Background. Vitamin D is important for bone health, although high loading doses have been associated with an increase in fracture risk. The mechanisms remain uncertain. Aim. We hypothesize that supraphysiological concentrations of 1,25 (OH)2 vitamin D may inhibit formation by increasing the production of Wnt inhibitors: sclerostin and DKK1. Subjects and Methods. We measured serum sclerostin and DKK1 in 34 patients (21 F, 13？M) aged mean (SD) 61.3 (15.6) years with vitamin D deficiency/insufficiency treated with a loading dose of vitamin D2 (300,000？IU) intramuscularly. Blood samples were taken at baseline and serially up to 3 months. Results. Serum 1,25 (OH)2 vitamin D increased markedly at 3 months (mean (SD) baseline 116 (63), 3 months？:？229 (142)？pmol/L, ). There was a significant correlation between sclerostin and DKK1 at baseline (, ) and at 3 months (, ). A significant inverse correlation was observed between sclerostin and eGFR at 3 months (, ). Sclerostin increased significantly at 3 months (). In a multilinear regression analysis with % change in sclerostin and DKK1 as dependent variable, a positive significant association was observed with % change in 1,25 (OH)2 vitamin D (), independent of changes in PTH and following correction for confounders such as age, gender, BMI, BMD and eGFR. Conclusions. Supraphysiological concentration in 1,25 (OH)2 vitamin D achieved following a loading dose of vitamin D increases sclerostin and may inhibit Wnt signalling. This may have detrimental effects on bone. 1. Introduction Vitamin D is important for the maintenance of skeletal health. The best-known physiological role of active vitamin D or 1,25 (OH)2 vitamin D concerns the maintenance of calcium and phosphate homeostasis by promoting their intestinal absorption, thus ensuring their availability for the skeletal mineralisation process [1]. To achieve this well-established endocrine effect, 1,25 (OH)2 vitamin D works in concert with 2 other hormones: parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) [2]. Aside from its well-characterised endocrine pathway, there is now a growing body of evidence which demonstrates that 1,25 (OH)2 vitamin D can directly affect bone cell differentiation and function by targeting key genes involved in bone formation and resorption [3]. The targets for 1,25 (OH)2 vitamin D include LRP5, the Wnt coreceptor that plays a key role in osteoblast proliferation, differentiation, and function. In addition, other genes which promote osteoclastogenesis are also regulated by 1,25 (OH)2 vitamin D and this includes RANKL,
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