Fluoride in Drinking Water, Diet, and Urine in Relation to Bone Mineral Density and Fracture Incidence in Postmenopausal Women

Background: Although randomized controlled trials (RCTs) have demonstrated that high fluoride increases bone mineral density (BMD) and skeletal fragility, observational studies of low-dose chronic exposure through drinking water (<1.5mg/L, the maximum recommended by the World Health Organization) have been inconclusive. Objective: We assessed associations of fluoride in urine, and intake via diet and drinking water, with BMD and fracture incidence in postmenopausal women exposed to drinking water fluoride ≤1mg/L. Methods: Data were from participants in the Swedish Mammography Cohort–Clinical, a population-based prospective cohort study. At baseline (2004–2009), fluoride exposure was assessed based on urine concentrations (n=4,306) and estimated dietary intake (including drinking water) (n=4,072), and BMD was measured using dual energy X-ray absorptiometry. Incident fractures were ascertained via register-linkage through 2017. Residential history was collected to identify women with long-term consistent drinking water exposures prior to baseline. Results: At baseline, mean urine fluoride was 1.2mg/g creatinine (±1.9) and mean dietary intake was 2.2mg/d (±0.9), respectively. During follow-up, 850, 529, and 187 cases of any fractures, osteoporotic fractures, and hip fractures, respectively, were ascertained. Baseline BMD was slightly higher among women in the highest vs. lowest tertiles of exposure. Fluoride exposures were positively associated with incident hip fractures, with multivariable-adjusted hazard ratios of 1.50 (95% CI: 1.04, 2.17) and 1.59 (95% CI: 1.10, 2.30), for the highest vs. lowest tertiles of urine fluoride and dietary fluoride, respectively. Associations with other fractures were less pronounced for urine fluoride, and null for dietary fluoride. Restricting the analyses to women with consistent long-term drinking water exposures prior to baseline strengthened associations between fractures and urinary fluoride. Discussion: In this cohort of postmenopausal women, the risk of fractures was increased in association with two separate indicators of fluoride exposure. Our findings are consistent with RCTs and suggest that high consumption of drinking water with a fluoride concentration of ∼1mg/L may increase both BMD and skeletal fragility in older women. https://doi.org/10.1289/EHP7404

. Cross-sectional mean differences in BMD (β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d) with BMD at the lumbar spine and femoral neck among women with approximately constant drinking water fluoride concentrations from 1982 to baseline. Table S2. Hazard ratios of osteoporotic fractures, excluding vertebral fractures, and corresponding 95% confidence intervals by tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d). Table S3. Multivariable adjusted hazard ratios of total, osteoporotic and hip fractures and corresponding 95% confidence intervals by tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d), respectively. Multivariable models are further adjusted for baseline bone mineral density (BMD). Table S4. Cross-sectional mean differences in BMD (β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d) with BMD at the lumbar spine and femoral neck, among women of the Swedish Mammography Cohort -Clinical, including individuals excluded from main analysis because of missing bone mineral density data on either hip or spine. Table S5. Hazard ratios of total, osteoporotic and hip fractures and corresponding 95% confidence intervals by tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d), respectively, among women of the Swedish Mammography Cohort -Clinical, including individuals excluded from main analysis because of missing bone mineral density data on either hip or spine. Table S6. Cross-sectional mean differences in Bone mineral density (BMD)(β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) with BMD at the lumbar spine and femoral neck among women of the Swedish Mammography Cohort -Clinical with complete exposure data. Table S7. Hazard ratios of total, osteoporotic and hip fractures and corresponding 95% confidence intervals by tertiles of urinary fluoride (mg/g creatinine) among women of the Swedish Mammography Cohort -Clinical with complete exposure data. Table S8. Cross-sectional mean differences in Bone mineral density (BMD)(β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) with BMD at the lumbar spine and femoral neck among women of the Swedish Mammography Cohort -Clinical with urinary creatinine concentrations ranging between 0.3 g/L and 3.0 g/L. Table S9. Hazard ratios of total, osteoporotic and hip fractures and corresponding 95% confidence intervals by tertiles of urinary fluoride (mg/g creatinine) among women of the Swedish Mammography Cohort -Clinical with urinary creatinine concentrations ranging between 0.3 g/L and 3.0 g/L. Table S1.
Cross-sectional mean differences in BMD (β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d) with BMD at the lumbar spine and femoral neck among women with approximately constant drinking water fluoride concentrations from 1982 to baseline.
Hazard ratios of osteoporotic fractures, excluding vertebral fractures, and corresponding 95% confidence intervals by tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d). Multivariable-adjusted models were adjusted for age, education, height, total fat mass, lean body mass, parity, smoking status, physical activity, alcohol intake, diabetes, eGFR, tertiles of urinary excretion of calcium (for urinary fluoride) or tertiles of dietary intake of calcium (for dietary fluoride), use of calcium supplements, use of vitamin D supplements, ever use of estrogen and ever use of corticosteroids. Urinary fluoride models were additionally adjusted for serum Beta-CrossLaps (ng/L). Abbreviations: HR: hazard ratio, CI: confidence interval, eGFR: estimated glomerular filtration rate The total number of participants in the urinary fluoride and dietary fluoride analyses were 4,306 and 4,072, respectively. 234 women were excluded from the dietary fluoride analyses because of missing dietary fluoride information either due to responding to a shorter version of the FFQ or having missing / inadequate reported dietary intake (energy intake outside 3 SD of log-transformed mean) For each outcome, women contributed with person time from the date of clinical examination until the of date of the specific event studied, death, or end of follow-up at December 31 st , 2017. Multivariable-adjusted models were apart from baseline bone BMD adjusted for age, education, height, total fat mass, lean body mass, parity, smoking status, physical activity, alcohol intake, diabetes, eGFR, tertiles of urinary excretion of calcium (for urinary fluoride) or tertiles of dietary intake of calcium (for dietary fluoride), use of calcium supplements, use of vitamin D supplements, ever use of estrogen and ever use of corticosteroids. Urinary fluoride models were additionally adjusted for serum Beta-CrossLaps (ng/L). Abbreviations: HR: hazard ratio, CI: confidence interval, eGFR: estimated glomerular filtration rate The total number of participants in the urinary fluoride and dietary fluoride analyses were 4,306 and 4,072, respectively. 234 women were excluded from the dietary fluoride analyses because of missing dietary fluoride information either due to responding to a shorter version of the FFQ or having missing / inadequate reported dietary intake (energy intake outside 3 SD of log-transformed mean) For each outcome, women contributed with person time from the date of clinical examination until the of date of the specific event studied, death, or end of follow-up at December 31 st , 2017. Table S4.

Tertiles of urinary fluoride
Cross-sectional mean differences in BMD (β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d) with BMD at the lumbar spine and femoral neck, among women of the Swedish Mammography Cohort -Clinical, including individuals excluded from main analysis because of missing bone mineral density data on either hip or spine.  Table S5.

Tertiles of urinary fluoride
Hazard ratios of total, osteoporotic and hip fractures and corresponding 95% confidence intervals by tertiles of urinary fluoride (mg/g creatinine) and dietary fluoride (mg/d), respectively, among women of the Swedish Mammography Cohort -Clinical, including individuals excluded from main analysis because of missing bone mineral density data on either hip or spine.  Table S6.
Cross-sectional mean differences in Bone mineral density (BMD)(β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) with BMD at the lumbar spine and femoral neck among women of the Swedish Mammography Cohort -Clinical with complete exposure data.
Tertiles of urinary fluoride, n = 4,072 Multivariable-adjusted models were adjusted for age, education, height, total fat mass, lean body mass, parity, smoking status, physical activity, alcohol intake, diabetes, eGFR, tertiles of urinary excretion of calcium (for urinary fluoride) or tertiles of dietary intake of calcium (for dietary fluoride), use of calcium supplements, use of vitamin D supplements, ever use of estrogen and ever use of corticosteroids. Urinary fluoride models were additionally adjusted for serum Beta-CrossLaps (ng/L). Abbreviations: HR: hazard ratio, CI: confidence interval, eGFR: estimated glomerular filtration rate For each outcome, women contributed with person time from the date of clinical examination until the of date of the specific event studied, death, or end of follow-up at December 31 st , 2017. Table S8.
Cross-sectional mean differences in Bone mineral density (BMD)(β coefficients (95% CI), g/cm 2 ) across tertiles of urinary fluoride (mg/g creatinine) with BMD at the lumbar spine and femoral neck among women of the Swedish Mammography Cohort -Clinical with urinary creatinine concentrations ranging between 0.3 g/L and 3.0 g/L.