Dr. Connie Weaver Department of Nutrition Science Purdue University Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children: Bone and Calcium Outcome Dr. Connie Weaver Department of Nutrition Science Purdue University

Disclosure Member of the ILSI North America Caffeine Systematic Review Team Vice-Chair of ILSI Global Board of Trustees Science Advisory Board of Pharmavite Grant from Alliance of Potato Research and Education  

PECO Questions for the Bone and Calcium Outcome For [population], is caffeine intake above [dose], compared to intakes [dose] or less, associated with adverse effects on bone and calcium outcomes? Population Healthy Adults Pregnant Women Healthy Adolescents Children Exposure > 400 mg/day > 300 mg/day > 2.5 mg/kg-day Comparator ≤ 400 mg/day ≤ 300 mg/day ≤ 2.5 mg/kg-day Outcome Adverse effects on bone and calcium Example: For healthy adults, is caffeine intake above 400 mg/day, compared to intakes of 400 mg/day or less, associated with adverse effects on bone and calcium outcomes?

Caffeine

Characterization of Data for Bone and Calcium Outcome Data Type Characterization Number of studies 14 included; 26 excluded Study types All observational (cohort and cross-sectional); exception of 2 RCTs for calcium homeostasis Populations Adult (women/men; elderly; 1 study that included adolescents) Exposure Primarily dietary intake (e.g., food frequency questionnaires) – coffee, soda, tea, chocolate ~1/2 specifically evaluated caffeine Categorical groupings (e.g., <1 cup/day, >3 cups/day) Outcome (Endpoints) Risk of fracture (6) Bone mineral density (BMD) and osteoporosis (9) Calcium homeostasis (2)

Results: Risk of Fracture and Fall Discuss importance of calcium? Urinary calcium excretion is affected by calcium intake, so calcium intake needs to be considered in the analysis. Altered calcium balance through perturbing calcium excretion can influence bone mas The majority, although not all, of the data demonstrate a lack of effects of caffeine consumption at levels both above (up to 760 mg/day) and below 400 mg/day Effects <400 were of low magnitude (RR = <1.2) or were reported in analyses that did not consistently control for calcium intake Moderate confidence: findings generally consistent, most studies controlled for calcium intake

Results: BMD and Osteoporosis Discuss importance of calcium? Urinary calcium excretion is affected by calcium intake, so calcium intake needs to be considered in the analysis. Altered calcium balance through perturbing calcium excretion can influence bone mas The majority of studies support that the comparator of 400 mg/day in healthy adults is not harmful with respect to BMD and osteoporosis More evidence is needed for effects of caffeine intake between 200 and 400mg/day Effects <400 or >400 were associated with subgroups, single sites, and/or not associated with downstream events Moderate to low confidence: findings inconsistent, methods for controlling for calcium intake uncertain

Evaluation of Individual Study Quality (Risk of Bias) Overall “probably low” risk of bias across body of evidence Limited by exposure characterization (Q3, Q11) Consideration of calcium intake inconsistent (Q4) +2: Definitely low +1: Probably low -1: Probably high -2: Definitely high

Factors that increased or decreased confidence in the body of evidence by endpoint No. of Studies Initial Confidence Rating Based on study type and study features (OHAT, 2015) Overall RoB Domain-based evaluation of risk of bias per the OHAT RoB tool (OHAT, 2015) Indirectness Was the study designed to evaluate the PECO? Magnitude Strength of effect (when effect observed below the comparator) Confounding Were plausible confounders that would change the observed effect accounted for? Consistency Were findings consistent in demonstrating effects or lack of effects at or below the comparator Final Confidence Rating What is the overall rating when factors that increase or decrease confidence were considered Risk of fracture and fall 6 Moderate - ↓ ↓ / - ↑ / - BMD and osteoporosis 7 Moderate to low ↑ increased confidence - no change to confidence ↓ decreased confidence

Developing Conclusions for the Outcome: Integration of Weight of Evidence Considerations

WoE Conclusion: Bone and Calcium Outcome The comparator, 400 mg/day, was found to be an acceptable intake that is not associated with significant concern regarding overt, adverse effects on bone or calcium endpoints, particularly under conditions of adequate calcium intake. Some effects below the comparator; limited to physiological effects following acute exposure (altered calcium homeostasis) and subgroups in analyses of clinical endpoints (including those with low calcium intake) Effects generally low magnitude and/or were of overall low/negligible consequence to downstream events Several studies also reported on a lack of effect on the clinical endpoints following chronic consumption below the comparator, as well as above the comparator Moderate level of confidence evidence base Key limitations: inability to fully accommodate calcium intake, high level of indirectness, uncertainty in exposure estimates From manuscript: When the weight of evidence was considered, the comparator, 400 mg/day, was found to be an acceptable intake that is not associated with significant concern regarding overt, adverse effects on bone or calcium endpoints, particularly under conditions of adequate calcium intake. Although effects were observed at exposures below the comparator they were often limited to physiological effects following acute exposure (altered calcium homeostasis), and subgroups in analyses of clinical endpoints, including those with low calcium intake. Such effects were generally of low magnitude, and/or were of overall low/negligible consequence to downstream events. Several studies also reported on a lack of effect on the clinical endpoints following chronic consumption below the comparator, as well as above the comparator. Based on the underlying study type (11 observational, 2 RCTs, 1 meta-analysis) that constitute this evidence base, there is a moderate level of confidence in the research, which supports this conclusion. Key limitations that precluded a higher level of confidence were the inability to fully accommodate for calcium intake, the high level of indirectness, as well as an uncertainty in exposure estimates

Future Research Needs Non-adult populations Role of calcium Understanding physiology