The pleiotropic effects of vitamin D in bone

Abstract

A current controversial question related to vitamin D supplementation is what level of serum 25-hydroxyvitamin D3 (25(OH)D₃) is required to reduce the incidence of osteoporotic fractures. The reasoning behind vitamin D supplementation has been mostly derived from the role of vitamin D to promote intestinal calcium absorption and reduce bone resorption. While minimum 25(OH)D₃ levels of 20 nmol/L are required for sufficient intestinal calcium absorption to prevent osteomalacia, the mechanistic details of how higher 25(OH)D₃ levels, well beyond that required for optimal calcium absorption, are able to prevent fractures and increase bone mineral density is unclear. Substantial evidence has arisen over the past decade that conversion of 25(OH)D₃ to 1,25(OH)₂D₃ via the 1-alpha hydroxylase (CYP27B1) enzyme in osteoblasts, osteocytes, chondrocytes and osteoclasts regulates processes such as cell proliferation, maturation and mineralization as well as bone resorption, which are all dependent on the presence the of the vitamin D receptor (VDR). We and others have also shown that increased vitamin D activity in mature osteoblasts by increasing levels of VDR or CYP27B1 leads to improved bone mineral volume using two separate transgenic mouse models. While questions remain regarding activities of vitamin D in bone to influence the anabolic and catabolic processes, the biological importance of vitamin D activity within the bone is unquestioned. However, a clearer understanding of the varied mechanisms by which vitamin D directly and indirectly influences mineral bone status are required to support evidence-based recommendations for vitamin D supplementation to reduce the risk of fractures.

This article is part of a Special Issue entitled ‘Vitamin D workshop’.

Introduction

It is well established that raising the vitamin D status, as indicated by the serum 25-hydroxyvitamin D₃ (25(OH)D₃) levels, is an effective preventative strategy for reducing the risk of fractures in the elderly [1]. There has, however, been debate in the field as to what level of circulating 25(OH)D₃ is sufficient to improve bone mineral density and lower fracture risk. Some difficulty in answering this question can be attributed to the fact that the level of 25(OH)D₃ required for adequate renal synthesis of 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) to normalise intestinal calcium absorption and maintain plasma calcium homeostasis is considerably lower than that required to prevent fractures [2], [3]. Clinical studies have demonstrated that only when 25(OH)D₃ levels fall below 20 nmol/L does marked secondary hyperparathyroidism develop as a consequence of impaired 1,25(OH)₂D₃ synthesis and intestinal calcium malabsorption [2]. While at 25(OH)D₃ levels of 40 nmol/L there is no apparent substrate limitation on the production of circulating 1,25(OH)₂D₃ levels nor impairment of intestinal calcium absorption, the development of osteoporosis can nevertheless occur in animal models and the risk of hip fracture in the elderly is increased compared to those with 25(OH)D₃ levels in excess of 75 nmol/L [1], [4], [5], [6], [7], [8], [9]. How raising 25(OH)D₃ status to 75 nmol/L and above can increase bone mineral density and reduce fracture risk is not immediately clear. Addressing this question is necessary in order to provide a better rationale for vitamin D supplementation for those with moderate vitamin D insufficiency. Possibly the most promising explanation for the need to maintain higher levels of serum 25(OH)D₃ than that required to normalise intestinal calcium absorption, is the fact that several bone cell types, such as osteoblasts and osteoclasts, are sites for the substrate-dependent synthesis of 1,25(OH)₂D₃ [10], [11], [12], [13], [14], [15], [16], [17], [18]. Investigations into the role of the direct activities of vitamin D within bone may not only provide the key to the physiological basis as to why increased serum 25(OH)D₃ levels improve bone health, but also may provide an important explanation into the pleiotropic effects of vitamin D within bone.