Picking a bone with fluoride – dose-response meta-analysis on exposure to fluoride and bone density

Abstract There are still uncertainties around the effects, beneficial and adverse, of water fluoride exposure on bone density and strength. We selected bone mineral density (BMD) for investigation as it is recognized as the major non-invasive indicator of bone strength, representing its clinical assessment standard. The aim of this systematic review and meta-analysis was to characterize for the first time the relation between fluoride exposure and BMD through a dose-response approach, using a one-stage dose-response meta-analysis based on a cubic spline random-effects model. Out of 1201 potentially relevant literature records retrieved, after removing duplicates, title/abstract screening, and full-text evaluation, 16 studies were eligible for this review, 12 of which were also suitable for the dose-response meta-analysis. We observed an almost linear association between fluoride and BMD, yielding a mean difference of 2.60 (95% CI 0.17 to 0.40) at 4 mg/L of fluoride exposure. This pattern was also confirmed for hip BMD (MD = 2.83; 95% CI 0.11 to 0.40 at 4 mg/L). However, sex-specific analyses showed different patterns of association. In males, the relation between fluoride exposure and BMD was almost linear until 0.75 mg/L (MD = 0.24; 95% CI -0.22to 0.37), after which it plateaued. Females showed a slight increased BMD at 1 mg/L (MD = 0.05; 95% CI -0.02 to 0.16) but decreasing values above 2.5 mg/L (MD=-0.22; 95% CI -2.72 to 2.38 at 4 mg/L), with an indication of an inverted U-shaped association. This pattern was clearer when we restricted our analysis to hip BMD (MD=-0.56; 95% CI -2.98 to 1.85 at 4 mg/L). Sensitivity analyses examining both bone-specific BMD and conducting risk of bias assessments are currently underway. Moreover, imprecision of the estimates, especially in stratified analyses, and potential for residual confounding, underscore the need for further prospective studies, to more adequately assess the relation between fluoride exposure and bone density and strength. Key messages • At fluoride exposure below 1 mg/L, we observed a linear correlation between fluoride exposure and increase bone density in the overall pooled dose-response analysis of eligible studies. • Sex-specific patterns: males show positive response until certain exposure threshold; while females demonstrate an increase only at low doses of exposure and a downward trend at higher exposures.