To the best of our knowledge, this is the first study to compare the effectiveness of ROMO between patients receiving concomitant GC therapy and those not receiving GC therapy after adjustment for baseline characteristics using IPTW. The main finding is that, although changes in BTMs were comparable between groups, percentage changes in BMD differed by skeletal site. Specifically, the percentage change in LS BMD was similar in both groups, whereas smaller BMD gains at the TH and FN were observed in GC users. These findings may reflect differential biological effects of GC on trabecular versus cortical bone.

In the weighted analysis, there were no significant differences in BTM trajectories between GC users and non-users. In both groups, ROMO was associated with an increase in PINP and a decrease in TRACP-5b. GC is known to suppress Wnt signaling-mediated bone formation and promote bone resorption, partly by enhancing sclerostin production by osteocytes [23]. Taken together, these findings suggest that the effects of GC therapy at a mean dose of 5.4 mg/day (PSL-equivalent) on BTMs may have been at least partly offset by ROMO, an anti-sclerostin antibody. Because BTMs were not measured during the early phase after ROMO initiation, we cannot exclude the possibility that the PINP response was delayed in GC users, making the elevation appear more sustained at 6 or 12 months. Whether this reflects GC exposure itself or the underlying autoimmune or inflammatory background remains uncertain and warrants further investigation.

Notably, despite comparable BTM responses, BMD changes showed clear site-specific differences. For LS BMD, the percentage increase did not differ significantly between groups. Because the LS contains a higher proportion of trabecular bone and has a larger remodeling surface than cortical-rich sites, bone turnover tends to be more active, and BMD changes in this region may be more directly influenced by remodeling dynamics [24, 25]. Accordingly, consistent with the similar BTM changes, ROMO may have produced comparable increases in LS BMD regardless of concomitant GC use.

By contrast, at the TH and FN, the BMD response was significantly attenuated in the GC concomitant group compared with the non-GC group. Although FN BMD was a secondary endpoint in this study, the attenuated response observed in GC users may still be clinically relevant [26, 27]. It remains unclear whether this difference persists over time or improves with longer follow-up or sequential therapy. This site-specific attenuation was also supported by multivariable regression, in which GC dose was identified as a significant negative predictor of hip BMD gain. Several mechanisms may contribute to this divergence.

First, effects on angiogenesis and cortical microarchitecture may be involved. GC has been reported to suppress vascular endothelial growth factor production in cortical bone and to impair the intraosseous microvascular network, thereby promoting cortical porosity [28]. Second, reduced intestinal calcium absorption and decreased renal calcium reabsorption associated with GC use may lead to compensatory increases in cortical bone resorption to maintain serum calcium levels [29]. Third, inflammatory cytokines may play an important role. In patients with rheumatoid arthritis (RA), which accounted for a substantial proportion of our GIOP cohort, inflammatory cytokines such as tumor necrosis factor-α can induce Dickkopf-related protein 1 (Dkk-1) production by synovial cells [30], and circulating Dkk-1 levels have been reported to be higher in RA than in healthy controls [31]. Moreover, interleukin (IL)−6 has been shown to suppress osteogenesis through sclerostin-independent signaling pathways involving mitogen-activated protein kinase kinase 2 (MEK2) and AKT serine/threonine kinase 2 (Akt2) [32]. Collectively, these findings suggest that, in autoimmune diseases such as RA, local cortical bone formation may be suppressed through inflammation-driven, sclerostin-independent inhibitory pathways, including Dkk-1 and IL-6 signaling. Fourth, reduced walking ability due to joint disease may decrease mechanical loading on the lower limbs and thereby limit periosteal apposition [33]. Indeed, we previously reported that FN BMD increase by ROMO was negatively associated with impaired physical function in RA patients without GCs [34].

Taken together, GC-related suppression of cortical angiogenesis and increased porosity, as well as cytokine- and disuse-related structural vulnerability of cortical bone, may not be fully captured by changes in BTMs. These factors also may not be sufficiently compensated by ROMO-induced activation of Wnt signaling [35]. However, this should not be interpreted as evidence that GCs exert a stronger direct effect on cortical than trabecular bone. Rather, although early GC-induced bone loss is generally more pronounced at trabecular-rich sites, the present findings may suggest that, in patients with long-term GC exposure, recovery at cortical-rich sites was relatively limited during ROMO treatment.

From a clinical perspective, the present findings can be interpreted in the context of previous reports. In a prior study, we reported that, among GC-treated patients receiving a mean PSL-equivalent dose of approximately 5 mg/day, ROMO increased LS, TH, and FN BMD at 12 months to an extent comparable to, or greater than, denosumab (DMAb), a therapy with established efficacy for GIOP [9]. We also reported that, in patients with GIOP, ROMO increased LS BMD to a similar degree, and increased TH BMD earlier compared to teriparatide (TPTD) [11]. Previous studies have suggested favorable effects of ROMO in GIOP; however, the present study was not designed to compare ROMO directly with DMAb or TPTD, and therefore no conclusions regarding comparative effectiveness should be drawn. Rather, the present findings provide practical implications for optimizing and monitoring the response to ROMO in GC-treated patients in real-world practice.

From a practical standpoint, because smaller BMD gains at cortical-rich sites such as the TH and FN were observed in GC users, treatment response to ROMO should be monitored not only at the LS but also at the hip. Adequate calcium and vitamin D supplementation, maintenance of physical function and weight-bearing activity, and minimization of GC exposure whenever clinically feasible may help preserve hip bone. In addition, sequential therapy following ROMO with DMAb, which may improve cortical porosity, could be considered [36]. Overall, comprehensive care with an explicit focus on cortical bone protection may be warranted in GC-treated patients.

Several limitations should be acknowledged. First, because this was an observational study, causal relationships cannot be established. Although IPTW was used to adjust for measured baseline characteristics, residual confounding due to unmeasured factors, such as nutritional status, physical activity, and comorbidity burden, may have influenced the observed BMD responses. Second, we did not adjust for the activity of the underlying diseases requiring GC therapy or for the degree of systemic inflammation, which may independently influence bone metabolism. In addition, the rheumatic and immunologic diseases requiring GC therapy, together with reduced mobility and concomitant treatments, may themselves have affected BMD responses, particularly at cortical-rich sites. Moreover, because this was a retrospective observational study, although concomitant GC use during ROMO therapy could be ascertained, detailed information on GC dose changes over time, prior GC exposure, cumulative GC dose, and duration of immunosuppressive medication exposure was not consistently available and therefore could not be evaluated. Third, GC exposure in the concomitant group was relatively low, and it remains unclear whether similar findings would be observed with higher-dose GC co-administration, including doses as high as PSL 1 mg/kg/day. Fourth, because the study population was overwhelmingly female, meaningful evaluation of sex-specific differences was not feasible, and the generalizability of the present findings to men may be limited. Finally, the sample size of the GC user group was relatively small, limiting statistical power for fracture outcomes. Therefore, whether ROMO reduces fracture risk—the ultimate goal of osteoporosis treatment—remains uncertain. Further studies with larger cohorts, including investigations incorporating sequential treatment strategies, are warranted.

In conclusion, ROMO appears to be a potent therapeutic option for increasing LS BMD in patients with GIOP. However, smaller gains in TH BMD were observed in GC users, which may have reflected not only GC use but also underlying disease-related factors.