ABSTRACT
Pharmacologists have been interested in vitamin D since its metabolism was elucidated in the early 1970s. Despite the synthesis of thousands of vitamin D analogues in the hope of separating its calcemic and anti-proliferative properties, few molecules have reached the market for use in the treatment of clinical conditions from psoriasis to chronic kidney disease. This review discusses vitamin D drugs, recently developed or still under development, for use in various diseases, but in particular bone disease. In the process we explore the mechanisms postulated to explain the action of these vitamin D analogues including action through the vitamin D receptor, action through other receptors e.g. FAM57B2 and dual action on transcriptional processes.
Subject(s)
24,25-Dihydroxyvitamin D 3/therapeutic use , Bone Density Conservation Agents/therapeutic use , Bone Diseases, Metabolic/drug therapy , Bone Remodeling/drug effects , Calcifediol/therapeutic use , Calcitriol/therapeutic use , Vitamins/therapeutic use , 24,25-Dihydroxyvitamin D 3/adverse effects , 24,25-Dihydroxyvitamin D 3/pharmacokinetics , Animals , Bone Density Conservation Agents/adverse effects , Bone Density Conservation Agents/pharmacokinetics , Bone Diseases, Metabolic/diagnosis , Bone Diseases, Metabolic/physiopathology , Calcifediol/adverse effects , Calcifediol/pharmacokinetics , Calcitriol/adverse effects , Calcitriol/pharmacokinetics , Humans , Receptors, Calcitriol/agonists , Receptors, Calcitriol/metabolism , Signal Transduction , Treatment Outcome , Vitamins/adverse effects , Vitamins/pharmacokineticsABSTRACT
Therapy for X-linked hypophosphatemia (XLH) only partially corrects skeletal lesions and is often complicated by hyperparathyroidism. 24,25(OH)2 D3 improves skeletal lesions in a murine model of XLH and suppresses PTH secretion in animals. Therefore, we undertook a placebo-controlled trial of 24,25(OH)2 D3 supplementation to standard treatment in patients with XLH to improve bone disease and reduce hyperparathyroid complications. Fifteen subjects with XLH receiving standard treatment [1,25(OH)2 D3 or dihydrotachysterol plus phosphate] were evaluated, supplemented with placebo, and reevaluated one yr later. 24,25(OH)2 D3 supplementation was then begun and studies repeated after another year. Each patient underwent a detailed evaluation of calcium homeostasis over a 24-h period. Rachitic abnormalities were assessed radiographically in children. Adults underwent bone biopsies. 24,25(OH)2 D3 normalized PTH values in nine subjects (peak PTH was 46.5 +/- 6.6 pmol/L at entry, 42.3 +/- 5.9 pmol/L after placebo, and 23.3 +/- 5.4 pmol/L after 24,25(OH)2 D3). Nephrogenous cAMP decreased at night, coincident with the decrease in PTH, and serum phosphorus was slightly greater with 24,25(OH)2 D3. Radiographic features of rickets improved during 24,25(OH)2 D3 supplementation in children, and osteoid surface decreased in adults. 24,25(OH)2 D3 is a useful adjunct to standard therapy in XLH by effecting correction of hyperparathyroidism and improvement of rickets and osteomalacia.
