Efficacy and Safety of Romosozumab in Postmenopausal Women with Osteoporosis and Renal Impairment

Relationship between CKD and Osteoporosis

The prevalence of CKD in women over 65 in the USA ranges between 12% and 16%. Mild to moderate decline in renal function occurs in up to 85% of women with osteoporosis. CKD predisposes to metabolic bone disease, inducing both quantitative and qualitative changes in bone tissue, thereby increasing the risk of fractures.

Bisphosphonates are typically used as first-line drugs in the treatment of osteoporosis. However, due to renal excretion, they are contraindicated in patients with severe renal function decline. Denosumab is not excreted by the kidneys but increases the risk of hypocalcemia in patients with CKD.

FRAME and ARCH - Basic Results

The FRAME study (Fracture Study in Postmenopausal Women with Osteoporosis) compared romosozumab administered at a dose of 210 mg subcutaneously once a month for one year with a placebo in postmenopausal women with osteoporosis. Romosozumab reduced the relative risk of vertebral compression fractures by 73% and the risk of overall fractures by 36%.

The ARCH study (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk) compared romosozumab with alendronate administered for at least one year in postmenopausal women with osteoporosis at high risk. After a year of romosozumab treatment, the relative risk of vertebral compression fractures decreased by 37%, hip fractures by 36%, and nonvertebral fractures by 26%.

Post-hoc Analysis, Its Methodology, and the Studied Population

In the post-hoc analysis of the FRAME and ARCH studies, patients were categorized based on the eGFR values at study entry. These values were calculated using the MDRD equation. eGFR of ≥90 ml/min was considered normal renal function, 60–89 ml/min as mildly decreased, and 30–59 ml/min as moderately decreased. Patients with severe renal impairment (eGFR ≤29 ml/min) were excluded from the analysis. The outcomes monitored included the percentage change in bone mineral density (BMD) in the lumbar spine, hip, and femoral neck, and the incidence of new vertebral fractures. All these were assessed after 12 months of monitoring.

Findings

The analysis included 7147 patients from the FRAME study and 4077 from the ARCH study. At study entry, mild and moderate declines in renal function were noted in 69% and 19% of participants, respectively, in the FRAME study, and in 61% and 24% of participants, respectively, in the ARCH study. Both studies found a significantly greater percentage increase in BMD after 12 months of romosozumab treatment compared to the control group across all renal function categories.

In the FRAME study, romosozumab reduced the relative risk of vertebral fractures compared to placebo by 72% (95% confidence interval [CI]: 14–91; p = 0.017) in patients with moderately decreased renal function (eGFR 30–59 ml/min) and by 70% (95% CI: 40–85; p < 0.001) in patients with mildly decreased renal function (eGFR 60–89 ml/min). In patients with normal renal function, romosozumab treatment led to an 84% reduction in the relative risk of vertebral fractures (95% CI: 30–96; p = 0.005).

Compared to alendronate in the ARCH study, the incidence of new vertebral fractures in patients with mildly decreased renal function decreased by 51% (95% CI: 14–91; p = 0.017), by 19% (95% CI: -28 to 49; p = 0.39) in those with moderate renal function decline, and by 57% in women with normal eGFR (95% CI: 1–81; p = 0.04).

The reduction in the relative risk of nonvertebral fractures was also significantly greater with romosozumab compared to controls, regardless of baseline eGFR.

The incidence of adverse events, including asymptomatic hypocalcemia and changes in renal function, was comparable across all renal function subgroups at study entry.

Renal function remained stable over 12 months of treatment with both romosozumab and the control treatments. In the FRAME study, the average change in eGFR was -0.7 ml/min/1.73 m² in the romosozumab group and -1.2 ml/min/1.73 m² in the placebo group, and in the ARCH study, +0.7 ml/min/1.73 m² in the romosozumab group and +0.1 ml/min/1.73 m² in the alendronate group.

Conclusion

The combination of osteoporosis and CKD increases the risk of fractures and associated morbidity and mortality. The post-hoc analysis of the FRAME and ARCH studies indicates that romosozumab can be effectively used to treat postmenopausal women with osteoporosis and concomitant mild to moderate renal impairment. Additionally, romosozumab use had no negative impact on renal function and did not increase the incidence of adverse events.

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Source: Miller P. D., Adachi J. D., Albergaria B. H. et al. Efficacy and safety of romosozumab among postmenopausal women with osteoporosis and mild-to-moderate chronic kidney disease. J Bone Miner Res 2022; 37 (8): 1437–1445, doi: 10.1002/jbmr.4563.