Vitamin D supplementation: upper limit for safety revisited?
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REVIEW
Vitamin D supplementation: upper limit for safety revisited? René Rizzoli1 Received: 20 June 2020 / Accepted: 4 August 2020 © The Author(s) 2020
Abstract Vitamin D overdosing includes hypercalcemia, hypercalciuria, and mineral deposits in soft tissues. A safety upper limit of 4000 IU/day, which is consistently accepted, has been challenged, since the risk of adverse events in other systems than calcium-phosphate homeostasis may depend not only on the dose, but on the outcome, the treatment regimen, and possibly the age, sex and vitamin D status. The therapeutic window of vitamin D supplementation may be narrower than hitherto recognized. The prevention and/or correction of vitamin D deficiency/insufficiency with 800–1000 IU/daily of vitamin D or 10 µg/day of calcifediol are safe. Because of their potential harm, larger doses given on the long term or in intermittent regimens should not be selected. Keywords Osteoporosis · Falls · Fracture · Bone health · Sarcopenia
Introduction Vitamin D is an important regulator of calcium and phosphate homeostasis. Synthesized in the skin under the influence of UV light, vitamin D (cholecalciferol) undergoes a first hydroxylation in position 25 in the liver, leading to 25-hydroxyvitamin D (calcifediol), and a second one in position 1 in the kidney, leading to the active metabolite 1,25-dihydroxyvitamin D (calcitriol) [1]. The latter step is stimulated by PTH, IGF-I and by low calcium or phosphate intakes or concentrations. Calcitriol stimulates intestinal trans-epithelial transport of calcium and phosphate through both genomic and non-genomic mechanisms [1]. Calcitriol is a potent stimulator of bone resorption [2], by increasing the expression and production of RANKL by osteoblasts [3]. Vitamin D deficiency impairs hypertrophic cartilage and bone mineralization, leading to rickets in children and osteomalacia in adults. Vitamin D status is evaluated by the measurement of circulating 25-hydroxyvitamin D (25OHD), preferentially with a standardized assay. Infusion of calcium and phosphate in vitamin D-deficient rats results in normal mineralization of hypertrophic cartilage and bone [4]. In systemic VDR knock-out model, rickets and osteomalacia can * René Rizzoli [email protected] 1
Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, 1211 Geneva 14, Switzerland
be prevented by a diet rich in calcium and phosphate with lactose supplements to improve intestinal calcium absorption [1, 5]. By promoting optimal extra-cellular calcium and phosphate concentrations, the vitamin D system ensures the mineralization of newly deposited bone and cartilage matrix [6]. In a recent report, an infant with hypophosphatasia suffered vitamin D deficiency-induced rickets, although serum calcium and phosphate were always entirely normal [7]. However, rickets was cured by vitamin D treatment alone, confirming some in vitro data which indicate a direct effect of vitamin D on osteoblast mediated mineralization [8]. These findings indicate that optimal extracel
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