Refractory Denosumab-induced Hypocalcemia in a High-risk Patient With Osteoblastic Metastatic Prostate Adenocarcinoma

Abstract

Denosumab is a frequently used medication, mainly for the treatment of osteoporosis and prevention of skeletal-related events in patients with metastatic cancer. However, the treatment can be associated with adverse events including hypocalcemia. We discuss the therapeutic challenges of denosumab-induced hypocalcemia in a patient with metastatic prostate adenocarcinoma. This 87-year-old patient presented to the emergency department after being found on the floor with altered mental status. Denosumab had been initiated 3 weeks earlier for stage 4 prostate adenocarcinoma with osteoblastic bone metastatic lesions. Blood analyses showed severe hypocalcemia (3.89 mg/dL [0.97 mmol/L]), which did not improve despite progressive incremental parenteral calcium administration and cholecalciferol supplementation. Management required 64 days of admission and titration of calcitriol. The patient was discharged after stabilizing plasma calcium level. Outpatient palliative care was later initiated because of progressive prostate adenocarcinoma, which ultimately led to the patient's death. Patients with metastatic bone disease, especially when treated with denosumab for prevention of skeletal-related events, present an increased risk of severe and even refractory hypocalcemia. More data are needed for optimal risk stratification of these patients, to identify robust predictors of hypocalcemia and to define the appropriate timing for starting calcium and vitamin D supplementation in high-risk individuals.

Keywords: denosumab; hypocalcemia; prostate adenocarcinoma and skeletal-related events.

Figure 1.

Imaging study using computed tomography scan showing diffuse osteoblastic bone lesions: (A) axial views with focus on iliac bones and sacrum; (B) axial view focused on spinal column; and (C) sagittal view showing the lumbar and dorsal columns including a T12 compression fracture (white arrow).

Figure 2.

Dynamic of serum calcium level before, at the time of admission, and after admission. Timing of cessation of parental calcium supplementation and of initiation of calcitriol are indicated. The patient continuously received oral calcium and cholecalciferol. The origin of the x-axis represents the day of admission. Palliative care was initiated on discharge as illustrated. The red interrupted horizontal line indicates the lower limit of normal calcium level assessed by UV spectrophotometric method (Cobas 8000 C702, Roche Diagnostics).

Figure 3.

Physiologic response to maintain calcium homeostasis in hypocalcemia: elevation of iPTH due to activation of CaSR. After 25-hydroxylation in the liver and 1-alpha-hydroxylation in the kidney (not shown), calcitriol (1α,25(OH)₂D₃) acts on pathway 1 (intestinal calcium absorption), pathway 2 (renal calcium reabsorption), and pathway 3 (bone resorption as a result of RANKL secretion by osteoblasts that induces osteoclasts differentiation, maturation, and proliferation from HSC). In our patient, initiation of calcitriol has enabled interruption of parenteral calcium supplementation by optimizing mobilization of calcium from the skeleton, increasing renal reabsorption of calcium mainly in the proximal tubule (60%-70% of calcium absorption potency) [24], and improving intestinal calcium absorption in the remaining proximal parts of the intestine after ileo-colectomy. Calcitriol-mediated regulation of intestinal calcium absorption in this case, involves more the transcellular (instead of the paracellular) pathway by upregulating calcium-sensitive transmembrane transporters including the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) and member 5 (TRPV5), K⁺-dependent Na⁺/Ca2⁺ exchanger (NCKX), Na⁺/Ca2⁺ exchanger 1 (NCX1), and Na⁺/K⁺ ATPase (NKA). The intestinal calcium homeostasis regulation process also involves calcium-binding proteins such as calbindin-D9k and calmodulin [25, 26]. Created in BioRender. Eric Balti. (2025) https://BioRender.com/bzqfv3a.