Severe Hypocalcemia Associated With Denosumab in Metastatic Castration-Resistant Prostate Cancer: Risk Factors and Precautions for Treating Physicians

Autio, Karen A.; Farooki, Azeez; Glezerman, Ilya G.; Chan, Amelia; Schneider, Coursen; Barr, Hallie C.; Seyboth, Brian; Kampel, Lewis J.; Danila, Daniel C.; Rathkopf, Dana E.; Slovin, Susan F.; Scher, Howard I.; Morris, Michael J.

doi:10.1016/j.clgc.2014.11.008

Cited by 28 publications

(30 citation statements)

References 16 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%

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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%

“…Some earlier reports support this interpretation. The majority of patients in a couple of studies developed hypocalcemia after a first dose of either 60 mg or 120 mg denosumab 14,26. This may be explained by most patients having low bone turnover after the first course of denosumab.…”

Section: Discussionmentioning

confidence: 99%

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

Ishikawa¹,

Nagai²,

Sakamoto³

et al. 2016

TCRM

View full text Add to dashboard Cite

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“…Of the 60 patients analyzed, 9 developed severe hypocalcemia to a degree that they required hospitalization and intravenous calcium supplementation. Aggressive metastatic disease as reflected by higher PSA and alkaline phosphatase levels, and baseline Vitamin D deficiency tended to be risk factors for severe hypocalcemia whereas prior bisphosphonate therapy and concurrent steroid administration did not appear to be risk factors [14]. Another analysis identified reduced creatinine clearance (less than 50 ml/min) and no prior exposure to bisphosphonates as risk factors for severe hypocalcemia [15].…”

Section: Discussionmentioning

confidence: 99%

Severe Refractory Hypocalcemia in a Patient with Metastatic Prostate Carcinoma Following Denosumab Injection

Ali¹,

Farhat²,

Imran³

et al. 2016

J Clin Case Rep

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An 86-year-old male with a history of metastatic castrate sensitive prostate cancer received a single dose of Denosumab for his bony metastases. Two weeks later, he presented to the hospital due to left foot cellulitis and was incidentally found to have profound hypocalcemia whereas his serum calcium was normal at the time of Denosumab injection. A thorough workup was undertaken which showed severe Vitamin D deficiency. He was diagnosed with Denosumab induced hypocalcemia with underlying Vitamin D deficiency which was refractory to supplemental calcium and Vitamin D. This case demonstrates the potential of Denosumab to cause profound hypocalcemia which can be resistant to therapy. Bone metastasis is a common clinical encounter and Denosumab is an effective therapy to prevent skeletal related events (SRE). Therefore, given its widespread use, it is extremely important to identify and treat risk factors that may aggravate hypocalcemia when treated with Denosumab.

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“…RANK–RANKL interaction is an important pathway responsible for calcium metabolism blocking which leads to reduced release of calcium from the bone 10. Risk factors for denosumab-induced hypocalcaemia include osteoblastic metastases, elevated PSA levels, high alkaline phosphatase, vitamin D deficiency, concomitant bisphosphonates use, and renal dysfunction with creatinine clearance of less than 30 mL/min and/or dialysis dependence 3. Our patient had metastatic prostate cancer, an elevated PSA, a high alkaline phosphatase and ESRD, thus posing a high cumulative risk for development of hypocalcaemia on receiving denosumab.…”

Section: Discussionmentioning

confidence: 99%

“…However, it can potentially cause severe, symptomatic and life-threatening hypocalcaemia in patients at risk 3. We present a case of severe and difficult-to-correct hypocalcaemia causing abnormal electrocardiographic findings in a patient with metastatic prostate cancer and dialysis-dependent end-stage renal disease (ESRD).…”

Section: Introductionmentioning

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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Severe Hypocalcemia Associated With Denosumab in Metastatic Castration-Resistant Prostate Cancer: Risk Factors and Precautions for Treating Physicians

Cited by 28 publications

References 16 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

Severe Refractory Hypocalcemia in a Patient with Metastatic Prostate Carcinoma Following Denosumab Injection

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

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