Efficacy and Safety of Romosozumab Among Postmenopausal Women With Osteoporosis and Mild-to-Moderate Chronic Kidney Disease

Abstract

Patients with osteoporosis and chronic kidney disease (CKD) are at increased risk of fracture and associated negative outcomes, including increased mortality. The present post hoc analysis of two randomized, multicenter, phase 3 clinical trials-Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH)-investigated the efficacy and safety of romosozumab in postmenopausal women with osteoporosis and mild-to-moderate CKD. The analysis included data from 7147 patients from FRAME and 4077 from ARCH. Eighty-one percent of patients from FRAME and 85% from ARCH had mild or moderate reduction in estimated glomerular filtration rate (eGFR) at baseline, and part of this reduction is likely age related. During the 1-year double-blind phases of the trials, patients received romosozumab 210 mg sc or placebo monthly in FRAME and romosozumab 210 mg sc monthly or alendronate 70 mg po weekly in ARCH. Bone mineral density (BMD) at the lumbar spine, total hip, and femoral neck and vertebral and nonvertebral fractures were assessed at baseline and month 12. In both trials, the least-square mean percent change from baseline BMD was significantly greater in the romosozumab groups versus controls across all kidney function categories at month 12. Romosozumab reduced the relative risk of new vertebral fractures at month 12 among patients with eGFR of 30-59, 60-89, and ≥90 mL/min by 72% (95% confidence interval [CI] 14-91; p = 0.017), 70% (40-85; p < 0.001), and 84% (30-96; p = 0.005), respectively, in FRAME versus placebo, and by 51% (5-75; p = 0.04), 19% (À28 to 49; p = 0.39), and 57% (1-81, p = 0.04), respectively, in ARCH versus alendronate. Incidences of adverse events, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups. Romosozumab is an effective treatment option for postmenopausal women with osteoporosis and mild-tomoderate reduction in kidney function, with a similar safety profile across different levels of kidney function.

Impact of romosozumab on serum calcium concentration and factors predicting the fluctuations in calcium concentration upon romosozumab administration: A multicenter retrospective study

“…Although renal dysfunction is a risk factor associated with the development of hypocalcemia upon denosumab administration ( Tsvetov et al, 2020 ), our results showed that the degree of reduction in calcium concentration upon romosozumab administration was not affected by renal function. In support of our findings, in a post-hoc study of clinical trials, the degree of decrease in serum calcium did not differ between patients with moderate renal dysfunction and those without renal dysfunction ( Miller et al, 2022 ). However, it should be noted that in our study population, the creatinine concentrations were within the normal range in most patients; thus, we were not able to evaluate patients with impaired renal function.…”

Influence of Renal Function on Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose of Romosozumab

“…In the post hoc analyses of 2 pivotal phase 3 clinical trials assessing romosozumab, namely, ARCH and FRAME, similar efficacy and safety of romosozumab was observed in women with postmenopausal osteoporosis with normal renal function and in those with mild to moderate CKD. 23 Additionally, in a recent study, improvement in bone density was reported after 6 months of romosozumab treatment in patients with osteoporosis requiring hemodialysis. 24 Thus, increase in BMD after romosozumab treatment does not seem to be dependent on the stage of RI in the patient.…”

“…In the post hoc analysis of phase 3 trials, FRAME and ARCH, of 9770 women with postmenopausal osteoporosis and mild to moderate CKD, only 2 women with mild CKD and treated with romosozumab reported AEs of mild to moderate hypocalcemia. 23…”

“…Based on the results from the phase 3 studies and postmarket observations, BMD change after treatment with romosozumab was not significantly affected in patients with CKD. 23,24 Therefore, dose adjustments are not required for romosozumab administration in these patients. A single dose of romosozumab of 210 mg SC was found to be safe in patients with CKD (stage 4 RI and ESRD-RH).…”

Romosozumab improves low bone mineral density in a postmenopausal woman undergoing chronic hemodialysis and treated with a calcium-sensing receptor agonist

“…In contrast, Moe et al demonstrated in a CKD rat study that in the presence of high levels of PTH, serum Ca levels were lower than in the low PTH group independently of the class of anti-osteoporotic drugs, and the efficacy of romosozumab was reduced due to the activation of Wnt signaling by PTH that may bypass the LRP signaling ( Moe et al, 2015 ). Two recent post hoc analyses investigated the efficacy and safety of romosozumab among postmenopausal women with osteoporosis and mild-to-moderate CKD (stages 1–3) ( Miller et al, 2022 ; Miyauchi et al, 2022 ). Both studies demonstrated that BMD at the lumbar spine, total hip, and femoral neck, significantly increased as a result of treatment with romosozumab for 1 year.…”