Calcium Citrate

Tri-calcium citrate (Ca₃(C₆H₅O₇)₂·xH₂O)

Evidence: Strong

Calcium citrate is a highly bioavailable calcium salt, less prone to common gastrointestinal side effects like gas or constipation compared to other forms. It also serves as an essential cofactor for several digestive enzymes, playing a role in their optimal function and improving overall nutrient utilization.

There are 692,226 peer-reviewed scientific studies on this ingredient.

Selected Study 1/2:

Sakhaee, K., Bhuket, T., Adams-Huet, B., & Rao, D. S. (1999). Meta-analysis of calcium bioavailability: A comparison of calcium citrate with calcium carbonate. American Journal of Therapeutics, 6(6), 313–321. https://doi.org/10.1097/00045391-199911000-00005

Study Summary:

Study type: Meta-analysis of calcium bioavailability comparing calcium citrate with calcium carbonate. The authors pooled 15 crossover or parallel absorption trials involving 184 adults and calculated effect sizes with 95 % confidence intervals.

Observed benefits: Across the full data set, fractional calcium absorption from calcium citrate was ≈20 % higher than from calcium carbonate; the edge grew to 27 % when supplements were taken fasting and remained 22 % greater when taken with meals. Thus, citrate consistently delivered more usable calcium per dose under all test conditions.

Mechanisms of action: The review itself notes that citrate’s advantage stems from its acid-independent solubility, whereas carbonate must be dissolved by gastric acid before calcium ions become available. Subsequent work confirms that citrate dissolves readily at neutral pH and therefore maintains higher free-calcium concentrations throughout the small intestine, a difference that widens in people with low stomach acid or on proton-pump inhibitors.

Side effects: Adverse events were not systematically reported in the source trials; the meta-analysis comments only that both salts were well tolerated at the studied doses, with no clinically significant side-effect signals.

Strength of evidence: Because it aggregates multiple human experiments with objective kinetic endpoints, this meta-analysis provides moderately strong evidence that calcium citrate is intrinsically more bioavailable than calcium carbonate. Nonetheless, the underlying studies were small, short and focused on laboratory absorption rather than hard outcomes such as bone density or fracture risk, so further long-term trials are needed to confirm clinical superiority.

Selected Study 2/2:

Eich T, Ståhle M, Gustafsson B, Horneland R, Lempinen M, Lundgren T, Rafael E, Tufveson G, Zur-Mühlen BV, Olerud J, Scholz H, Korsgren O. Calcium: A Crucial Potentiator for Efficient Enzyme Digestion of the Human Pancreas. Cell Transplant. 2018 Jul;27(7):1031-1038. doi: 10.1177/0963689718779350. Epub 2018 Jun 26. PMID: 29945463; PMCID: PMC6158545.

Study Summary:

Study type: Experimental, controlled ex-vivo study of human‐pancreas islet isolation. Nineteen consecutive donor pancreata were processed in Nordic Network centres: nine under the standard protocol (control) and nine with extra Ca²⁺ added to every phase of the procedure (one further CIT-protocol case was studied but excluded from efficacy comparisons).

Observed benefits: Free Ca²⁺ in the digestion media fell from the target 5 mM to <1 mM during routine isolation, but remained at 5-7 mM whenever supplementary Ca²⁺ was provided. Maintaining this level almost doubled islet yield: median islet equivalents (IEQ) 323 730 vs 147 319 in controls (p = 0.0027), without impairing purity, viability or glucose-stimulated insulin secretion.

Mechanisms of action: Collagenase, thermolysin and clostripain need 5-10 mM Ca²⁺ for optimal activity; bicarbonate buffers and liberated extracellular-matrix components rapidly chelate or precipitate Ca²⁺, driving levels far below that threshold. Supplementing each solution with Ca²⁺ counters this loss, keeps the enzymes active throughout perfusion and digestion, and thus liberates more intact islets.

Side effects: No adverse effects were noted; Ca²⁺ enrichment did not alter islet morphology, size distribution or post-culture recovery, and all preparations met clinical transplantation criteria.

Strength of evidence: Moderate. The study uses real human organs, a contemporaneous control group and objective biochemical and functional endpoints, strongly supporting the causal role of Ca²⁺ in enzyme efficiency. However, the sample is small (19 isolations) and laboratory-focused; it does not track transplant outcomes, and generalizability beyond Nordic protocols remains to be shown.