The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland

Romosozumab is a bone-forming agent that inhibits sclerostin, exerting a dual effect on bone by increasing bone formation and decreasing bone resorption [1, 2]. It leads to substantial gains in bone mineral density (BMD) at both the lumbar spine and hip [3‐5], and reduces the incidence of fractures in postmenopausal women [4, 5]. Romosozumab has demonstrated significantly greater efficacy in reducing fracture risk compared to alendronate [5]. In Switzerland, romosozumab is approved for the treatment of postmenopausal women at high risk of fragility fractures, and may be authorized as an exception for men with a very high fracture risk [6]. Specifically, reimbursement is provided for the following patients: those who have experienced a major osteoporotic fracture within the last 24 months and who have a T-score ≤ -3.5 SD (lumbar spine or hip); those with two major osteoporotic fractures; and those without fractures but with a very high fracture risk. This very high fracture risk category is defined by FRAX® Switzerland as exceeding the intervention threshold by 20%, as per the recommendations of the Swiss Association against Osteoporosis [7]. While romosozumab may be used as a first-line therapy, most patients meeting the reimbursement criteria are likely to have been pre-treated with antiresorptive agents. Both clinical trials and real-world data have shown that prior antiresorptive therapy blunts the BMD gains under romosozumab [8‐10]. In a randomised phase III trial, the effect of romosozumab on BMD and bone strength was assessed against teriparatide in patients previously treated with oral bisphosphonates for at least 3 years [11]. However, there is limited knowledge regarding the effects of romosozumab after treatment with parenteral bisphosphonates, denosumab or teriparatide. Our study aims to evaluate the impact of romosozumab on BMD in a real-world population, taking into account prior oral and parenteral therapies, and to identify the most relevant predictors of BMD gains at both the lumbar spine and total hip.

In this prospective, registry-based cohort study, treatment with romosozumab for 12 months led to BMD increases at both the lumbar spine and total hip. The BMD changes, however, were highly variable, particularly in pre-treated patients (78% of all patients who received romosozumab had received prior antiresorptive therapies for a median duration of 6 years). These pre-treated patients showed a significantly lower BMD response at both the lumbar spine and hip compared to treatment-naïve patients, and the duration of antiresorptive pre-treatment was associated with the BMD response at both locations. Previous studies in Japanese patients reported that the effect of romosozumab depended on a history of prior treatment [9], as well as its duration [10]. However, the authors only differentiated between pre-treatment for 1 year versus more than 1 year. In clinical practice, it is probable that patients eligible for romosozumab therapy have undergone prior treatment with antiresorptive agents, and also potentially anabolic agents, for an extended period. Accordingly, our study population was treated with various, individualized regimens before the initiation of romosozumab. However, most received parenteral bisphosphonates as their last treatment cycle before starting romosozumab. Only one patient with long-term denosumab therapy (8 years) was switched directly to romosozumab, and this individual showed BMD loss at the total hip of -9%, while the BMD at the lumbar spine did not change significantly (+ 1.2%). Transitioning to romosozumab after 12 months of denosumab appears to improve lumbar spine BMD and maintain total hip BMD [8, 16], but less is known about the BMD changes after switching from long-term denosumab therapy to romosozumab. This sequence could be unfavourable due to the increased overshoot of bone resorption following long-term denosumab treatment [17]. Thus, almost all patients in our study who received prior denosumab therapy received at least 1 year of bisphosphonates (mainly zoledronate) before they were switched to romosozumab. In these patients (n = 29), the duration of prior denosumab therapy did not correlate with the BMD response at the lumbar spine, while the duration of prior bisphosphonate therapy was associated with a significantly lower BMD increase at both the lumbar spine and total hip under romosozumab. While bisphosphonates bind to the bone mineral and remain in the skeleton after treatment discontinuation [18], the monoclonal antibody denosumab exhibits transient treatment effects and may therefore have less of an impact on future responses to anabolic agents. Nevertheless, it remains unclear why prior antiresorptive therapies mitigate the BMD response to romosozumab. While it is understandable that previous antiresorptive therapy blunts the BMD response to teriparatide, given that the majority of bone formation is remodeling based [19], one might anticipate that prior antiresorptive therapies would have less of an impact on the BMD response to romosozumab, which primarily involves modeling-based bone formation. One theory, as discussed by Cosman et al. [8], posits that some of the initial BMD gain (i.e., the weak antiresorptive effect of romosozumab) might be attributed to overfilling of the remodeling cavities present at the time romosozumab is administered. The bone remodeling surface area is smaller in patients who have received prior antiresorptive agents compared with those who have not. Another potential explanation is that even modeling-based bone formation requires active bone surfaces, whose area may be reduced in patients who have received prior treatment. This hypothesis is supported by our observation that higher baseline CTX levels are associated with a better BMD response to romosozumab, even among treatment-naïve patients. Additionally, due to the coupling between osteoclasts and osteoblasts during antiresorptive treatments, there might be a reduction in bone-forming osteoblasts prior to romosozumab treatment in pre-treated patients.

Other predictors of BMD response in this study were age (only lumbar spine) and BMI (only total hip and femoral neck). Surprisingly, neither baseline nor follow-up P1NP levels after 1–3 months of romosozumab treatment were associated with BMD responses at the lumbar spine or hip, which is in contrast to prior reports [20]. However, we observed significantly higher P1NP levels at month 2 of romosozumab therapy in treatment-naïve compared to pre-treated patients. One possible explanation for this discrepancy could be variations in the timing of P1NP level measurements during follow-up, as this timing has not been standardised across all patients.

The BMD changes under romosozumab in pre-treated patients were comparable to those in the STRUCTURE trial, where patients were switched to either romosozumab or teriparatide after 3 or more years of oral bisphosphonates [11]. In that randomised controlled trial, areal BMD measurements were performed along with quantitative CT evaluations of integral, cortical and trabecular volumetric bone mineral density at the hip, as well as assessments of bone strength by infinitive analysis. In contrast to teriparatide, 1 year of romosozumab led to significant increases of volumetric cortical BMD and bone strength, whereas both treatments increased integral and trabecular BMD. Thus, prior antiresorptive therapies did not completely mitigate these improvements in the STRUCTURE trial, leaving it unclear how the fracture rate under romosozumab could differ in pre-treated versus treatment-naïve patients.

The findings of this study are limited by its observational nature, relatively small sample sizes and unequal subgroups. Since the treatment-naïve patients demonstrated lower T-scores than the pre-treated patients, the percentage BMD gains are presumably overestimated, and the true differences might be smaller. Further, even though the patients were prospectively enrolled and monitored, there was a partial lack of information on BTM parameters during romosozumab therapy, which could limit the reliability of the associated results. The strength of this study lies in the precise recording of therapies administered prior to romosozumab, including specific agents and treatment durations.

We conclude that prior antiresorptive therapy, particularly the long-term administration of bisphosphonates, blunted the BMD response to romosozumab, and the duration correlated with changes at both the lumbar spine and total hip. On the other hand, there was a variable BMD response in treatment-naive individuals, indicating that other factors may also play a role. It will be of considerable interest to analyse fracture data trends within a substantially expanded cohort undergoing the transition from long-term antiresorptive therapy to treatment with romosozumab.