Effects of denosumab on fracture and bone mineral density by level of kidney function

Abstract

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 AE 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function. ß

Retracted: Bone Mineral Density Predicts Fractures in Chronic Kidney Disease

“…(21) Our findings are also consistent with what has been reported in post hoc analyses from the registration trials for antiresorptive agents used in the treatment of osteoporosis. (22)(23)(24)(25) Some women in these trials had an eGFR consistent with stage 4 CKD, and some had stage 5 CKD despite a serum creatinine in the normal range. In these post hoc analyses, low BMD was a strong and consistent risk factor for fracture.…”

BMD and Fracture Risk in CKD

“…The use of drugs such as bisphosphonates, teriparatide, and denosumab, which have been shown to reduce fracture incidence in patients with normal kidney function, is controversial in patients with CKD. Post hoc analyses of several phase III studies suggest these agents can be administered safely to patients with mild to moderate CKD without biochemical evidence of the mineral and bone disorder and that fracture risk is reduced significantly (23)(24)(25)(26)(27). However, those studies included relatively few subjects with more severe CKD.…”

Combination Therapy of Denosumab and Calcitriol for a Renal Transplant Recipient with Severe Bone Loss due to Therapy-Resistant Hyperparathyroidism

“…Next, we address the hypocalcemia induced by DMAb in patients with CKD. Previous studies reported that hypocalcemia was the most common adverse effect of DMAb (Jamal et al 2011;Chen et al 2014). In addition, recent studies showed that treatment with DMAb induced severe hypocalcemia in CKD patients (particularly, CKD stage 4-5D patients complicated with SHPT) compared to the general population (Jamal et al 2010;Dave et al 2015).…”

“…Also, in other previously reported cases regarding DMAb therapy for CKD patients, severe hypocalcemia was observed just after administration (Talreja 2012;McCormick et al 2012;Torregrosa 2013;Agarwal et al 2013;Ungprasert et al 2013;Farinola and Kanjanapan 2013;Dusilova Sulkova et al 2014). On the other hand, rapid increase in i-PTH levels is also recognized to be associated with DMAb therapy in patients with CKD (Jamal et al 2011;Chen et al 2014;Dave et al 2015). Of note, Chen et al (2014) showed that a high i-PTH level was an important predictor of severe hypocalcemia.…”

“…However, a clinical study by Block et al (2012) indicated that treatment with DMAb resulted in rapid reduction of bone turnover markers in patients with CKD, which was sustained from the first observation at day 2 to the end of the study at day 113. In addition, Jamal et al (2011) showed that DMAb is effective in improving the BMD of patients with CKD in a short period of time. Moreover, Chen et al (2014) showed that DMAb is effective in restor- Resected parathyroid gland showed a single enlarged nodule of uniform parenchymal cells such as an adenoma.…”