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

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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.

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Diagnostic criteria for primary osteoporosis: year 2012 revision.

Masao Fukunaga, Toshitsugu Sugimoto, Hiroaki Ohta … (2013)

In 1995, the Japanese Society for Bone and Mineral Metabolism (now the Japanese Society for Bone and Mineral Research) established the Osteoporosis Diagnostic Criteria Review Committee. Following discussion held at the 13th scientific meeting of the Society in 1996, the Committee, with the consensus of its members, proposed diagnostic criteria for primary osteoporosis. The Committee revised those criteria in 1998 and again in 2000. The Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis aimed at obtaining international consistency and made a revised edition based on the new findings in 2012.

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A Single-Dose Study of Denosumab in Patients With Various Degrees of Renal Impairment

Geoffrey A Block, Henry G. Bone, Liang Fang … (2012)

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.

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The use of calcium and vitamin D in the management of osteoporosis

John A Sunyecz (2008)

Osteoporosis poses a significant public health issue, causing significant morbidity and mortality. Calcium and vitamin D utilization in the optimization of bone health is often overlooked by patients and health care providers. In addition, the optimal standard of care for osteoporosis should encompass adequate calcium and vitamin D intake. Dietary intake or supplementation with calcium and vitamin D will be reviewed, including recent recommendations for increased vitamin D intake. Compliance to calcium and vitamin D therapy is paramount for effective prevention of osteoporotic fractures. A recently released algorithm (FRAX) estimating absolute fracture risk allows the health care provider to decide when pharmacologic therapy is warranted in addition to calcium and vitamin D. When pharmacologic therapy is advised, continued use of calcium and vitamin D is recommended for optimal fracture risk reduction. A ‘bricks and mortar’ analogy is often helpful when counseling patients and this analogy will be explained. This manuscript reviews relevant data related to calcium and vitamin D use for patients at risk for fracture due to bone loss.

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Author and article information

Journal

Journal ID (iso-abbrev): Ther Clin Risk Manag

Title: Therapeutics and clinical risk management

Publisher: Informa UK Limited

ISSN: 1176-6336

ISSN (Print): 1176-6336

Publication date (Electronic): 2016

Volume: 12

Affiliations

[1 ] Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo.

[2 ] Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi.

[3 ] Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo; Department of Orthopaedic Surgery, Yamanashi Red Cross Hospital, Yamanashi.

[4 ] Department of Public Health, Showa University School of Medicine, Tokyo, Japan.