The Free Hormone Hypothesis: Is Free Serum 25‐Hydroxyvitamin D a Better Marker for Bone Mineral Density in Older Women?

It is presently unclear whether free serum 25‐hydroxyvitamin D (S‐25(OH)D) better reflects bone health than total S‐25(OH)D. We have previously shown that summer total S‐25(OH)D values are more useful to predict bone mineral density (BMD) than winter values. Our objective was therefore to compare the relative importance of free and total S‐25(OH)D for BMD by season. BMD was measured by dual‐energy X‐ray absorptiometry (DXA) in 5002 Swedish women (mean age 68 years) randomly selected from a large population‐based longitudinal cohort study. Free S‐25(OH)D was analyzed by a commercial ELISA and total S‐25(OH)D by HPLC–tandem mass spectrometry (MS/MS). Free and total S‐25(OH)D co‐varied with season, with 26% and 29% higher values in August compared with those in January–March (nadir). There were no differences in mean BMD between categories of free or total S‐25(OH)D in samples collected during winter. Women with higher total S‐25(OH)D measured during summer had higher BMD at the total hip. Compared with women who had total S‐25(OH)D values above 80 nmol/L during summer, adjusted BMD at the total hip was 6% (95% CI, 1% to 11%) lower for S‐25(OH)D concentrations between 30 and 40 mmol/L, and 11% (95% CI, 3% to 19%) lower for those with total S‐25(OH)D <30 nmol/L. In contrast, free S‐25(OH)D measured during summer was not associated with BMD. Compared with women who had highest free S‐25(OH)D measured during summer (>8.8 pmol/L), those with intermediate (2.4–3.5 pmol/L) and lowest (<2.4 pmol/L) free S‐25(OH)D during summer did not have lower total hip BMD values (3% [95% CI, −2% to 7%] and −2% [95% CI, −8% to 4%]). In addition, we found no added value for the prediction of BMD with the combined measurement of total and free S‐25(OH)D during summer or winter. We conclude that vitamin D status assessed by direct measurements of free S‐25(OH)D does not reflect BMD better than total S‐25(OH)D. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.