Risk of low bone mineral density in patients with rheumatoid arthritis treated with biologics

Rheumatoid arthritis (RA) is a systemic inflammatory disease that can cause local joint deformity, including erosions of bone and narrowing of the joint space, and extra-articular symptoms, including anemia, pneumonitis and osteoporosis. Osteoporosis increases the risk of fracture and causes pain and disability, impairing the quality of life of patients with RA. High disease activity, glucocorticoid therapy, immobility, advanced age, low body mass and female sex are reportedly risk factors for osteoporosis in patients with RA [ 1]. Inflammation is the one of the key triggers of bone resorption and contributes to local and generalized osteoporosis [ 2]. Inflammatory cytokines activate osteoclast differentiation, which resorb bone matrix. Osteoclasts play a central role in bone resorption in RA, orchestrated by T-lymphocytes, monocytes and fibroblasts in the synovium of inflammatory joints, which produce osteoclast differentiation-inducing factors. Osteoclast differentiation is mainly promoted by the receptor activator of nuclear factor-kappa B ligand (RANKL), which is up-regulated by a large number of the inflammatory cytokines involved in the pathogenesis of RA [ 2]. A better understanding of the pathogenesis of RA has improved treatment of the disease, particularly the targeting of key molecules by biologics [ 3– 5]. Beyond the control of RA activity, there is evidence that biologics might also have beneficial effects on bone metabolism and bone remodeling [ 6]. We examined the bone mineral density (BMD) of patients with RA treated with biologics, and aimed to establish which factors were associated with low BMD.

The Japanese Society for Bone and Mineral Research proposed revised diagnostic criteria for primary osteoporosis in 2012. Primary osteoporosis is diagnosed when BMD is <80 % of YAM with evidence of a fragility fracture, or <70 % of YAM [ 7– 9]. We therefore elected to identify risk factors for a BMD <70 % of YAM.

Although the presence of osteoporosis, as identified by DEXA, is the best predictor of fracture in patients with RA [ 12], many indices of risk have been reported to identify low BMD, including the Simple Calculated Osteoporosis Risk Estimation (SCORE), the Osteoporosis Risk Assessment Instrument (ORAI), the Osteoporosis Self-Assessment Tool, the Osteoporosis Index of Risk (OSIRIS) and the Fracture Risk Assessment Tool (FRAX). Although these indices have substantial sensitivity in populations not affected by RA, they do not satisfactorily predict low BMD in RA [ 13]. We showed that age, female sex, disease duration, history of vertebral fracture, Steinbrocker classification, and lower BMI were associated with a greater risk of bone loss in patients with RA treated by biologics. There is still substantial debate about the risk factors for osteoporosis in patients with RA. The erythrocyte sedimentation rate, DAS, corticosteroid therapy, anti-resorptive osteoporosis treatment, MHAQ score, swollen joint count, tender joint count, hormone replacement therapy, disease severity, BMI, immobilization, and disease duration have all been implicated [ 14– 18]. Disease duration and disease activity has been considered the most important risk factors for osteoporosis [ 2, 19, 20]. Although our risk factors were found in patients with RA treated with biologics, these risk factors are compatible with those in the general population [ 21– 23]. We also found that methylprednisolone therapy, serum CRP concentration, DAS28-CRP, CDAI and SDAI were not risk factors for low BMD. These discrepancies may be a consequence of treatment with biologics. Before suppression of disease activity by biologics, bone loss might already be advanced. Bone loss is often found in patients with recent-onset RA [ 24] and bone loss has reportedly already started during the autoimmune phase of RA, long before inflammation occurs [ 25], implying that therapy for osteoporosis should be initiated promptly. Further research will be needed to establish whether these factors could be used prospectively as predictors of osteoporosis and fracture in patients with RA. We found only one English-language paper in PubMed that showed the relationship between the Steinbrocker classification and bone loss in patients with RA. The article reported that a higher Steinbrocker classification is a risk factor for bone loss of the femoral neck and lumbar spine [ 26]. Our findings are compatible with this report.

As well as influencing disease activity, biologics may prevent bone loss via a direct effect on bone metabolism. It is well recognized that TNFα induces differentiation of osteoclast precursors through a synergistic action with RANKL [ 27]. Bone metabolism and remodeling are regulated by a balance between TNF superfamily molecules, RANKL, osteoprotegerin, osteoclastogenesis inhibitory factor and TNF-related apoptosis-inducing ligand [ 12, 28, 29]. These cytokines are responsible for the imbalance between bone resorption and formation in RA, which may explain the ability of biologics not only to suppress systemic inflammation, but also to prevent bone loss [ 30– 33]. Nonetheless, there appears to be no significant difference in BMD change in biologics responders and non-responders [ 34, 35]. In addition, we found that the class and duration of biologics therapy was not significantly different in the BMD <70 % of YAM and BMD ≥70 % of YAM groups. Sequential evaluation of BMD during biologics therapy should help to illuminate their influence on bone density.

Although the proportion of patients treated with anti-osteoporosis drugs was significantly higher in the BMD <70 % of YAM group, bone loss could not be completely prevented. In addition, the proportion of patients treated with PTH was significantly higher in the BMD <70 % of YAM group, even though the absolute number of patients was only four. These findings suggest that patients who possess the risk factors that we have identified require earlier and more intensive treatment to prevent bone loss.

Our study has some limitations. First, data collection was retrospective. Second, BMD was measured once in each patient, so longitudinal data are not available. Third, we did not measure the change in biomarkers of bone remodeling in the blood or urine. Although there is reportedly no change in the indices of bone remodeling after 1 year of biologics treatment [ 30, 35], we are now examining longitudinal changes in BMD and biomarkers of bone turnover in a prospective study.

We identified risk factors for bone loss in patients with RA treated with biologics. As fragility bone fracture may substantially impair quality of life, and also has substantial adverse socioeconomic consequences, our findings suggest that osteoporosis should be detected and addressed promptly in patients with bDMARD-treated RA who possess these risk factors.