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Calcium, vitamin D and aortic valve calcification: to the bone or to the heart?
  1. Jutta Bergler-Klein
  1. Department of Cardiology, Medical University of Vienna, Vienna, Austria
  1. Correspondence to Professor Jutta Bergler-Klein, Dept. of Cardiology, Medical University of Vienna, Vienna 1090, Austria; jutta.bergler-klein{at}meduniwien.ac.at

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Calcium and vitamin D supplement: right or wrong?

Intuitively, one might think that supplementing vitamins and minerals would be the right thing to do especially in older and comorbid people. Every year, billions of dollars are spent in this belief.1 However, we may all be wrong.

A present study in this journal demonstrates a significantly increased cardiovascular (CV) mortality in elderly patients supplementing calcium, be it with or without vitamin D, who initially presented with mild to moderate aortic stenosis (AS) in a longitudinal analysis of a large contemporary echocardiography database cohort of 2657 patients.2 Patients were followed for aortic valve replacement (AVR) and/or death, as well as AS progression. About half of the study population was on supplementation, with about 40% taking calcium including vitamin D or not during more than 5.5 years. The absolute risk of CV mortality was strikingly higher with 13.7 for calcium±vitamin D supplementation and 9.6 for vitamin D only, compared with 5.8 per 1000 person-years in no supplementation. Surprisingly, also all-cause mortality was significantly higher with calcium addition. In almost half of the patients with calcium administration, AVR was performed during the follow-up, whereas AVR was needed in only 11% of non-supplementers. Interestingly, when stratifying by osteoporosis status, the differences in survival and AVR persisted unaltered between the groups.2

Calcium: the secret key?

Calcification is the cardinal process driving a vicious cycle that propagates aortic valve (AV) stiffness and obstruction.3 Disruption of the endothelial layer promotes the uptake of oxidised lipids and immune cells, promoting an inflammation–calcification loop with fibrotic remodelling of the aortic leaflets.4 Activation of the valvular interstitial cells (VICs) induces their osteogenic osteoblastic differentiation and collagen secretion, leading to further calcium deposition similar to skeletal bone formation.

Although multifactorial contributing pathways have been identified, so far no medical therapy has proven effective in stopping or reversing the fibrocalcific progression of AS.3 4 Despite that lipid accumulation is involved in the early initiation phase of AS, statins were not effective in the later propagation phase.

Dysregulated phosphate calcium metabolism is a major determinant in the development of aortic leaflet sclerosis and calcified AS, as triggered by impaired renal function, and in primary or secondary hyperparathyroidism.3 4 Identifying susceptible risk factors for valve calcification, which might be modified by non-invasive measures, such as targeted medication or dietary changes, instead of the purely mechanical surgical AVR approach, is highly desirable.

Serum levels of calcium appear to be less influenced by dietary intake, for example, by dairy products and food, whereas artificial calcium supplementation generated higher immediate serum calcium availability, which might prompt more ectopic valve mineralisation or vascular arterial atherosclerosis. Similarly, bone demineralisation releases excessive calcium and phosphate into the circulation in osteoporosis, which may induce the aortic VIC osteoblastic transformation.5 High serum calcium levels were pinned to a high prevalence of AV calcification in a cardiac CT scan study, similarly to high phosphorus and low magnesium levels.6 These micronutrients may contribute to lesion formation and initiate the mineralisation process in the aortic leaflets in the early pathogenesis stage.4 Interestingly, the progression of AV calcification, once established, was not further influenced by the serum levels, which compares similarly with the current study, where the temporal progression of AS severity was independent of any supplementation.2 However, mortality and incident of AVR were significantly magnified by calcium addition, which also appeared to worsen symptoms occurrence, as well as further vascular atherosclerosis degeneration.

Excitingly, vitamin D supplementation alone remained neutral with respect to AVR and was not linked to any mortality increase in multivariable analyses, so that the assumed beneficial effects concerning osteoporosis and bone metabolism are maintained in patients with AS.2

Bone and heart

Osteoporosis and lower bone mineral density, as often present in elderly individuals, have been associated with faster progression of AS and valve calcifications, also of the mitral valve ring.5 Osteoporosis has a major public health impact and more than 70% of related fractures occur in women, mainly postmenopausal, although also premenopausal women and men are affected.7 About half of white women have low bone mass with osteopenia or osteoporosis by age 60 years. However, the optimal intake and the actual utility of calcium supplements remain controversial, as increased risks of CV disease (CVD) and stroke among calcium users were repeatedly pointed out in cohort studies and meta-analyses.1 The US Institute of Medicine (report 2011) and recent guidelines recommend a primarily dietary calcium intake of 1200 mg/day for women >50 and men >70 years old, with risk of harm rising over 2000 mg/day and supplementation only in insufficient diet, as well as additional vitamin D depending on measured serum levels.7 Previous studies on calcium supplementation did not address AS adequately so far, highlighting the current research.2

On the other hand, men and women with osteoporosis present not only a higher risk of all-cause, but particularly also CV mortality.8 Individuals with osteoporosis had a higher prevalence of other comorbidities, and especially smoking in men. Notably, the risk of CV mortality was 68% higher in men with osteoporosis, and the incidence of CVD was 24% higher in women with osteoporosis. It has therefore recently been recommended that management of osteoporosis should include screening for CV and respiratory disease risk.

Importantly, in the present study in AS, the mortality increase with calcium supplementation persisted in women or men, and was independent of the osteoporosis status at entry.2 The findings were irrespective of vitamin D administration. In contrast, bisphosphonates and other osteoporosis treatments (alendronate or denosumab) could not halt the progressive AV calcification.3 4 However, as limitation for interpretation in the present context, in the SALTIRE II Study, patients with AS needing an obligatory treatment for osteoporosis with alendronate, denosumab or supplementation with calcium were excluded in the analysis.

Limitation of the present study of Kassis et al is that the actual dietary food consumption or other supplemental intake of calcium or vitamin D could not exclusively be determined, for example, of over-the-counter or alternative products.2 Another issue to consider is that the patients taking calcium supplementation had more comorbidities at baseline, such as chronic kidney disease, diabetes, and more pre-existent CVDs, for example, coronary, atrial fibrillation or heart failure, and more patients had diagnosis of osteoporosis. However, the frequency of multiple concomitant diseases is well in line with previous reports and real life in patients with osteoporosis, and there was no difference in age in patients taking calcium or not.8

To give or not to give: take home message

In conclusion, the safety of artificial supplementary calcium intake has to be considered in an individual and careful view. Evaluation of underlying CVD and risk factors such as lipids, smoking, hypertension or concomitant kidney disease should be taken into account of the overall clinical situation of the patient if osteoporosis treatment or prevention is aimed for. Calcium supplementation was associated with higher all-cause and CV mortality, and higher AVR intervention rates for AS (figure 1). Vitamin D appeared to be safe and did not influence the progression of AS. Future studies in osteoporosis should focus even more on CV events determining the overall mortality. Visualisation of CV calcifications in osteoporosis imaging modalities (eg, X-ray, CT) should be particularly included in the stratification of when to give only vitamin D or also additional calcium. In patients with calcific AS and high-risk CV, the present study strongly adds to the evidence that long-term continuous calcium supplementation should be avoided if not mandatory.2

Figure 1

Artificial calcium supplementation and bone demineralization in osteoporosis may activate osteoblastic transformation of the aortic valve interstitial cells. Excessive calcium may lead to higher incidence of AVR and higher CV mortality in patients with aortic stenosis. AVR, aortic valve replacement; CV, cardiovascular.

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Acknowledgments

The author would like to thank Dr. Andreas Spannbauer, Medical University of Vienna, for his excellent input to the graphic design.

References

Footnotes

  • Contributors JB-K is the sole contributor of this invited editorial.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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