Oral glucocorticoids (GCs), also known as oral corticosteroids, are widely used for the treatment of a variety of inflammatory and allergic disorders. Estimates in the US suggest that 1–3% of men and women over age 50 years are receiving long-term GC therapy (1). Data from the UK also report frequent use of GC therapy in the elderly (2). It is now well recognized that treatment with GCs can lead to rapid loss of bone mineral density (BMD) and to an increased risk of fracture (3). Several epidemiologic studies have reported a doubling of the risk of hip fracture in GC users (4–6). In the largest of these studies, a rapid increase in fracture risk following the start of GC therapy and a strong correlation of risk with daily GC dose were found (6, 7). Two smaller studies demonstrated that the cumulative (compared with daily) GC dose was the stronger predictor of fracture (8, 9).
Fractures in GC users may occur as a consequence of bone loss; however, there is increasing interest in the possible role of microarchitectural change in GC-induced fractures. Recently, the hypothesis was proposed that osteocyte apoptosis could lead to a deterioration of bone quality, with rapid increases in the risk of fracture (10). Consistent with the notion of a non–BMD-related mechanism being responsible for inducing fractures, Luengo et al observed that GC users with a fracture had considerably higher BMD than did patients with involutional osteoporosis and fracture (11). However, this observation was not confirmed in a second observational study (12).
Accordingly, we used data from the placebo arms of 2 large randomized, controlled trials of risedronate, to evaluate the predictors of vertebral fracture in GC users. In addition, we determined the BMD threshold for vertebral fracture by comparing postmenopausal GC users with postmenopausal GC nonusers.
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- PATIENTS AND METHODS
We have utilized data from 2 large, prospective, randomized, controlled trials to show that the daily GC dose, and not the cumulative dose, is a strong predictor of the risk of vertebral fracture. We have also demonstrated that postmenopausal GC users have considerably higher fracture risks than do nonusers of GCs, at similar baseline levels of BMD.
This study is the first prospective study to evaluate the incidence of fractures in patients on GC therapy, and clarifies whether the risk increase is related to the daily dose (rapid onset) or the cumulative dose (long-term effect) of GCs. Our findings are consistent with those of a large, retrospective epidemiologic study, which reported that the risk of nonvertebral fractures was increased by 54% in the first year of GC treatment (with daily doses >7.5 mg of prednisolone) (3, 6). The risk of fracture was primarily related to the daily dose and not the cumulative dose (7). These findings support the notion that fractures can occur rapidly in patients receiving GC therapy.
We found that the BMD threshold for fracture was different in (postmenopausal) GC users compared with nonusers. This issue is controversial, and published data are inconsistent. Two studies have shown that the distribution of BMD among cases of vertebral fracture was similar between GC users and nonusers (12, 21). The main limitation of these previous analyses is their reliance on prevalent fracture; BMD in patients with prevalent fractures is related not only to the underlying incidence rate of fracture, but also to the duration of therapy or disease (3). Therefore, the BMD of patients with incident fractures will be very different from that of patients with prevalent fractures. We believe it is inappropriate to make inferences on the BMD threshold for new fractures on the basis of prevalent cases only. Furthermore, in the study by Selby et al, both the prevalence and severity of vertebral fracture were considerably higher in GC users compared with nonusers, despite the apparently similar levels of BMD (12).
Other studies support our observations that GC therapy influences fracture risk by a mechanism independent of BMD (3, 11, 22, 23). One such mechanism for the rapid onset of fracture risk could be osteocyte apoptosis, leading to a deterioration of bone quality and early increases in fracture risk (10). Osteocyte apoptosis is prevalent in GC-induced osteoporosis (24), and preliminary results of an animal study demonstrated that osteocyte viability was an important determinant of bone strength independent of BMD (25). The network of osteocytes probably participates in the detection of microdamage and the transmission of signals that lead to bone repair by remodeling. Osteocyte apoptosis could compromise this mechanism, leading to microdamage accumulation and increased bone fragility (24). The adverse effects of GC therapy on the formation of osteoblasts (24) could further reduce this repair of microdamage.
Guidelines have been developed to establish intervention thresholds in GC-induced osteoporosis. The recent guidelines of the American College of Rheumatology advocate intervention in all patients who start GC therapy at ≥5 mg/day and in those patients on a long-term regimen of GCs with a BMD below a T score of −1.0 (26). Guidelines from the UK advocate an intervention threshold at a T score of −1.5 (27). The results of this study support the use of a higher BMD threshold in patients receiving GC therapy, since the postmenopausal women receiving GCs had considerably higher risks of fracture than did the GC nonusers at similar levels of BMD. There are, however, insufficient data in our study to establish whether a threshold of −1.0 would be clearly preferable to that of −1.5.
Our study has several limitations. One is the small size of the population of GC users, which restricted our ability to identify all risk factors for fracture and could lead to statistically significant, but imprecise, estimates of fracture risk. A second limitation is that we did not adjust for disease severity in the comparison of GC users and nonusers. This is particularly relevant in drawing conclusions about the etiology of the increased risk of fracture in GC users. BMD measurements are primarily used to identify patients at high risk for fracture, irrespective of the underlying etiology of the reduced BMD. This study addressed whether BMD measurements predicted fracture in a comparable manner between GC users and nonusers.
In the BMD threshold analysis, the vertebral fracture classification of nonusers was based on both a quantitative and a semiquantitative classification method, whereas that of GC users was based on a quantitative classification only. However, a radiologist visually adjudicated any differences in classification between the quantitative and semiquantitative methods among nonusers. We found that almost all verified vertebral fractures in the nonusers were identified by both the quantitative and semiquantitative method. A study comparing the reproducibility of different definitions of vertebral deformity also reported good concordance between these methods if used in combination with a visual assessment (28). Any bias due to the use of an additional method in identifying potential fractures in nonusers would have resulted in an overestimate of fracture incidence in the nonusers and an underestimate of the risk of fracture in GC users.
In conclusion, this study demonstrates that the risk of vertebral fracture increases rapidly in patients starting GC therapy. Our findings support the hypothesis that treatment with GCs influences the occurrence of fracture by a mechanism independent of BMD. Consequently, different BMD-intervention thresholds should be utilized in patients undergoing GC therapy.