The Association of Methotrexate, Sulfasalazine, and Hydroxychloroquine Use With Fracture in Postmenopausal Women With Rheumatoid Arthritis: Findings From the Women's Health Initiative

Abstract

This study was conducted to evaluate the extent to which disease-modifying antirheumatic medications (DMARDs) used as part of a triple therapy for the treatment of rheumatoid arthritis (RA) including methotrexate, sulfasalazine, and hydroxychloroquine are associated with fractures in postmenopausal women with RA. Incident fractures following use of methotrexate, sulfasalazine, and/or hydroxychloroquine in postmenopausal women with RA in the Women's Health Initiative were estimated by Cox proportional hazards using hazard ratios (HRs) and 95% CIs after consideration of potential confounders. There were 1201 women with RA enrolled in the Women's Health Initiative included in these analyses, of which 74% were white, 17% were black, and 9% were of other or unknown race/ethnicity. Of the women with RA, 421 (35%) had not used methotrexate, sulfasalazine, or hydroxychloroquine, whereas 519 (43%) women had used methotrexate, 83 (7%) sulfasalazine, and 363 (30%) hydroxychloroquine alone or in combination at some time during study follow-up. Over a median length of 6.46 years of follow-up, in multivariable adjusted models, no statistically significant association was found between methotrexate (HR, 1.1; 95% CI, 0.8-1.6), sulfasalazine (HR, 0.6; 95% CI, 0.2-1.5), or hydroxychloroquine (HR, 1.0; 95% CI, 0.7-1.5) use and incident fractures or between combination therapy with methotrexate and sulfasalazine or methotrexate and hydroxychloroquine use (HR, 0.9; 95% CI, 0.5-1.6) and incident fractures. In conclusion, postmenopausal women with RA receiving any component of triple therapy should not be expected to have any substantial reduction in fracture risk from use of these DMARDs.

Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview

“…If methotrexate is not appropriate, sulfasalazine and leflunomide are recommended. Experiments in cell and animal models have shown that methotrexate induces bone turnover by decreasing the differentiation of osteoblasts, production of bone matrix, and expression of RANKL; however, the dose used in the treatment of rheumatoid arthritis has little influence on bone metabolism and the development of osteoporosis [ 34 ].…”

The Effect of Anti-rheumatic Drugs on the Skeleton

“…When tested on osteoblasts HCQ treatment was found to decrease human mesenchymal stem cells derived osteoblast differentiation and mineralization in vitro [35]. The WHI observational study in RA patients taking HCQ have not found a difference in fracture rate in comparison to HCQ non-users [27].…”

“…BMD measurements of the children between 5 and 10 years showed that children whose mothers were treated with SSZ during pregnancy had a higher total body BMD [32] compared to children of mothers who were not treated with SSZ. Subsequent studies ,however, do not confirm any beneficial impact of SSZ on fracture risk [27].…”

“…Out of the 15 cases in whom fracture healing was reported at least 53.3% had stopped MTX [25]. The previously mentioned WHI study, however, did not detect any difference in lower limb fractures, in MTX users vs non-users [27]. This may be due to the fact that insufficiency fractures are frequently under-or misdiagnosed in patients with rheumatoid arthritis [28].…”

Celastrol Exerts Cardioprotective Effect in Rheumatoid Arthritis by Inhibiting TLR2/HMGB1 Signaling Pathway-Mediated Autophagy

“…Those with family history and chronic inflam-mation as well as smokers are most often affected [3,4]. It is increasingly appreciated that RA is associated with substantial social burden, deceased life quality and comorbidities, including fracture and cardiovascular events [5,6]. In recent years, there has been growing awareness on the role of RA in the onset and development of cardiovascular diseases [7].…”