Measurements of the Vitamin D Metabolome in the Calgary Vitamin D Study: Relationship of Vitamin D Metabolites to Bone Loss.

In a 36 month RCT examining the effect of high dose vitamin D 3 on radial and tibial total bone mineral density (TtBMD), measured by high resolution peripheral quantitative tomography (HR-pQCT), participants (311 healthy males and females aged 55-70 years with DXA T-scores > -2.5, without vitamin D deficiency) were randomized to receive 400 IU (N = 109); 4,000 IU (N = 100); 10,000 IU (N = 102) daily. Participants had HR-pQCT radius and tibia scans and blood sampling at baseline, 6, 12, 24 and 36 months. This secondary analysis examined the effect of vitamin D dose on plasma measurements of the vitamin D metabolome by liquid chromatography-tandem mass spectrometry (LC-MS/MS), exploring whether the observed decline in TtBMD was associated with changes in four key metabolites [25-(OH)D 3 ; 24,25-(OH) 2 D 3 ; 1,25-(OH) 2 D 3 ; and 1,24,25-(OH) 3 D 3 ]. Relationship between peak values in vitamin D metabolites and change in TtBMD over 36 months was assessed using linear regression, controlling for sex. Increasing vitamin D dose was associated with a marked increase in 25-(OH)D 3 , 24,25-(OH) 2 D 3 and 1,24,25-(OH) 3 D 3 , but no dose-related change in plasma 1,25-(OH) 2 D 3 was observed. There was a significant negative slope for radius TtBMD and 1,24,25-(OH) 3 D 3 (-0.05, 95%CI -0.08, -0.03, p < 0.001) after controlling for sex. A significant interaction between TtBMD and sex was seen for 25-(OH)D 3 (female: -0.01, 95%CI -0.12,-0.07; male: -0.04, 95%CI -0.06,-0.01, p = 0.001) and 24,25-(OH) 2 D 3 (female: -0.75, 95%CI -0.98, -0.52; male: -0.35, 95%CI -0.59, -0.11, p < 0.001). For the tibia there was a significant negative slope for 25-(OH)D 3 (-0.03, 95%CI -0.05, -0.01, p < 0.001), and 24,25-(OH) 2 D 3 (-0.30, 95%CI -0.44, -0.16, p < 0.001), and 1,24,25-(OH) 3 D 3 (-0.03, 95%CI -0.05, -0.01, p = 0.01) after controlling for sex. These results suggest vitamin D metabolites other than 1,25-(OH) 2 D 3 may be responsible for the bone loss seen in the Calgary vitamin D Study. Although plasma 1,25-(OH) 2 D 3 did not change with vitamin D dose, it is possible rapid catabolism to 1,24,25-(OH) 3 D 3 prevented detection of a dose-related rise in plasma 1,25-(OH) 2 D 3 . This article is protected by copyright. All rights reserved.