Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children: Bone and Calcium Outcome D R. C O N N I E W E A V E R D E PA R T M E N T O F N U T R I T I O N S C I E N C E P U R D U E U N I V E R S I T Y 1
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 2
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 Healthy Pregnant Women Healthy Adolescents Healthy Children Exposure > 400 mg/day > 300 mg/day > 2.5 mg/kg-day > 2.5 mg/kg-day Comparator 400 mg/day 300 mg/day 2.5 mg/kg-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? 3
Caffeine 4
Characterization of Data for Bone and Calcium Outcome Data Type Characterization Number of studies 14 included; 26 excluded Study types Populations All observational (cohort and cross-sectional); exception of 2 RCTs for calcium homeostasis 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) 5
Results: Risk of Fracture and Fall 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 6
Results: BMD and Osteoporosis 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 7
Bone and Calcium Studies - Risk of Bias 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) Albrand et al., 2003 Barbour et al., 2010 El Maghraoui et al., 2010 Fung et al., 2014 Hallstrom et al., 2006 Hallstrom et al., 2010 Hallstrom et al., 2013 Harter et al., 2013 Heaney and Rafferty, 2001 Jha et al., 2010 Lee et al., 2014 Rapuri et al., 2001 Ribeiro-Alves et al., 2003 Wetmore et al., 2008 Defi Pro nite bab Defi Pro nite bab Pro Pro bab bab Pro Defi bab nite Pro Defi bab nite Defi nite Defi nite Pro bab Q1: Randomization Q2: Allocation Concealment Q3: Identical experimental conditions Q4: Confounding (design/analysis) Q6: Blinding during study Q7: Missing outcome data Q8: Exposure characterization, confidence Q9: Outcome assessment Q10: Outcome reporting Q11: Other (i.e. Exposure characterization, purity) Pro Defi Pro Pro Defi bab Pro nite bab bab nite bab Pro bab Pro Pro Pro Defi Pro bab bab Defi Pro bab nite bab Pro nite bab Pro Pro bab Defi Pro Pro bab bab Defi Pro nite bab bab Defi nite bab Pro Pro nite Pro bab bab Defi Pro bab Defi nite bab nite Pro Pro Defi bab bab nite Meta-analysis Pro Pro Pro Pro bab bab bab Pro bab bab Pro Pro Pro Pro Pro bab bab bab bab bab +2: Definitely low +1: Probably low -1: Probably high -2: Definitely high 8
Factors that increased or decreased confidence in the body of evidence by endpoint 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 - / - / - / - Moderate BMD and osteoporosis 7 Moderate / - - - / - Moderate to low increased confidence - no change to confidence decreased confidence 9
Developing Conclusions for the Outcome: Integration of Weight of Evidence Considerations 10
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 11
Future Research Needs Non-adult populations Role of calcium Understanding physiology 12