Time Course of Calcium Concentrations and Risk Factors for Hypocalcemia in Patients Receiving Denosumab for the Treatment of Bone Metastases From Cancer

Ikesue, Hiroaki; Tsuji, Toshikazu; Hata, Kojiro; Watanabe, Hiroyuki; Mishima, Koji; Uchida, Mayako; Egashira, Nobuaki; Miyamoto, Toshihiro; Baba, Eishi; Akashi, Koichi; Takayama, K.; Nakanishi, Yoichi; Tokunaga, Eriko; Okamoto, Tatsuro; Maehara, Yoshihiko; Yokomizo, Akira; Naito, Seiji; Kubo, Makoto; Tanaka, Masao; Masuda, Satohiro

doi:10.1177/1060028014539919

Cited by 24 publications

(41 citation statements)

References 52 publications

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“…To identify risk factors for hypocalcemia, we first compared various baseline clinical demographic parameters between hypocalcemic and normocalcemic patients following denosumab administration. Although patients who developed hypocalcemia had normal baseline calcium concentrations, the mean was slightly lower than in those who did not have normal baseline calcium concentrations, consistent with recent findings by Autio et al26 In contrast, other reports found no significant difference in baseline serum corrected calcium concentration between hypocalcemic and normocalcemic groups 17,18. Nevertheless, hypocalcemia should be corrected prior to administration of denosumab.…”

Section: Discussionsupporting

confidence: 86%

“…This may be explained by most patients having low bone turnover after the first course of denosumab. Furthermore, some previous studies17,18 have reported that prior use of zoledronic acid reduced the incidence of denosumab-induced hypocalcemia. Although they provided other reasons, this effect is most likely because of the induction of low bone turnover after zoledronic acid administration.…”

Section: Discussionmentioning

confidence: 92%

“…To prevent hypocalcemia following denosumab administration, prophylactic administration of calcium and/or vitamin D is recommended for osteoporosis and bone metastases patients unless albumin-adjusted serum calcium concentrations are high 15–18. While prophylactic administration of calcium and/or vitamin D is now deemed essential, reports of severe hypocalcemia despite calcium and vitamin D supplementation exist 8,11,17,18. Therefore, identification of potential risk factors for hypocalcemia is critical.…”

Section: Introductionmentioning

confidence: 99%

“…In patients with bone metastases, lower baseline estimated glomerular filtration rate (eGFR) is an important risk factor for hypocalcemia induced by denosumab 17,18. However, patients with both osteoporosis and bone metastases developed denosumab-induced severe hypocalcemia with mild-to-moderate CKD (30–89 mL/min/1.73 m 2 ) 8,9,11.…”

Section: Introductionmentioning

confidence: 99%

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

Ishikawa¹,

Nagai²,

Sakamoto³

et al. 2016

TCRM

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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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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Ishikawa¹,

Nagai²,

Sakamoto³

et al. 2016

TCRM

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“…Denosumab-induced hypocalcaemia can last weeks to months despite therapy requiring frequent monitoring. The risk of hypocalcaemia has been found to be highest in the first 2 weeks 14. High doses of calcium and vitamin D are typically given for treatment.…”

Section: Discussionmentioning

confidence: 99%

Denosumab causing severe, refractory hypocalcaemia in a patient with chronic kidney disease

et al. 2018

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Denosumab is a fully human monoclonal antibody that is being increasingly used for the treatment of osteoporosis and prevention of skeletal-related events (SREs) in bone metastases from primary tumours. It has improved efficacy, better tolerability and convenient administration via subcutaneous route, in comparison with bisphosphonates; however, it has been reported to cause severe hypocalcaemia in certain high-risk individuals. We report the case of a 71-year-old man with a history of haemodialysis-dependent end-stage renal disease who developed severe hypocalcaemia with electrocardiographic changes after being started on denosumab for prevention of SREs from a recently diagnosed metastatic prostate cancer. He was admitted to the hospital for close monitoring and received multiple doses of intravenous calcium gluconate, along with haemodialysis with high calcium bath. We aim to highlight the risk of severe, life-threatening hypocalcaemia associated with denosumab and to recognise patients at risk of developing this serious adverse effect, so that prompt treatment and preventive strategies can be implemented.

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Development of Risk Prediction Model for Grade 2 or Higher Hypocalcemia in Patients With Bone Metastasis Treated With Denosumab Plus Cholecalciferol (Vitamin D₃)/Calcium Supplement

Ikegami

Hashiguchi

Kizaki

et al. 2022

The Journal of Clinical Pharma

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Denosumab‐induced hypocalcemia is sometimes severe, and although a natural vitamin D/calcium combination is used to prevent hypocalcemia, some patients rapidly develop severe hypocalcemia even under supplementation. It is clinically important to predict this risk. This study aimed to develop a risk prediction model for grade ≥2 hypocalcemia within 28 days after the first denosumab dose under natural vitamin D/calcium supplementation. Using a large database containing multicenter practice data, 2399 patients with bone metastasis who were treated with denosumab between June 2013 and May 2020 were retrospectively analyzed. Background factors in patients who developed grade ≥2 hypocalcemia within 28 days after the first denosumab dose and those who did not were compared by univariate analysis. Multivariate analysis was conducted to develop a risk prediction model. The model was evaluated for discriminant performance (receiver operating characteristic–area under the curve, sensitivity, specificity) and predictive performance (calibration slope). A total of 124 patients in the hypocalcemia group and 1191 patients in the nonhypocalcemia group were extracted. A risk prediction model consisting of sex, calcium, albumin, alkaline phosphatase, osteoporosis, breast cancer, gastric cancer, proton pump inhibitor combination, and pretreatment with zoledronic acid was developed. The receiver operating characteristic–area under the curve was 0.87. Sensitivity and specificity were 83% and 81%, respectively, and the calibration slope indicated acceptable agreement between observed and predicted risk. This model appears to be useful to predict the risk of denosumab‐induced hypocalcemia and thus should be helpful for risk management of denosumab treatment in patients with bone metastases.

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Time Course of Calcium Concentrations and Risk Factors for Hypocalcemia in Patients Receiving Denosumab for the Treatment of Bone Metastases From Cancer

Abstract: Our results support more frequent monitoring of serum calcium concentrations at baseline and during the first 2 weeks of treatment in patients receiving denosumab, especially those with an eGFR <30 mL/min.

Cited by 24 publications

References 52 publications

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

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

Denosumab causing severe, refractory hypocalcaemia in a patient with chronic kidney disease

Development of Risk Prediction Model for Grade 2 or Higher Hypocalcemia in Patients With Bone Metastasis Treated With Denosumab Plus Cholecalciferol (Vitamin D₃)/Calcium Supplement

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Time Course of Calcium Concentrations and Risk Factors for Hypocalcemia in Patients Receiving Denosumab for the Treatment of Bone Metastases From Cancer

Abstract: Our results support more frequent monitoring of serum calcium concentrations at baseline and during the first 2 weeks of treatment in patients receiving denosumab, especially those with an eGFR <30 mL/min.

Cited by 24 publications

References 52 publications

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

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

Denosumab causing severe, refractory hypocalcaemia in a patient with chronic kidney disease

Development of Risk Prediction Model for Grade 2 or Higher Hypocalcemia in Patients With Bone Metastasis Treated With Denosumab Plus Cholecalciferol (Vitamin D3)/Calcium Supplement

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Development of Risk Prediction Model for Grade 2 or Higher Hypocalcemia in Patients With Bone Metastasis Treated With Denosumab Plus Cholecalciferol (Vitamin D₃)/Calcium Supplement