Summary
1. Introduction
Sustaining an sufficient calcium consumption by way of dietary sources or dietary supplements is broadly considered a secure and efficient technique for the prevention and therapy of osteoporosis. In each postmenopausal girls and older males calcium supplementation or elevated dietary calcium by way of fortified milk has been proven to gradual or forestall bone loss at frequent fracture websites such because the hip and backbone [1,2,3,4,5]. It’s seemingly that these optimistic results on bone density translate into anti-fracture efficacy, because the findings from a latest meta-analysis of randomized managed trials (RCTs) in adults aged 50 years and older reported that calcium supplementation or mixed calcium and vitamin D supplementation decreased the relative threat of fractures by 12% [6]. At current, most dietary tips advocate that older adults and the aged purpose for a ordinary complete calcium consumption (food regimen and dietary supplements) of 1,000 to 1,300 mg per day. These necessities are primarily based largely on information from calcium stability research and the dedication of the ‘maximal calcium retention’ or the brink worth at which stability doesn’t additional enhance as consumption will increase [7]. Nonetheless, latest information primarily based on calcium intakes round predicted zero stability means that calcium necessities ought to be within the vary of 741 to 1035 mg/d for wholesome adults, no matter age or intercourse [8]. Whereas it’s past the scope of this overview to debate the particular deserves related to the dedication of calcium necessities for adults, it is very important spotlight that many aged individuals don’t receive ample calcium by way of dietary sources alone. In consequence, calcium dietary supplements are broadly really helpful and have historically been thought-about a secure various to assembly calcium necessities. The most typical unwanted effects relate to bloating, constipation and extra uncommonly, a barely elevated threat of kidney stones [9].
Over the previous twenty years there was a rising physique of proof to counsel that using calcium [13,14,15,16,17,18,19] or calcium-vitamin D dietary supplements [10,11,12] could result in numerous non-skeletal well being advantages, together with useful results on heart problems (CVD) and associated threat elements, kind 2 diabetes, sure cancers and even mortality. As an example, a number of scientific trials and meta-analyses have reported that calcium supplementation could enhance serum lipids concentrations [15,16,17] and blood strain [18,19]. Primarily based on these findings, one may anticipate that elevated calcium would have protecting results on varied cardiovascular endpoints, such myocardial infarction (MI), coronary coronary heart illness (CHD) or stroke. Nonetheless, there’s rising information from varied research (observational, an RCT and a meta-analysis) that long-term use of calcium dietary supplements in wholesome older adults, notably girls, might not be secure as a result of it might have an adversarial impact on cardiovascular outcomes [20,21,22]. As a result of ageing can also be related to an elevated incidence of CVD, even a slight improve in adversarial vascular occasions could be clinically necessary as a result of it would counterbalance any useful results of calcium dietary supplements in stopping osteoporosis and fractures.
This overview gives an summary of the most recent proof regarding the consequences of calcium supplementation on vascular illness and associated threat elements and related mortality within the aged. A number of critiques have just lately evaluated the affect of dairy meals on heart problems threat [23,24], and thus we won’t give attention to their potential results. Nonetheless, the final consensus from these critiques is that dairy meals consumption is just not related to the next threat of CVD.
2. Calcium Supplementation, Cardiovascular Illness and Mortality
There have been numerous giant observational epidemiological and potential research which have investigated the affiliation between calcium consumption and calcium complement use, and heart problems threat and associated mortality in older ladies and men. Sometimes, the findings from these research point out both a impartial impact [25,26,27] or a modest protecting impact of a excessive complete calcium consumption in opposition to vascular illness and even mortality [10,14,28]. With regard to the particular results of calcium dietary supplements nonetheless, most research so far have reported a non-significant impact. For instance, in a potential research of 34,486 postmenopausal Iowa girls aged 55–69 years adopted for 8 years, the relative threat of ischemic coronary heart illness (IHD) mortality was 0.67 (95% CI, 0.47–0.94) for ladies within the highest in comparison with lowest quartile for complete calcium consumption (food regimen + dietary supplements) [14]. In distinction, for ladies (n = 56) taking >500 mg/d of calcium dietary supplements there was no important threat discount [multivariate relative risk (RR) 0.88 (95% CI, 0.64, 1.23)] [14]. Related non-significant findings with regard to calcium complement use have been reported in a 12 yr potential research in 39,800 males aged 40–75 years enrolled within the Well being Professionals Comply with Examine [25]. On this research, the multivariate RR for growing IHD within the highest quintile of calcium complement use (median 1000 mg/d) in contrast with non-users was 0.87 (95% CI, 0.64, 1.19); the RR for nonfatal MI and IHD have been 1.02 (95% CI, 0.71, 1.46) and 0.61 (95% CI, 0.34, 1.10), respectively [25]. Two different giant research additionally reported that the RR of stroke was no totally different in males or girls who obtained 400 mg/d or extra of supplemental calcium in contrast with non-users [26,27]. Knowledge from a small research of acute hip fracture sufferers confirmed that using prescribed calcium and vitamin D dietary supplements post-fracture was related to a 36% and 43% discount in demise in ladies and men, respectively, after 3 years [28]. Opposite to all these findings, a latest potential research in 10,555 Finnish girls aged 52-62 years who have been freed from coronary coronary heart illness (CHD) at baseline and adopted for a imply of 6.55 years, reported that girls utilizing calcium dietary supplements (or calcium plus vitamin D) had a 24% elevated threat of CHD in comparison with non-users [1.24 (95% CI, 1.02, 1.52)] [21]. It’s considerably tough to elucidate these findings provided that the typical age of the ladies was 57 years, and people taking dietary supplements had a decrease BMI, have been extra usually non-smokers or former people who smoke and had much less diabetes and hypertension mortality than non-users.
Though there aren’t any RCTs which have particularly evaluated the impact of calcium complement use on CVD occasions or associated mortality, numerous research have pre-specified or carried out secondary analyses to evaluate the impact of calcium supplementation on varied cardiovascular endpoints, together with MI, stroke, CHD, sudden demise or their mixture (Desk 1). Of those, the findings from a latest preplanned secondary evaluation of a 5-year RCT of 1471 wholesome, aged postmenopausal girls who obtained calcium citrate (1,000 mg/d) or placebo has obtained probably the most consideration as a result of it has raised issues in regards to the cardiac security for supplemental calcium [20]. Nonetheless, an accompanying editorial highlighted that information from this research weren’t completely constant, and thus should be interpreted cautiously [29]. Within the evaluation primarily based on self-report after which adjudication by physicians (verified), these receiving calcium supplementation had a elevated threat of MI (RR self report 2.24, p < 0.001; RR verified 2.12, p < 0.05) and the composite endpoint of MI, stroke or sudden demise (RR self report 1.66, p < 0.01; RR verified 1.47, p = 0.08) [30] (Figure 1). When the authors then searched the New Zealand hospital database of hospital admissions to identify additional vascular events that might have been missed, no statistically significant differences were detected between the calcium and placebo groups for either MI [RR 1.49 (95% CI, 0.86. 2.57)] or the composite endpoint [RR 1.21 (95% CI, 0.84, 1.74)] [30] (Figure 1). However, rate ratio analysis revealed a trend for an increased risk of MI (1.67, p = 0.058) and the composite endpoint (1.43, p = 0.043). These findings do not provide conclusive evidence, although surprisingly the authors maintain that ‘..there are reasonable grounds for doubting the safety of calcium supplements..’ and suggest ‘.. there should be a reappraisal of their role in the management of osteoporosis..’ [31]. This view is not universally shared. Other investigators have raised concerns about various aspects of this study, including the relatively small number of vascular events and the wide confidence intervals, the borderline significance of many of the findings, and the failure to consider other important confounders, including serum 25-hydroxyvitamin D [32,33]. It is therefore critical that the results from other similar calcium supplementation studies be considered when evaluating the clinical and public health significance of these findings. A summary of the key findings from the various RCTs that have evaluated the effects of calcium supplementation or combined calcium-vitamin D supplementation on cardiovascular related endpoints is presented in Table 1. In all these previous RCTs (with the exception of the Auckland study) there were no statistically significant adverse (nor beneficial) effects of calcium supplementation on CVD risk. For example, in an Australian study of 1460 postmenopausal women aged ≥70 years who were randomized to take calcium carbonate (1,200 mg/d) or placebo for 5 years, Prince et al. [3] reported that incident IHD was no different between the supplemented and placebo group [HR 1.12 (95% CI, 0.77,1.64)]. Similarly, secondary analysis of a 4-year RCT in 1179 postmenopausal women aged >55 years in the US discovered no extra incidence of MI or different vascular occasions within the calcium handled (1,400–1,500 mg/d calcium citrate or carbonate) in comparison with placebo group [34]. Nonetheless, the members on this research have been ~10 years youthful than the Auckland girls. Regardless of this, it’s intriguing that each these trials have been much like the Auckland research when it comes to their design, research length, variety of members and baseline calcium intakes (~850–1,000 mg/d), however failed to look at any important adversarial results. As well as, the dose of calcium was much less within the Auckland research (1,000 mg/d versus 1,200–1,500 mg/d). Nonetheless, one potential rationalization for the contrasting outcomes could relate to the kind of calcium dietary supplements used. Ladies within the Auckland trial consumed calcium citrate, whereas calcium carbonate was used within the Australian research and carbonate or citrate within the US trial. Calcium citrate has been reported to have superior bioavailability in contrast with calcium carbonate [35], and results in a higher acute rise in ionized calcium focus [36]. These findings, along with the truth that calcium carbonate should be taken with meals, could also be one rationalization for the contrasting outcomes. Variations in serum 25-hydroxyvitamin D [25OHD] ranges might also be a contributing issue provided that low vitamin D has been related to an adversarial cardiovascular threat profile and elevated threat of CV occasions [37,38]. Serum 25OHD ranges weren’t reported within the Auckland research, however within the Australian and US trials ranges ranged from a imply of 67 to 72 nmol/L.
When evaluating the potential adversarial results of calcium complement use on vascular occasions and associated mortality, it is usually value contemplating information from two of the biggest trials [RECORD study and the Women’s Health Initiative (WHI)] that have been designed to look at the consequences of calcium carbonate and/or vitamin D on fracture incidence [39,41]. In each these research, no important general impact of complement use on cardiovascular occasion charges or mortality was noticed [10,39,41]. The RECORD Examine didn’t report vascular occasions, however there have been no variations in demise charges between calcium complement customers and non-users (17.7% vs. 16.2%) [39]. Within the WHI trial involving over 36,000 postmenopausal girls, the HR was 1.04 (95% CI, 0.92–1.18) for MI or CHD demise [41] and 0.91 (95% CI, 0.83, 1.01) for complete mortality [10]. There was a development for a rise in a composite end-point of MI, demise from CHD, coronary artery bypass graft or percutaneous coronary intervention [HR 1.08 (95%CI 0.99–1.18)] [41]. A serious limitation of this research is that over 50% of the ladies have been utilizing non-study calcium dietary supplements. Curiously, when the evaluation was restricted to girls not self administering calcium, there was a 17% important elevated threat of MI or coronary revascularization [HR 1.17 (95% CI, 1.01, 1.36)] [22]. Nonetheless, in a subsequent research the authors reported that in girls youthful than 70 years of age, there was a development towards a discount within the threat of complete, cardiovascular and most cancers mortality in these receiving calcium plus vitamin D supplementation [10]. When deciphering these findings and people from the RECORD research, it is very important think about using vitamin D given the proof that supplemental vitamin D could cut back heart problems threat and all-cause mortality [43]. Different potential necessary confounding elements should even be thought-about when evaluating the outcomes of the WHI research, together with non-compliance and using HRT.
In gentle of the rising concern {that a} excessive supplemental calcium consumption could also be related to an elevated threat for cardiovascular occasions, two latest research have reviewed the obtainable calcium supplementation RCTs that included cardiovascular endpoints [22,44]. Wang et al. [44] carried out a scientific overview of potential research and RCTs that examined calcium supplementation, vitamin D supplementation or each on subsequent cardiovascular occasions. When the information from the RCTs have been mixed, the RR for CVD was 1.14 (95% CI, 0.92, 1.41) for calcium dietary supplements versus placebo, and 1.04 (95% CI, 0.92, 1.18) for mixed calcium plus vitamin D versus double placebo. There was additionally no important impact of vitamin D supplementation on CVD [RR 0.90 (95% CI, 0.77, 1.05)] [44]. Primarily based on these findings, the authors concluded that calcium dietary supplements appear to have minimal cardiovascular results, however a limitation of this research is that solely a small variety of trials have been included within the meta-analysis. A more moderen and complete meta-analysis included a bigger variety of trials (n = 15), with patient-level information obtainable for 5 research (n = 8151), and trial-level information for 11 research (n = 11,921) with a imply follow-up of 4 years [22]. The inclusion standards for this research have been placebo managed trials >12 months in length with a calcium complement dose >500 mg/d and no less than 100 members [22]. For members allotted to calcium dietary supplements, the HRs for MI have been 1.31 (95% CI, 1.02, 1.67) and 1.27 (95% CI, 1.01, 1.59) for the patient- and trial- degree information, respectively. This means that using calcium dietary supplements was related to an ~30% improve in heart problems threat. Nonetheless, since these outcomes are presently solely obtainable in summary type, it’s tough to offer a extra complete analysis of the methodology and research findings.
3. Calcium Supplementation, Lipids and Blood Strain
If using calcium dietary supplements is related to an elevated threat of heart problems, one may anticipate that different frequent cardiovascular threat elements, comparable to ldl cholesterol, lipids and blood strain, would even be adversely affected. Opposite to this speculation, the findings from numerous scientific trials have proven that calcium supplementation was related to enhancements in serum lipids concentrations, notably in girls [15,16,17]. This impact is reported to be because of the binding of calcium to fatty acids and bile acids within the intestines, which ends up in a discount in fats absorption [16,45]. It has additionally been proposed {that a} discount in parathyroid hormone (PTH) and/or 1,25-dihydroxyvitamin D following calcium supplementation could result in a lower in intracellular calcium which reduces calcium flux into adipocytes [46]. This will likely then inhibit lipogenesis and promote lipolysis [46], resulting in decrease adiposity and thus favorable results of lipid and lipoprotein ranges. This proposed impact of calcium on adipocyte lipid metabolism, together with the reported pressor results of calcium on vascular easy muscle cells [47], might also clarify the findings that calcium supplementation can decrease the chance of hypertension. Outcomes of a number of meta-analyses of RCTs point out that calcium supplementation can result in small however important reductions in each systolic and diastolic blood strain [18,19], with the best blood-pressuring reducing results noticed in these with the bottom baseline calcium intakes ( < 600–800 mg/d) earlier than supplementation [19,48] and/or those that are hypertensive [49]. Primarily based on these findings, it will seem that any potential adversarial results of calcium on cardiovascular endpoints are unlikely to be secondary to modifications in both lipids or blood strain.
4. Calcium Supplementation and Vascular Calcification – “calcium overdose”
Vascular calcification is a marker of sub-clinical atherosclerotic illness, and an impartial predictor of subsequent vascular morbidity and mortality in women and men, together with CHD, CVD and mortality [50]. In sufferers with kidney illness, there’s proof from scientific trials exhibiting that using calcium dietary supplements is related to elevated vascular calcification [51]. For instance, the outcomes from a 12 month trial in 200 hemodialysis sufferers evaluating calcium acetate or carbonate with a non-calcium primarily based binder (sevelamer) confirmed that calcium supplementation result in a extra fast improve in each coronary and aortic calcification [52]. Within the Auckland Calcium Examine, the authors speculated that the upward developments in cardiovascular occasion charges may very well be associated to the age of the members and their related discount in renal operate [20]. The imply glomerular filtration fee (GRF) of the ladies on this research was 61 (SD 11) mL/min [31], which signifies {that a} portion of ladies had impaired renal operate. In 90 pre-dialysis sufferers with a imply GRF of ~30 mL/min, supplementation with calcium carbonate for a mean of two years resulted in a major improve in coronary artery calcification (CAC), however these modifications in complete calcium scores (TCS) weren’t considerably totally different from controls (178 vs. 205) [53]. Subsequently, it’s questionable whether or not impaired renal operate is a probable purpose for the elevated vascular threat within the postmenopausal girls receiving calcium within the Auckland trial.
In apparently wholesome older women and men, there are few research which have investigated the consequences of elevated calcium on the development of vascular calcification. Bhakta et al. [54] carried out a retrospective evaluation in a subgroup of members (n = 257) enrolled within the potential Epidemiology of Coronary Artery Calcification research in Minnesota who have been aged >60 years and had full 4-year follow-up on aortic worth calcification (AVC) as assessed by electron beam computed tomography (EBCT). In girls, the development of AVC or CAC over a imply of three.7 years was no totally different between those that reported utilizing calcium dietary supplements (n = 25) and people who didn’t (n = 114); no males within the research reported utilizing calcium dietary supplements. Equally, the findings from a 2-year RCT involving 163 wholesome males aged 57 ± 10 years who had taken 1200 mg/d of supplemental calcium or placebo revealed that supplementation was not related to a rise in coronary calcification assessed by computed tomography (CT) [55]. In distinction, in a retrospective evaluation of a 2-year RCT, we reported that supplementing the food regimen with calcium and vitamin D3 fortified milk (1,000 mg/d and 800 IU/d) could speed up stomach aortic calcification (AAC) measured by CT in older males, however solely in those that introduced with AAC previous to the graduation of the research [56]. On this subgroup of males, who had a imply dietary calcium consumption at research entry of ~900 mg/d, the imply AAC scores elevated considerably within the milk relative to regulate group [mean change (95%CI); 24 (7, 42); controls 6 (-5, 18), P < 0.05], impartial of age, BMI, anti-hypertensive or lipid-lowering medicine use, smoking, train or blood strain [56]. It's tough to elucidate these outcomes given that there have been no variations between the fortified milk and management teams for modifications in weight, fats mass, blood strain, lipids, serum calcium, GFR, fats or saturated fats consumption. As well as, baseline serum 25OHD ranges have been ~75 nmol/L, and elevated additional following supplementation which could be anticipated to have a protecting impact. The event of vascular calcification is a fancy course of that's not solely depending on the physio-chemical results of calcium and phosphate, but in addition on elements that may regulate the differentiation of easy muscle cells to osteoblast-like cells; much like these in osteogenesis. Potential mediators embody each inhibitors [pyrophosphate; osteoprotegerin (OPG); osteopontin, matrix Gla protein (MGP), fetuin A, parathyroid hormone-related protein (PTHrP); fibroblast growth factor 23 (FGF 23)] and activators [phosphorus, calcium, alkaline phosphatase; bone morphogenetic protein 2, 1,25(OH)2D; osteocalcin; osteonectin; oxidized low density lipoprotein (LDL), advanced glycation end products (AGEs)] that regulate this course of [51]. Earlier analysis has proven that serum OPG, which inhibits osteoclast differentiation and exercise and stimulates osteoclast apoptosis, is said to cardiovascular occasions [57], and the presence and/or severity of aortic calcification in sufferers present process haemodialysis [58] or these with peripheral vascular illness [59]. Nonetheless, in 80 wholesome older girls from the Auckland Calcium Examine, no variations have been noticed for the modifications in serum OPG and MGP in girls handled with calcium or placebo for five years [31].
5. Calcium Supplementation and Cerebrovascular Illness Danger
A number of the early work inspecting the connection between calcium and cerebrovascular illness means that there could also be a protecting impact of calcium. For instance, in an ecologic research of aged individuals from the southwest of France, a excessive degree of calcium in consuming water was related to a decrease threat of noncerebrovascular (10%) and cerebrovascular (14%) associated demise [60]. Calcification of vascular easy muscle has additionally been related to mind lesions, that are a marker of cerebrovascular illness. Within the aged, there’s some proof {that a} excessive calcium consumption is related to mind lesions. Payne et al. [61] examined the connection between dietary calcium and vitamin D intakes and mind lesions, measured by MRI scans, in 232 aged women and men (95 with present or prior melancholy, 137 with out melancholy). They discovered that each calcium and vitamin D have been positively related to the next complete quantity of mind lesions, even after controlling for potential confounders, together with age, hypertension, diabetes, coronary heart illness, kilocalories, group (melancholy or no melancholy), and lesion load (excessive or low). Moreover, the authors’ earlier work discovered that people consuming high-fat dairy merchandise (1.8 serves per day) had 1.5 instances higher mind lesion quantity than these consuming 0.3 serves per day [62]. Though cause-and-effect can’t be established from these cross-sectional research, the obvious hyperlink between calcium and mind lesions warrants additional analysis provided that mind lesions have additionally been linked to an elevated threat of cognitive impairment, dementia, and melancholy.
6. Calcium Supplementation and Kidney Stones
Kidney stones have been linked to a excessive calcium consumption, however this seems to depend upon the supply of calcium. A number of potential research reported {that a} food regimen excessive in calcium is related to a decreased threat of kidney stones, probably by lowering intestine absorption of oxalate which is among the principal parts of kidney stones [63,64]. In distinction, using calcium dietary supplements has been related to an elevated threat, though these discovering will not be constant. As an example, information from the 7-year Ladies’s Well being Initiative (WHI) trial revealed that the chance of kidney stones (renal calculi) was elevated by 17% in these receiving calcium and vitamin D dietary supplements [HR 1.17 (95% CI, 1.02, 1.34) [9]. In distinction, a scientific overview of calcium supplementation trials in postmenopausal girls revealed that the majority research present no improve in stone threat with a excessive calcium consumption (food regimen or dietary supplements), and in reality a number of trials reported an inverse affiliation between calcium consumption and stone threat [65].