon R, van Schoor NM, Vanderschueren D, Verschueren S, Kuchuk N, Milisen K, Boonen S. Reducwwing fracture risk with calcium and vitamin D. Clin Endocrinol (Oxf). 2010 Sep;73(3):277–85.
  21. Schaafsma, A., et al., Mineral, amino acid , and hormonal composition of chicken eggshell powder and the evaluation of its use in human nutrition. Poult Sci, 2000. 79(12): p. 1833–8.
  22. Gueguen, L. and A. Pointillart, The bioavailability of dietary calcium. J Am Coll Nutr, 2000. 19(2 Suppl): p. 119S–136S.

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