A number of different methods of assessment have been utilized to determine the effects of ICS on bone, including biochemical markers of bone turnover such as osteocalcin and hydroxyproline, bone mineral density, and the risk of fracture at various sites (59-63). Short-term changes in biochemical markers are of uncertain clinical relevance and the limitations of bone mineral density measurement have been increasingly recognized as well. In particular, there is evidence that the adverse effects of cortico-steroids are primarily a consequence of disruption of bone architecture and collagen structure rather than demineralization (64,65) and that the increased risk of fracture with steroid use is only partially due to the reduction in bone mineral density (66). Furthermore, the correlation between corticosteroid use and reduction in bone mineral density is poor and the size of the effect on bone mineral density does not appear to explain the risk of fracture associated with corticosteroid therapy (66). As a result changes in bone mineral density can now be considered to be an indirect marker of the risk of fracture with the use of ICS. A more clinical relevant approach for determining the adverse effects of ICS on bone is the direct assessment of the risk of fracture.
Recently two large population-based case-control studies of ICS and hip fracture have enabled the dose-response relationship of the effects on bone of ICS to be determined (63,67). In the U.K. General Practice Research Database study there was a small dose-dependent increase in the risk of fracture up to a dose of 1600 mg/day, with the risk increasing more markedly at higher doses (63). When adjustment was made for exposure to oral corti-costeroids and other confounding factors, the relative risk increased from
1.39 at the 800-1600 mg dose range with a further increase to 1.87 in the 1.6% of the population prescribed >1600 mg/day (Fig. 5). As 98% of subjects were prescribed either BDP or budesonide, these doses can be considered to relate to BDP or equivalent. The data from this study relates to older patients, and it could be proposed that the risk may be higher for future generations who will have been exposed to ICS from an earlier age, although some of the increase in risk will potentially be offset if courses of oral steroids are avoided.
Similar risks were observed in a cohort study in which a risk of non-vertebral fracture of 1.28 was observed in asthmatic patients taking >700 mg of ICS per day, compared with a non-asthmatic control group (68). The other major study, of case-control design, examined the association of ICS use and risk of fracture from a Canadian population-based cohort (67). Among subjects followed for over eight years, the rate of hip fracture was only elevated with daily doses of more than 2000 mg of BDP or equivalent (RR 1.61 95% CI 1.04-2.50). For upper extremity fracture, the rate increased by 12% with every 1000 mg increase in the daily dose of ICS.
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