This non-interventional, prospective, multicenter study provides novel insights into the adherence and safety of calcium citrate supplementation in an elderly osteopenic population. The primary objective of the study, to evaluate adherence in this population was achieved; mean adherence rate was 76.6 ± 29.5%, with a median of 91.0% observed up to 1 year, indicating satisfactory adherence overall. Moreover, approximately one-third of the subjects achieved 100% adherence, reflecting a high level of commitment to this supplementation regimen. Importantly, AR episodes to calcium supplementation were reported by a low percentage of participants (3.9%) and were strictly related to gastrointestinal disorders, with no serious ARs observed. As expected, in subjects achieving an adherence of ≥ 80%, a lower rate of AEs was reported compared to subjects with an adherence < 80% where the rate of AEs was 41.6%. This association was also confirmed through multivariate logistic regression analysis, which also demonstrated no significant association between calcium citrate supplementation and concomitant vitamin D assumption. Additionally, beneficial effects of calcium citrate supplementation were observed in blood pressure measurements, nutritional status, in circulatory system and musculoskeletal disorders, suggesting potential amelioration of related health conditions.
As for any treatment, adherence is the most important factor affecting the effectiveness supplementations. Results from community based trials in which the adherence to calcium supplementation was moderate or low have often been negative, whereas studies carried out on institutionalized patients with supervised pill administration resulted in significant benefit [18]. However compliance to long-term calcium and vitamin D supplementation was found to be between 20% and 60% [19, 20]. In our study, we found high levels of adherence among elderly subjects (mean rate: 76.6 ± 29.5%), which is consistent with the findings of the POSSIBLE-US study by Barrett-Connor et al. [21]. In the POSSIBLE-US study, the probability of persisting on calcium therapy (i.e., adherence to treatment) during the first 12 months was over 75% for both subjects using calcium only and those using supplements. It is important to note that adherence to osteoporosis treatment, including calcium supplementation can vary widely. A review by Yeam et al. (2018) [8] reported a prevalence of osteoporotic medication adherence ranging from 12.9–95.4%. This wide range indicates the diverse nature of adherence rates in different populations and settings. While adherence to calcium citrate supplementation in elderly individuals can be challenging, our study demonstrated high levels of adherence among this population.
There has been some controversy in the literature over the past decade regarding the cardiovascular safety of calcium supplements. Two meta-analyses by Bolland et al. (2010 and 2011) suggested an increased risk of cardiovascular events, particularly MI, in patients taking calcium supplements [22, 23]. However, Lewis et al. (2012) subsequently demonstrated that calcium supplementation primarily increases gastrointestinal (GI) AEs while not significantly impacting MI rates [9]. Other studies do not support the notion of cardiovascular risk associated with calcium supplementation [10, 11, 24]. GI disorders related to calcium supplementation, instead, are well described [24, 25]. Our study aligns with these findings, as we did not observe any serious AR, but only 50 AE episodes, predominantly (79.1%) GI related.
Data derived from recent studies consistently indicate that calcium supplements do not pose an elevated cardiovascular risk. The 5-year post-intervention outcomes of The Women’s Health Initiative (WHI) study, as reported by Cauley et al.[26], demonstrated no significant differences in the risk of MI, stroke, or mortality between the calcium/vitamin D group and the placebo group [26]. This finding is supported by additional safety data from various large prospective studies [27, 28]. Given the importance of calcium and vitamin D for maintaining bone health, these findings provide reassurance regarding their safety and efficacy in maintaining bone homeostasis [24].
Adherence was also found to be negatively associated with the presence of AEs. In contrast to this observation, Conti et al. (2012) [29] reported a negative impact on adherence during subsequent control visits when AE episodes were associated with calcium and vitamin D supplementation. Nevertheless, the specific type of calcium supplement used in their study was not specified, necessitating further investigation. In this study we found no correlation between AEs and concomitant vitamin D supplementation, suggesting that the use of vitamin D does not contribute to increased AE risk.
An interesting finding that emerged from our analysis was that blood pressure was observed to significantly decrease during the course of the study and an improvement in various health indicators, such as nutritional status, circulatory system, and musculoskeletal system were also seen. Our findings align with existing literature, which provides substantial evidence supporting the beneficial effects of calcium supplementation on lipid profiles and blood pressure. A randomized controlled trial (RCT) that included 223 postmenopausal women examined the impact of calcium supplementation versus placebo on lipid profiles. The study revealed that calcium citrate supplementation led to a 7% increase in high-density lipoprotein and a 6% decrease in low-density lipoprotein after one year of follow-up [30]. Other data suggest that calcium supplements may induce transient hypercalcemia and reduce parathyroid hormone (PTH) levels, which could potentially contribute to lowered blood pressure [31, 32]. A systematic review of 42 trials investigating the effect of calcium supplementation on blood pressure demonstrated a reduction in systolic blood pressure by 1.44 mm Hg (95% CI, − 2.20 to − 0.68; P < 0.001) and a decrease in diastolic blood pressure of 0.84 mm Hg (95% CI, − 1.44 to − 0.24; P < 0.001). These findings are consistent with our own observations, providing additional support for the positive impact of calcium supplementation on lipid profiles and blood pressure, reinforcing the potential benefits of incorporating calcium supplements into one's health regimen.
A Cochrane meta-analysis by Cormick and colleagues including 18 studies and 3,140 patients evaluated the use of calcium supplementation for primary hypertension in normotensive people[33]. Results of this large analysis showed that reductions in blood pressure of any magnitude have the potential to significantly improve health by reducing the risk of vascular disease and a reduction in SBP of 2 mmHg led to 10% reduction in stroke mortality and a 7% reduction in mortality from ischemic heart disease. In our study, the blood pressure reduction was statistically significant in the 166 subjects who had both baseline and post-baseline measurements: 2.8 ± 13.9 mmHg in SBP (p = 0.0102) and 2.1 ± 10.4 in DBP (p = 0.0116), therefore in agreement with this meta-analysis. While these BP lowering effects of calcium supplementation are more increasingly recognised, the precise mechanisms by which calcium citrate elicits these effects is not yet fully understood.
It is recognised that calcium intake can regulate BP by modifying intracellular calcium in vascular smooth muscle cells and altering vascular volume via the renin–angiotensin–aldosterone system and low calcium intake increases the production of parathyroid hormone resulting in vasoconstriction and an increase in BP[34]. Typically, osteopenic/osteoporotic individuals have decreased levels of calcium and it is correction of a potential deficit may counteract adverse BP effects as observed in our cohort.
It is also worth noting that small but statistically significant changes were also observed for some haematological variables but these changes were clinically negligible and all were within normal reference range.