High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis

Abstract

Hypocalcemia is the most common major adverse event in patients with osteoporosis receiving the bone resorption inhibitor denosumab; however, limited information is available regarding risk factors of hypocalcemia. Therefore, this study aimed to identify the risk factors of hypocalcemia induced by denosumab treatment for osteoporosis. We retrospectively reviewed the records of patients who had received initial denosumab supplemented with activated vitamin D for osteoporosis. Serum levels of the following bone turnover markers (BTMs) were measured at baseline: bone-specific alkaline phosphatase (BAP), total N-terminal propeptide of type 1 procollagen (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and urinary cross-linked N-telopeptide of type 1 collagen (NTX). Of the 85 denosumab-treated patients with osteoporosis studied, 22 (25.9%) developed hypocalcemia. Baseline serum total P1NP, TRACP-5b, and urinary NTX were significantly higher in patients with hypocalcemia than in those with normocalcemia following denosumab administration (all P<0.01). Multivariate logistic regression analysis revealed that patients with total P1NP >76.5 μg/L, TRACP-5b >474 mU/dL, or urinary NTX >49.5 nmol bone collagen equivalent/mmol creatinine had a higher risk of hypocalcemia (P<0.01). Our study suggests that denosumab may have a greater impact on serum calcium levels in patients with postmenopausal osteoporosis with higher baseline bone turnover than in patients with postmenopausal osteoporosis with normal baseline bone turnover, because maintenance of normal serum calcium in this subgroup is more dependent on bone resorption. Close monitoring of serum calcium levels is strongly recommended for denosumab-treated patients with high bone turnover, despite supplementation with activated vitamin D and oral calcium.

High bone turnover status as a risk factor in symptomatic hypocalcemia following denosumab treatment in a male patient with osteoporosis

“… 12 , 15 However, increasing attention has been paid to high bone turnover as a risk factor for denosumab-induced hypocalcemia. 11 , 16 , 19 Among these risk factors, our patient had high bone turnover and vitamin D deficiency in the present case. Symptomatic hypocalcemia occurred only once, at 2 weeks following the initial administration, throughout the three courses of denosumab.…”

“… 17 The generally recognized risk factors for hypocalcemia are renal impairment and lack of prophylactic administration of calcium and activated vitamin D. We recently reported that high bone turnover was also associated with a higher risk of denosumab-induced hypocalcemia in patients with postmenopausal osteoporosis. 16 However, all cases of hypocalcemia in that series were asymptomatic. Here, we present the case of a male patient with symptomatic hypocalcemia and high bone turnover status induced by a single, 60 mg dose of denosumab, even though he was receiving prophylactic vitamin D and had normal renal function.…”

“…We have previously demonstrated that denosumab administration has a greater impact on serum calcium levels in patients with high bone turnover as maintaining normocalcemia in this group is more dependent on bone resorption. 16 Following our article, one recent study investigated calcium levels after administration of denosumab after switching from the naïve, bisphosphonate, selective estrogen receptor modular or teriparatide therapies. 19 The authors concluded that serum calcium levels of patients switching from teriparatide therapies to denosumab showed a significant decrease compared with the other groups, meaning that high bone turnover is potentially a risk factor in denosumab-induced hypocalcemia.…”

“… 11 – 14 In general, most incidents of hypocalcemia are asymptomatic, especially in patients with osteoporosis. 15 , 16 Hypocalcemia is most common with the use of denosumab for the prevention of skeletal-related events in patients with bone metastases. 17 The generally recognized risk factors for hypocalcemia are renal impairment and lack of prophylactic administration of calcium and activated vitamin D. We recently reported that high bone turnover was also associated with a higher risk of denosumab-induced hypocalcemia in patients with postmenopausal osteoporosis.…”

Hypocalcemia in a Patient with Cancer

“…Phase 3 trials of denosumab in patients with cancer and metastatic bone lesions showed a 5.2% incidence of hypocalcemia, most of which was mild and asymptomatic, but 2% of cases were high-grade (19). Hypocalcemia was also seen in patients receiving denosumab for low bone density if they had concomitant vitamin D deficiency and higher baseline bone turnover rates (20). Small trials in patients with severely reduced renal function have documented a potentially higher incidence of hypocalcemia after treatment with denosumab in this group (21).…”