Severe hypocalcemia following a single injection of denosumab in a patient with renal impairment

Monitoring renal function and adjusting dosing for patients with impaired renal function are not required with denosumab (60 mg every 6 months). However, these patients have an increased risk for developing hypocalcemia. This case report describes a patient with renal impairment who developed severe hypocalcemia after receiving denosumab.


Introduction
A new antiresorptive therapy, denosumab (Prolia, Amgen Inc., Thousand Oaks, CA, USA; 60 mg every 6 months), is approved in the United States and Europe for the treatment of women with postmenopausal osteoporosis who are at high risk for fracture 1,2 . Approval in this setting was based on the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 months (FREEDOM) trial, which randomized women aged 60-90 years with postmenopausal osteoporosis (N ¼ 7868; T-score 5À2.5 but !À4.0) to receive denosumab (60 mg every 6 months) or placebo for 36 months. The trial showed that denosumab significantly reduced the risk of fracture (vertebral, p50.001; nonvertebral, p ¼ 0.01) 2 . In the oncology setting, denosumab (Xgeva, Amgen Inc., Thousand Oaks, CA, USA; 120 mg every 4 weeks) is approved in the United States and Europe for use in patients with bone metastases from solid tumors, but not in patients with multiple myeloma 3 .
Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kB ligand (RANKL), a key mediator of bone remodeling through the inhibition of osteoclast activity. Subset analyses of the FREEDOM trial showed that denosumab (60 mg every 6 months) was not associated with an increase in adverse events among patients with severe renal impairment (n ¼ 73; creatinine clearance [CrCl] 15-29 mL/min) or impaired renal function (n ¼ 2817; CrCl 30-59 mL/min) compared with those with normal renal function (n ¼ 4911; CrCl ! 60 mL/min) 4 . Thus, the label for denosumab (60 mg every 6 months) does not require monitoring renal function prior to administration and only states that patients with CrCl530 mL/min or receiving dialysis are at increased risk for hypocalcemia 1 .
Bisphosphonates, another class of antiresorptive agent approved for the treatment of postmenopausal osteoporosis, are not indicated for patients with severe renal impairment (i.e., CrCl530-35 mL/min) [5][6][7][8] . Because denosumab has no such limitations and has been shown to be effective for the treatment of postmenopausal osteoporosis, it is considered a viable alternative for this patient population. Moreover, because denosumab is not contraindicated in patients with renal impairment, no dose adjustments based on renal function are available. However, patients with renal impairment who receive denosumab have an increased risk for the development of hypocalcemia 1 . Although no cases of symptomatic hypocalcemia were reported in the FREEDOM trial or in a trial of denosumab (60 mg every 6 months) compared with alendronate in postmenopausal women with osteoporosis 2 , the denosumab label states that severe hypocalcemia can occur in patients receiving denosumab 1 . Furthermore, because of an imbalance in the number of serious infections and dermatologic adverse events in the FREEDOM trial and the increased risk for developing hypocalcemia, the US Food and Drug Administration required a risk evaluation and mitigation strategy (REMS) for denosumab 9 . The REMS includes a medication guide that lists hypocalcemia as a side-effect and warns that this condition is often asymptomatic, but does not suggest routine monitoring of calcium levels 9 .
Untreated hypocalcemia may lead to chronic conditions such as cataract formation, prolonged QT interval, hypotension, congestive heart failure, seizures, or dementia. To minimize the risk for developing hypocalcemia, it is suggested that patients receiving antiresorptive therapy also receive daily calcium and vitamin D supplements. The denosumab label calls for concomitant calcium (1000 mg) and vitamin D (at least 400 mg), but monitoring of calcium levels prior to or during therapy is not required. Furthermore, although the denosumab label cautions that patients with severe renal impairment (i.e., CrCl 530 mL/min or receiving dialysis) are at risk for hypocalcemia, the only guidance provided by the label for use in this patient population is to supplement with calcium and vitamin D and to consider monitoring calcium levels 1 .

Case report
The importance of monitoring calcium levels in patients with renal impairment is highlighted by an individual case of a 68-year-old woman with renal impairment who developed severe hypocalcemia after receiving a single 60-mg dose of denosumab. Patient comorbidities included chronic obstructive pulmonary disease, hypertension, osteoporosis, depression, rheumatoid arthritis, polycystic kidney disease, and chronic renal insufficiency. The patient was not able to tolerate alendronate, an oral bisphosphonate prescribed by her private medical doctor, which was discontinued on April 19, 2010, by Dr T. If an oral agent is not well-tolerated, both intravenous and subcutaneous routes of administration for bone supportive care agents are feasible options. Denosumab (60 mg every 6 months) was chosen over the intravenous bisphosphonate zoledronic acid because of the patient's poor renal function. On October 13, 2010, denosumab was given per label to this patient with chronic renal insufficiency and no symptoms of hypocalcemia. Calcium (8.9 mg/dL) and serum creatinine (2.7 mg/dL) levels were last checked on June 2, 2010, 4 months prior to receiving denosumab. Other relevant laboratory values from this date included albumin (3.8 g/dL), alkaline phosphatase (47 U/L), total bilirubin (0.3 mg/dL), BUN (48 mg/dL), glucose (105 mg/dL), sodium (140 mg/L), potassium (4.7 mg/L), and chloride (109 mg/L).

Discussion
Antiresorptive therapies inhibit bone resorption, which can reduce serum calcium levels in both normal and hypercalcemic individuals. Normal serum calcium levels are influenced by the effect of vitamin D 1,25-dihydroxy and PTH on calcium absorption, urinary calcium excretion, and bone remodeling activity in the skeleton (primary reservoir of calcium in the body) 10 . Therefore, antiresorptive therapy-mediated inhibition of bone resorption can lead to lower serum calcium levels and secondary hyperparathyroidism 10 , which could contribute to hypocalcemia, especially in individuals deficient in serum vitamin D or PTH 11,12 . Finally, renal insufficiency can lead to impaired conversion of vitamin D to its active metabolite (vitamin D 1,25-dihydroxy) and also may be a contributing factor to hypocalcemia 13 .
This case suggests that guidelines recommending a modified dosing schedule of denosumab (with corresponding modified dose vials) may be beneficial for patients with renal impairment, not because of nephrotoxic effects of the drug, but to avoid severe hypocalcemia. Furthermore, the case highlights the importance of monitoring calcium levels and renal function before and during denosumab therapy in patients with multiple comorbidities. Indeed, without monitoring renal function, how is a clinician to determine if a patient is at increased risk for developing hypocalcemia? Patients benefit from careful monitoring regardless of the route of administration (i.e., intravenous or subcutaneous) of antiresorptive therapies, and renal monitoring has positive benefits, particularly for patients with multiple comorbidities.

Transparency
Declaration of funding Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.

Declaration of financial/other relationships
The author is on the speaker list for Warner Chilcott.