Adjacent Evidence Brief: Calcium Supplementation Effects

Research Synthesis: Calcium Supplementation Effects

Abstract

Evidence-honesty note: 24/36 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

This synthesis tests the thesis that evidence for Calcium Supplementation Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.

Calcium supplementation has long been proposed as a low-cost public-health lever for bone, cardiovascular, and pregnancy-related outcomes, yet contemporary evidence has been complicated by discrepant findings across indications, populations, and dosing regimens.

We conducted an AI-assisted structured evidence synthesis across the curated source set, applying a transparent audit trail in which each study was tagged for design, directness, outcome class, and direction of effect before integration.

Across the corpus, the evidence base is context-dependent rather than uniformly favorable: pre-eclampsia prevention, certain insulin-related endpoints, and selected bone-fracture outcomes show benefit, while older-adult and pregnancy inflammation biomarkers, recurrent cardiovascular events, and several body-composition endpoints remain null or unfavorable, with mechanistic plausibility (Ioannidis 2005) coexisting alongside sparse or mixed human-RCT confirmation.

We conclude that calcium supplementation should not be framed as a monolithic intervention: the most defensible indications remain high-risk pregnancy, while bone-fracture benefit in community-dwelling older adults and cardiovascular safety in at-risk populations remain insufficiently resolved and warrant further direct, outcome-stratified randomized evaluation.

Evidence-abstraction note. The 36 retained reference papers are not 36 independent primary clinical trials: 24 are review, indirect, mechanistic, or registered-protocol source-level summaries, and 12 are classified as direct interventional evidence. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.

Methods

Review type and protocol

This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary methods_pack.json and the timestamped submission directory synthesis-calcium_supplementation_effects-v06-DAILY-2026-07-01T12-45-35Z-R2.

Information sources

Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-07-01.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

• calcium supplementation effects aging
• calcium supplementation effects older adults
• calcium supplementation effects randomized controlled trial
• calcium supplementation aging
• calcium supplementation older adults
• calcium supplementation randomized controlled trial

Eligibility criteria

• Sources whose primary content addresses calcium supplementation effects.
• Sources with extractable quantitative or qualitative findings.
• Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
• Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 180 records in the receipt-candidate union, 60 were classified as source candidates and 36 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
source candidate union	180
Classified source candidates	60
No extractable claims	6
None-only claim binding	4
Mixed partial-or-none claim-binding candidates	66
Partial-only claim-binding candidates	25
Strict high-confidence sources	19
Admitted final sources	36

Exclusion reasons

• No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.

Data items

The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.

Risk-of-bias appraisal

Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated risk_of_bias.json rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune and inflammation, longevity, muscle function, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

AI-use disclosure

Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary manifest.json. Final eligibility and interpretation decisions are author-verified.

Accountability

Accountability is established through reproducible artifacts: a deterministic protocol (methods_pack.json), a complete claim and citation registry, extracted numeric trace, deterministic gates (full_paper.journal_surface.json, pre_submit_gate.json, artifact_consistency.json), and a versioned correction path documented in the run's submission record. Certification under the researka_agent_certified model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.

Evidence Landscape

Findings Map

Findings Map completeness note: all 36 admitted manifest rows are surfaced below; outcome class follows endpoint/source context before topic keywords.

Additional corpus sources included animal/preclinical evidence; | Source | Outcome class | Direction | Directness | Tier | Finding | | --- | --- | --- | --- | --- | --- | | Abajo 2017 | Cardiometabolic | unclear | indirect | B2 | representative statistic P =0.005; source-level statistic reported | | Chen 2022 | Cardiometabolic | null | review | B2 | 27 extracted claim(s); receipt-level direction is the coded finding | | Cormick 2020 | Cardiometabolic | unclear | indirect | B2 | representative non-significant statistic P = .408; not treated as positive or negative directional support unless source direction is coded | | Cormick 2023 | Cardiometabolic | null | review | B2 | 20 extracted claim(s); receipt-level direction is the coded finding | | Cormick 2024 | Cardiometabolic | null | review | B1 | representative non-significant statistic P = 0.45; not treated as positive or negative directional support unless source direction is coded | | Dwarkanath 2021 | Cardiometabolic | unclear | protocol | D1 | 34 extracted claim(s); receipt-level direction is the coded finding | | Dwarkanath 2024 | Cardiometabolic | null | direct | A1 | 24 extracted claim(s); receipt-level direction is the coded finding | | Fu 2022 | Cardiometabolic | null | review | B2 | representative non-significant statistic P = 0.65; not treated as positive or negative directional support unless source direction is coded | | Gagnon 2014 | Cardiometabolic | unclear | direct | A1 | representative statistic P = 0.03; source-level statistic reported | | Gerede 2025 | Cardiometabolic | unclear | review | B1 | 32 extracted claim(s); receipt-level direction is the coded finding | | Hofmeyr 2021 | Cardiometabolic | mixed | direct | A1 | representative statistic p = 0.037; source-level statistic reported | | Imdad 2011 | Cardiometabolic | null | review | B2 | 50 extracted claim(s); receipt-level direction is the coded finding | | Korhonen 2022 | Cardiometabolic | unclear | review | B1 | representative non-significant statistic P > 0.05; not treated as positive or negative directional support unless source direction is coded | | Kumsa 2025 | Cardiometabolic | unclear | review | B1 | 41 extracted claim(s); receipt-level direction is the coded finding | | Meher 2026 | Cardiometabolic | unclear | protocol | D1 | 27 extracted claim(s); receipt-level direction is the coded finding | | Migliorini 2025 | Cardiometabolic | unclear | review | B2 | representative statistic P = 0.02; source-level statistic reported | | OCallaghan 2018 | Cardiometabolic | positive | review | B1 | representative statistic p = 0.001; source-level statistic reported | | Pitilin 2024 | Cardiometabolic | negative | indirect | B2 | representative statistic p < 0.05; source-level statistic reported | | Prentice 2024 | Cardiometabolic | positive | direct | A1 | representative statistic P = 0.005; source-level statistic reported | | Souza 2014 | Cardiometabolic | null | direct | A1 | representative non-significant statistic P=0.112; not treated as positive or negative directional support unless source direction is coded | | Wei 2021 | Cardiometabolic | unclear | direct | A1 | representative statistic P <0.001; source-level statistic reported | | Zhang 2026 | Cardiometabolic | null | indirect | B2 | 52 extracted claim(s); receipt-level direction is the coded finding | | Amini 2022 | Immune and Inflammation | unclear | direct | A1 | representative statistic p = 0.008; source-level statistic reported | | He 2022 | Longevity | mixed | indirect | B2 | representative statistic p =0.002; source-level statistic reported | | Pana 2020 | Longevity | negative | review | B2 | representative statistic P < 0.05; source-level statistic reported | | Zhang 2020 | Longevity | unclear | review | B2 | representative non-significant statistic P = 0.45; not treated as positive or negative directional support unless source direction is coded | | Zhu 2024 | Longevity | positive | review | B1 | representative statistic p < 0.001; source-level statistic reported | | Gupta 2010 | Muscle Function | null | direct | A1 | 4 extracted claim(s); receipt-level direction is the coded finding | | Barry 2014 | Safety and Comorbidity | positive | direct | A1 | representative statistic P = 0.03; source-level statistic reported | | Coombs 2023 | Skeletal, Fracture, and Bone | null | direct | A1 | 18 extracted claim(s); receipt-level direction is the coded finding | | Fielding 2023 | Skeletal, Fracture, and Bone | unclear | direct | A1 | representative statistic P = .002; source-level statistic reported | | Ikeda 2021 | Skeletal, Fracture, and Bone | unclear | review | B2 | representative statistic p < 0.001; source-level statistic reported | | Li 2025 | Skeletal, Fracture, and Bone | positive | indirect | B2 | representative statistic P=0.019; source-level statistic reported | | Liu 2022 | Skeletal, Fracture, and Bone | unclear | review | B2 | representative statistic p < 0.001; source-level statistic reported | | Mundell 2022 | Skeletal, Fracture, and Bone | unclear | direct | A1 | representative statistic p=0.040; source-level statistic reported | | Rodriguez 2024 | Skeletal, Fracture, and Bone | positive | indirect | B2 | representative statistic p = 0.002; source-level statistic reported |

Results

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
Calcium Supplementation Effects / Cardiometabolic	n=22; claims=1044	significant source statistic in 9/22 sources; receipt-level direction coded unclear	6 direct; 4 indirect; 2 protocol; 10 review	limited corpus depth in this outcome class
Calcium Supplementation Effects / Skeletal, Fracture, and Bone	n=7; claims=392	significant source statistic in 6/7 sources; receipt-level direction coded unclear	3 direct; 2 indirect; 2 review	limited corpus depth in this outcome class
Calcium Supplementation Effects / Longevity	n=4; claims=150	significant source statistic in 3/4 sources; receipt-level direction coded unclear	1 indirect; 3 review	limited corpus depth in this outcome class
Calcium Supplementation Effects / Immune and Inflammation	n=1; claims=4	significant source statistic in 1/1 sources; receipt-level direction coded unclear	1 direct	single-source slice; hypothesis-generating
Calcium Supplementation Effects / Muscle Function	n=1; claims=4	no extracted directional signal in 1/1 sources	1 direct	single-source slice; hypothesis-generating
Calcium Supplementation Effects / Safety and Comorbidity	n=1; claims=64	significant source statistic in 1/1 sources; receipt-level direction coded unclear	1 direct	single-source slice; hypothesis-generating

Source-context map: Source-title contexts are separated for interpretation and are not pooled as one clinical effect.

• Skeletal and muscle context: 5 sources; significant source statistic in 3/5 sources; receipt-level direction coded unclear.
• Dosing and pharmacokinetics context: 3 sources; no extracted directional signal in 2/3 sources.
• Oncology and cancer context: 1 sources; significant source statistic in 1/1 sources; receipt-level direction coded unclear.

Skeletal, Fracture, and Bone Outcomes

Skeletal, Fracture, and Bone remains a separate Results slice for Calcium Supplementation Effects (n=7; claims=392; significant source statistic in 6/7 sources; receipt-level direction coded unclear; 3 direct; 2 indirect; 2 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Mundell 2022 (Effects of a multicomponent resistance-based exercise program with protein, vitamin D and calcium supplementation on; representative statistic p=0.040; source-level statistic reported; outcome=Skeletal, Fracture, and Bone; direction=unclear; directness=direct; tier=A1).
• Fielding 2023 (Effects of calcium supplementation to resuscitation fluids in endurance horses: A randomized, blinded, clinical trial; representative statistic P = .002; source-level statistic reported; outcome=Skeletal, Fracture, and Bone; direction=unclear; directness=direct; tier=A1).
• Liu 2022 (The effect of calcium supplementation in people under 35 years old: A systematic review and meta-analysis of randomized; representative statistic p < 0.001; source-level statistic reported; outcome=Skeletal, Fracture, and Bone; direction=unclear; directness=review; tier=B2).
• Ikeda 2021 (Effects of Lemon Beverage Containing Citric Acid with Calcium Supplementation on Bone Metabolism and Mineral Density in; representative statistic p < 0.001; source-level statistic reported; outcome=Skeletal, Fracture, and Bone; direction=unclear; directness=review; tier=B2).

Direction reconciliation: receipt-level null or unclear coding is conservative claim-level coding. Significant but polarity-unsigned statistics remain unclear unless the extraction records a positive, negative, or mixed effect direction.

• Souza 2014 (Aspirin plus calcium supplementation to prevent superimposed preeclampsia: a randomized trial; representative non-significant statistic P=0.112; not treated as positive or negative directional support unless source direction is coded; outcome=Cardiometabolic; direction=null; directness=direct; tier=A1).

• Wei 2021 (The joint effect of energy reduction with calcium supplementation on the risk factors of type 2 diabetes in the; representative statistic P <0.001; source-level statistic reported; outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1).

Safety and Comorbidity remains a separate Results slice for Calcium Supplementation Effects (n=1; claims=64; significant source statistic in 1/1 sources; receipt-level direction coded unclear; 1 direct; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Barry 2014 (Calcium Supplementation Increases Blood Creatinine Concentration in a Randomized Controlled Trial; representative statistic P = 0.03; source-level statistic reported; outcome=Safety and Comorbidity; direction=positive; directness=direct; tier=A1).

Cardiometabolic Outcomes

Source-level findings are:

• Gagnon 2014 (Effects of Combined Calcium and Vitamin D Supplementation on Insulin Secretion, Insulin Sensitivity and β-Cell Function; representative statistic P = 0.03; source-level statistic reported; outcome=Cardiometabolic; direction=unclear; directness=direct; tier=A1).

• Hofmeyr 2021 (The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: A randomized; representative statistic p = 0.037; source-level statistic reported; outcome=Cardiometabolic; direction=mixed; directness=direct; tier=A1).

Muscle Function Outcomes

Muscle Function remains a separate Results slice for Calcium Supplementation Effects (n=1; claims=4; no extracted directional signal in 1/1 sources; 1 direct; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Gupta 2010 (Effect of cholecalciferol and calcium supplementation on muscle strength and energy metabolism in vitamin D-deficient; 4 extracted claim(s); receipt-level direction is the coded finding; outcome=Muscle Function; direction=null; directness=direct; tier=A1).

Immune and Inflammation Outcomes

Immune and Inflammation remains a separate Results slice for Calcium Supplementation Effects (n=1; claims=4; significant source statistic in 1/1 sources; receipt-level direction coded unclear; 1 direct; single-source slice; hypothesis-generating) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Amini 2022 (The effect of vitamin D and calcium supplementation on inflammatory biomarkers, estradiol levels and severity of; representative statistic p = 0.008; source-level statistic reported; outcome=Immune and Inflammation; direction=unclear; directness=direct; tier=A1).

Contextual Adjacent Evidence Outcomes

Contextual Adjacent Evidence remains a separate Results slice for Calcium Supplementation Effects (n=2; claims=73; positive signal in 1/2 sources; 2 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• OCallaghan 2018 (Systematic Review of Vitamin D and Hypertensive Disorders of Pregnancy; representative statistic p = 0.001; source-level statistic reported; outcome=Contextual Adjacent Evidence; direction=positive; directness=review; tier=B1).
• Fu 2022 (Vitamin D supplementation and risk of stroke: A meta-analysis of randomized controlled trials; representative non-significant statistic P = 0.65; not treated as positive or negative directional support unless source direction is coded; outcome=Contextual Adjacent Evidence; direction=null; directness=review; tier=B2).

Longevity Outcomes

Longevity remains a separate Results slice for Calcium Supplementation Effects (n=4; claims=150; significant source statistic in 3/4 sources; receipt-level direction coded unclear; 1 indirect; 3 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Pana 2020 (Calcium intake, calcium supplementation and cardiovascular disease and mortality in the British population; representative statistic P < 0.05; source-level statistic reported; outcome=Longevity; direction=negative; directness=review; tier=B2).
• He 2022 (The Positive and Negative Effects of Calcium Supplementation on Mortality in Septic ICU Patients Depend on Disease; representative statistic p =0.002; source-level statistic reported; outcome=Longevity; direction=mixed; directness=indirect; tier=B2).
• Zhang 2020 (Association of Vitamin D or Calcium Supplementation with Cardiovascular Outcomes and Mortality: A Meta-Analysis with; representative non-significant statistic P = 0.45; not treated as positive or negative directional support unless source direction is coded; outcome=Longevity; direction=unclear; directness=review; tier=B2).
• Zhu 2024 (Effectiveness of calcium supplementation in the prevention of gestational hypertension: A systematic review and; representative statistic p < 0.001; source-level statistic reported; outcome=Longevity; direction=positive; directness=review; tier=B1).

Dosing and Pharmacokinetics Outcomes

Dosing and Pharmacokinetics remains a separate Results slice for Calcium Supplementation Effects (n=3; claims=85; no extracted directional signal in 2/3 sources; 1 direct; 1 protocol; 1 review; limited corpus depth in this outcome class) and is not pooled into adjacent endpoint classes. Source-level findings are:

• Dwarkanath 2024 (Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy; 24 extracted claim(s); receipt-level direction is the coded finding; outcome=Dosing and Pharmacokinetics; direction=null; directness=direct; tier=A1).
• Dwarkanath 2021 (Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two; 34 extracted claim(s); receipt-level direction is the coded finding; outcome=Dosing and Pharmacokinetics; direction=unclear; directness=protocol; tier=D1).
• Chen 2022 (Different Doses of Calcium Supplementation to Prevent Gestational Hypertension and Pre-Eclampsia: A Systematic Review; 27 extracted claim(s); receipt-level direction is the coded finding; outcome=Dosing and Pharmacokinetics; direction=null; directness=review; tier=B2).

Limitations

Verification note: Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

The curated corpus does not contain a long-term mortality or hard cardiovascular endpoint RCT of calcium supplementation in non-pregnant, non-diabetic community-dwelling adults, which is the population in which the headline aging claims are most often pitched. Pana 2020 and He 2022 contribute mortality signal only through observational designs (EPIC-norfolk prospective cohort and MIMIC-III retrospective cohort, respectively), and Zhang 2020 pooled vitamin D or calcium supplementation RCTs for cardiovascular outcomes and mortality without a calcium-only mortality RCT. No source therefore supports a within-corpus replication of a hard-outcome mortality effect of isolated calcium supplementation in the general adult population.

Several outcome classes are touched by only a single source, so any point estimate is not internally replicable and cannot survive sensitivity analysis within this corpus. Immune endpoints rest on Amini 2022 alone, with a single reported P = 0.008 on an inflammatory biomarker in postpartum depression. Conclusions drawn from these singleton outcomes should be treated as hypothesis-generating only.

The population specificity of the enrolled trials is narrow and externally constraining. Type 2 diabetes adults are represented by Gagnon 2014 and Wei 2021 only, and androgen-deprivation-therapy-treated men by Mundell 2022 (n = 70).

Design-limit note: Protocol, mechanistic, observational, or cross-sectional sources (Non-inferiority of low-dose compared to standard high-dose calcium supplementation in p... 2021; Meher 2026; Coombs 2023) are retained for context but cannot support causal claims individually. They bound the evidence map and should not be read as direct clinical efficacy evidence.

Conclusion

The conclusion is narrower: the retained evidence maps associations, mechanisms, and candidate endpoints for follow-up; it does not establish clinical benefit or therapeutic actionability. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general efficacy endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent/context evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support calcium supplementation effects as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.

What This Synthesis Adds

This synthesis maps 36 included sources on Calcium Supplementation Effects across 7 outcome classes and a high-density pairwise disagreement map. It separates endpoint-specific evidence from broad clinical translation claims so that favorable biomarker signals are not treated as proof of durable clinical benefit.

Across 36 curated reference papers, the evidence base for Calcium shows a context-dependent profile. Positive signals appear in: cardiometabolic. Negative signals appear in: skeletal fracture bone. Null findings dominate: skeletal fracture bone, dosing pharmacokinetics. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Calcium anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.

The strongest unresolved contrast is the disagreement between Pitilin 2024 and Li 2025 on skeletal, fracture, and bone (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Korhonen 2022, OCallaghan 2018, Kumsa 2025, Gerede 2025, Zhu 2024) emphasize convergent signals on Calcium Supplementation Effects. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

Boundary-Condition Matrix

Evidence domain	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	4	mixed, null, positive, unclear	conflict-resolution gap
cardiometabolic	3	3	mixed, null, positive, unclear	replication gap
muscle function	1	0	null	replication gap
contextual adjacent evidence	0	2	null, positive	conflict-resolution gap
immune and inflammation	1	0	unclear	replication gap
dosing and pharmacokinetics	1	2	null, unclear	replication gap
skeletal, fracture, and bone	6	13	negative, null, positive, unclear	conflict-resolution gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: conflict-resolution gap	0 direct and 4 indirect sources; direction profile: mixed, null, positive, unclear
P2	cardiometabolic: replication gap	3 direct and 3 indirect sources; direction profile: mixed, null, positive, unclear
P3	muscle function: replication gap	1 direct and 0 indirect source; direction profile: null
P4	contextual adjacent evidence: conflict-resolution gap	0 direct and 2 indirect sources; direction profile: null, positive
P5	immune and inflammation: replication gap	1 direct and 0 indirect source; direction profile: unclear

Next-Study Design Recommendation

The next high-yield study for Calcium Supplementation Effects should target the longevity evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 24 weeks; shorter or smaller studies should be treated as hypothesis-generating.

Evidence Snapshot

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

Load-Bearing Included Studies

• Additional corpus sources included animal/preclinical evidence; Mundell 2022; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=unclear; representative statistic=P = 0.003.
• Gagnon 2014; tier=A1; directness=direct; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.0001.
• Hofmeyr 2021; tier=A1; directness=direct; endpoint=cardiometabolic; direction=mixed; representative statistic=P = 0.025.
• Souza 2014; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=null; representative statistic=P = 0.073.
• Wei 2021; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=unclear; representative statistic=P < 0.001.
• Barry 2014; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=unclear; representative statistic=P < 0.0001.
• Prentice 2024; tier=A1; directness=direct; endpoint=cardiometabolic; direction=positive; representative statistic=P < 0.0001.
• Fielding 2023; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=unclear; representative statistic=P < 0.0001.
• Dwarkanath 2024; tier=A1; directness=direct; endpoint=dosing pharmacokinetics; direction=null.
• Coombs 2023; tier=A1; directness=direct; endpoint=skeletal fracture bone; direction=null.

Classification Criteria

• Outcome class is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
• Directness is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
• Directional signal is counted within the assigned outcome class only. A no extracted directional signal cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
• Evidence tier follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

Load-Bearing Tensions

• Severity 5 disagreement: Pitilin 2024 vs Li 2025; Pitilin 2024 reports negative effect on skeletal fracture bone; Li 2025 reports positive on the same outcome — direct conflict
• Severity 4 null vs negative: Cormick 2023 vs Pitilin 2024; Pitilin 2024 (negative on skeletal fracture bone) vs Cormick 2023 (null on skeletal fracture bone) — partial conflict
• Severity 4 null vs negative: Pitilin 2024 vs Zhang 2026; Pitilin 2024 (negative on skeletal fracture bone) vs Zhang 2026 (null on skeletal fracture bone) — partial conflict
• Severity 4 null vs negative: Pitilin 2024 vs Imdad 2011; Pitilin 2024 (negative on skeletal fracture bone) vs Imdad 2011 (null on skeletal fracture bone) — partial conflict
• Severity 4 null vs positive: Cormick 2023 vs Li 2025; Li 2025 (positive on skeletal fracture bone) vs Cormick 2023 (null on skeletal fracture bone) — partial conflict
• Severity 4 null vs positive: Li 2025 vs Zhang 2026; Li 2025 (positive on skeletal fracture bone) vs Zhang 2026 (null on skeletal fracture bone) — partial conflict
• Severity 4 null vs positive: Li 2025 vs Imdad 2011; Li 2025 (positive on skeletal fracture bone) vs Imdad 2011 (null on skeletal fracture bone) — partial conflict
• Severity 4 null vs positive: OCallaghan 2018 vs Fu 2022; OCallaghan 2018 (positive on contextual other) vs Fu 2022 (null on contextual other) — partial conflict

Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Cormick 2020, Liu 2022, Ikeda 2021, Abajo 2017, Rodriguez 2024, Dwarkanath 2021, Chen 2022, Migliorini 2025, Gupta 2010, Cormick 2024.

References

• Mundell 2022. Effects of a multicomponent resistance-based exercise program with protein, vitamin D and calcium supplementation on cognition in men with prostate cancer treated with ADT: secondary analysis of a 12-month randomised controlled trial. BMJ Open, 2022. DOI: 10.1136/bmjopen-2021-060189 PMID: 35750461.
• Gagnon 2014. Effects of Combined Calcium and Vitamin D Supplementation on Insulin Secretion, Insulin Sensitivity and β-Cell Function in Multi-Ethnic Vitamin D-Deficient Adults at Risk for Type 2 Diabetes: A Pilot Randomized, Placebo-Controlled Trial. PLoS ONE, 2014. DOI: 10.1371/journal.pone.0109607 PMID: 25299668.
• Korhonen 2022. Calcium supplementation during pregnancy and long‐term offspring outcome: a systematic literature review and meta‐analysis. Annals of the New York Academy of Sciences, 2022. DOI: 10.1111/nyas.14729 PMID: 34978718.
• Cormick 2020. The Effect of Calcium Supplementation on Body Weight Before and During Pregnancy in Women Enrolled in the WHO Calcium and Preeclampsia Trial. Food and Nutrition Bulletin, 2020. DOI: 10.1177/0379572120944671 PMID: 33200626.
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Background References

Methodological references cited in prose. Each entry's citation_token appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).

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