A single-dose study of denosumab in patients with various degrees of renal impairment

Abstract

This 16-week study evaluated pharmacokinetics and pharmacodynamics of denosumab in 55 subjects with renal function ranging from normal to dialysis-dependent kidney failure. Participants received a single 60-mg subcutaneous dose of denosumab. Kidney function groups were based on calculations using the Cockcroft-Gault equation and U.S. Food and Drug Administration (FDA) guidance in place when the study was designed. Renal function did not have a significant effect on denosumab pharmacokinetics or pharmacodynamics. These findings suggest denosumab dose adjustment based on glomerular filtration rate is not required. Rapid decreases in serum C-telopeptide in all groups were sustained throughout the study. The most common adverse events were hypocalcemia (15%), pain in extremity (15%), and nausea (11%). Most adverse events were mild to moderate in severity. Calcium and vitamin D supplementation was not initially required by the study protocol, but was added during the trial. No subject who received adequate calcium and vitamin D supplementation became hypocalcemic. Seven subjects had nadir serum calcium concentrations between 7.5 and <8.0 mg/dL (1.9 and <2.0 mmol/L), and 5 subjects (4 with advanced renal disease) had nadir serum calcium <7.5 mg/dL (<1.9 mmol/L). Two subjects (1 symptomatic, 1 asymptomatic) were hospitalized for intravenous calcium gluconate treatment. At the recommended dose, denosumab is a useful therapeutic option for patients with impaired renal function. Supplementation of calcium and vitamin D is strongly recommended when patients initiate denosumab therapy, particularly in patients with reduced renal function. © 2012 American Society for Bone and Mineral Research.

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

“…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). Furthermore, DMAb-induced hypocalcemia was demonstrated to develop during the first two weeks of DMAb administration in CKD patients (Block et al 2012). Our patient showed hypocalcemia in the 8 days following DMAb administration.…”

“…Moreover, there is no strong evidence to support its efficacy. 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.…”

“…At present, the reason why advanced CKD patients with SHPT are at higher risk of developing hypocalcemia is not completely understood. However, it is evident that the pharmacodynamic effect of DMAb induces hypocalcemia, rather than the desired pharmacokinetic effect, because the pharmacokinetic effect of DMAb is unaltered by renal impairment (Block et al 2012). Therefore, we consider that patients with advanced CKD are more dependent on PTH-mediated bone turnover, thereby causing osteoclast activity inhibition with DMAb to result in a hungry bone-like syndrome, which is known to cause severe hypocalcemia in HD patients after parathyroidectomy.…”

“…In addition, subcutaneous administration of DMAb every 6 months is sufficient to obtain inhibitory effects on bone resorption because of its long half-life in the body (Cummings et al 2009;Ivashkiv et al 2011). Since DMAb is not cleared by the kidneys, no dosage adjustment according to renal function is required (Block et al 2012). Therefore, we consider that this agent is beneficial for chronic kidney disease (CKD) patients with bone loss, especially for whom bisphosphonates are not recommended because of severe renal dysfunction (defined as estimated glomerular filtration rate (eGFR) < 30 mL/ min).…”

Denosumab for treatment of immobilization-related hypercalcemia in a patient with end-stage renal disease

“…Further, the effect of denosumab lasts several months which benefits patients by eliminating the need for frequent clinic visits. Hypocalcemia is the most concerning adverse effect of denosumab, especially in chronic kidney disease patients [11]. The possible mechanisms include: active vitamin D deficiency, hungry bone syndrome with hyperdynamic bone disease, concomitant use of cinacalcet, increased osteoprotegerin activity, and RANKL removal in HD patients [12].…”