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- PATIENTS AND METHODS
This 2-year observational study exploring BMD changes in a large cohort of patients with RA shows that bone loss can be prevented in this population, which is known to be at high risk for fractures (23–26). In the present study, BMD increased (0.16–1.64%) at all measurement sites in patients using antiresorptive drugs but decreased in those using calcium and vitamin D supplementation only (−1.99 to −1.39%) as well as in patients receiving no treatment for osteoporosis (−1.20 to −0.43%).
The magnitude of bone loss demonstrated in the current study was generally less than that shown in previously published longitudinal studies of patients with RA (6–13). In the preceding studies, annual BMD changes ranged from +0.2% to −2.0% in the lumbar spine and from −0.3% to −3.2% in the femoral neck (6–13). Also, patients who were receiving treatment for osteoporosis were either excluded from those studies (7, 8, 10, 11, 13) or comprised only a minority of the study population (6, 12), or information about their osteoporosis treatment was not reported (9). In accordance with results from several other longitudinal studies in patients with RA, we found that more BMD loss occurred at the hip than at the spine (6, 8, 10, 12). This variation may be explained by synovitis of the hip joint; subsequent impaired functional capacity may lead to impaired loading of the lower limbs in patients with RA. Alternatively, the observed difference may only be artificial, caused by increased osteoarthritis in the spine with aging.
In a Finnish population, the annual rate of BMD loss was estimated in cross-sectional studies to be −0.2% for the lumbar spine and −0.3% for the femoral neck in men (27), and −0.7% and −1.3%, respectively, in women ages 39 years and older (28). However, Melton et al (29), examining the rate of bone loss in men and women older than age 50 years, demonstrated that compared with longitudinal data, cross-sectional data overestimate the rate of bone loss (29). Using cross-sectional data, BMD for the total hip in women appeared to decline by −0.8% per year but by only −0.2% per year using longitudinal data; in men, the comparable figures were −0.4% and +0.03% (29). Compared with these longitudinal rates of annual BMD loss, the rates for our female patients with RA were slightly increased, but those for our male patients with RA were increased severalfold.
Previous controlled clinical trials showed that HRT and bisphosphonates are effective for the prevention and treatment of both primary osteoporosis and glucocorticoid-induced osteoporosis (30–33). In randomized, controlled trials of bisphosphonates for the prevention of glucocorticoid-induced osteoporosis, the annual increase in BMD among patients in the treatment group was 0.6–2.9% for the lumbar spine and 0.2–1.0% for the femoral neck, whereas among patients in the placebo group (calcium, alone or in combination with vitamin D), loss of BMD was −0.4% to −3.2% and −1.2% to −3.1%, respectively (31–33). The same pattern was observed in our study, supporting the ineffectiveness of calcium and/or vitamin D alone to stop bone loss. Our treatment strategy was based mainly on recommendations given in consensus statements published in the mid 1990s (3, 4), recommending HRT as the first treatment choice for female patients with RA. However, later guidelines for the prevention and therapy of glucocorticoid-induced osteoporosis recommended bisphosphonate therapy as the treatment of choice (5, 21).
Several authors have reported that patients using long-term corticosteroid therapy are receiving inadequate treatment for the prevention of bone loss (34–36), and that is especially true for male patients (34, 35). In the study by Buckley et al (35), 54% of the postmenopausal women and only 5% of the men who were receiving long-term corticosteroid treatment were also receiving antiresorptive treatment. Our patients with RA who were currently using corticosteroids at followup were, to some extent, treated with antiresorptive drugs more frequently (55% of women and 11% of men) than were patients described in these previous studies (34–36). However, our results (especially for male patients) are far from satisfactory, considering the recommendations of the ACR for prevention and treatment of glucocorticoid-induced osteoporosis, which were first presented in 1996 (3) and updated in 2001 (21). In our study, the greatest rate of BMD increase was observed in patients using HRT and bisphosphonates simultaneously. The additive effect of bisphosphonates and HRT on hip and spine BMD has previously been shown in postmenopausal osteoporosis (37–39) but not in randomized controlled trials in glucocorticoid-induced osteoporosis. Our data suggest that the combination of HRT and bisphosphonates may be considered in postmenopausal patients with RA who have severe or established osteoporosis.
We also explored the change in BMD between baseline and followup, using the WHO definition for osteoporosis (22). BMD increased in patients with a T score less than or equal to −2.5 SD at baseline, was unchanged in patients with a T score greater than −2.5 SD and less than −1 SD, and declined in patients with a T score greater than −1 SD (data not shown). The fact that BMD increased in patients with the lowest BMD (T score less than or equal to −2.5 SD) reflects a trend toward treating patients who have the lowest BMD levels.
Factors associated with BMD change in RA are difficult to examine, due to their complexity and interrelationships (e.g., measures of disease activity are suppressed and functional capacity is increased by using corticosteroids and DMARDs in RA) (40). This issue is further complicated by the use of potent drugs for osteoporosis that effectively increase bone mass (30, 32, 33). Despite these methodologic problems, our study demonstrated that corticosteroids (a well-known risk factor for bone loss) (41, 42) are associated with bone loss. However, the results for all measurement sites were not consistent. The negative effect of corticosteroids on bone may be balanced by reducing the impact of other factors contributing to RA, such as inflammation and immobility (6, 40). In the study by Ferraccioli et al (40), effective control of systemic inflammation in patients with RA who were aggressively treated with prednisone (5 mg daily), methotrexate (10 mg/week), and cyclosporine (3–5 mg/kg) led to a 3.9% increase in spine BMD. Van Schaardenburg et al (12), in their randomized study, found greater BMD loss in elderly patients with RA receiving prednisone compared with patients treated with chloroquine and healthy controls. Verhoeven and Boers (43) concluded, after reviewing the literature, that the use of short-term (≤1 year) low-dose corticosteroid treatment (<10 mg prednisone/day) has limited influence on BMD in RA.
In contrast to previously reported results, we did not find consistent relationships between bone loss and disease measures. Gough et al (6), examining patients with early RA, found that both level of disability and C-reactive protein level predicted BMD loss, but use of prednisolone did not. In a study by Mazzantini et al (11), patients with active RA lost significantly more BMD at the lumbar spine (−5.5%) than did those with less active disease (−1.1%). Our data may, however, suggest a role of inflammation in the pathogenesis of osteoporosis in RA. In bivariate analysis using cutoffs for SDD other than the 95% detection limit, ESR was significantly associated with bone loss for the total hip (data not shown), and the multivariate linear regression model revealed a possible association between elevated ESR and BMD reduction at the hip (P = 0.07).
The strength of our observational population-based study is that it provides insight into what takes place in the real world of patients with RA regarding the magnitude of BMD loss and the attitude of physicians toward the prevention and treatment of osteoporosis. Our study also had obvious limitations. Compared with a longitudinal observational study, a randomized controlled study design gives stronger evidence for treatment effects, but most researchers will agree that the 2 designs provide complementary information. The detection of potential risk factors associated with BMD loss in patients with RA should, therefore, be interpreted with caution, because no causality is established from multivariate statistical analyses, even when adjusting for confounders.
For the SDD estimation of the BMD measurement, using the approach described by Bland and Altman (20), we ideally should have used duplicate BMD measurements obtained from a representative sample of the RA patients who were examined. Ravaud et al (44) found that the cutoffs for SDD were inversely related to BMD level. The mean BMD level in our RA population was approximately 9–15% lower (10–15% in women, 2–12% in men) than that in the healthy female hospital workers used for the SDD estimation in our study (data not shown). However, we did not find any major differences between associations when different cutoffs (e.g., 75%, 90%, and 97.5% limits of agreement) were applied. The short (2-year) observational period in our study is one of the reasons why as many as 70% of the patients with RA did not undergo a change in BMD exceeding the SDD with 95% limits of agreement. By increasing the length of the observational period and by using the mean values of duplicate BMD measurements obtained from patients at baseline and followup, the number of patients with changes in BMD exceeding the SDD would have increased. However, such an approach would have limited the generalizability of our results.
In conclusion, the results of this study add evidence to the importance of treating patients with RA in accordance with current guidelines for the prevention of further bone loss. Only the group of patients with RA who were using antiresorptive drugs did not lose BMD during followup, emphasizing the potency of these drugs in protecting against bone loss. The male patients with RA, who had a higher rate of BMD loss than the female patients, had been treated less aggressively with antiresorptive drugs than had the female patients. Therefore, more attention should be focused on treatment of osteoporosis in male patients with RA. Whether these results also can be translated into effects on fractures (23–26) remains to be studied.