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What criteria exist to suggest use of denosumab for the treatment of hypercalcemia of malignancy over other calcium reducing options?

Introduction

Hypercalcemia is one of the most common complications of malignancy, occurring in up to 30% of patients with advanced cancer.1-3 Hypercalcemia may be associated with any malignancy type, but is more frequently observed in carcinomas of the breast, lung, kidney, head and neck. 2,3 Hematologically, the incidence of hypercalcemia is greatest with multiple myeloma.2,3 Primary mechanisms for hypercalcemia include increased bone resorption, increased gastrointestinal (GI) absorption of calcium, or increased renal tubular reabsorption of calcium.1-3  Tumors mediate this process through production of compounds like PTH-related protein (PTHrP), which increases bone resorption and renal tubular reabsorption, or via focal bone destruction through upregulation of osteoclast activating factors (OAF).1-3

Hypercalcemia is defined as an albumin adjusted total serum calcium (CSC) concentration greater than 10.5 mg/dL.2,4,5 Patients with mild to moderate hypercalcemia (10.5 to 13.9 mg/dL) may be asymptomatic upon presentation. Severe hypercalcemia is defined as a total serum calcium concentration greater than 14 mg/dL. Symptoms of hypercalcemia of malignancy (HCM) include nausea, vomiting, constipation, polyuria, and disorientation. Patients left untreated can progress to renal failure, coma, or life-threatening arrhythmias.2-5

The cornerstone of treatment for individuals with acute, symptomatic hypercalcemia (> 12 mg/dL) is aggressive fluid resuscitation with intravenous (IV) normal saline.1-5 Subsequent treatment can include the use of IV bisphosphonates or denosumab, glucocorticoids, and/or calcitonin (Table 1). In patients with access in place, hemodialysis can also be employed to reduce overall serum calcium in the blood. For patients with persistently elevated hypercalcemia requiring long-term control, IV bisphosphonates are used due to their relative cost and available evidence compared with other therapies;4,5 however, there are increasing numbers of case reports of denosumab use in patients with persistent hypercalcemia despite prior bisphosphonate therapy.6,7

Table 1. Agents used in the treatment of symptomatic hypercalcemia.4,8,9
AgentMode of ActionOnset of ActionCautions
Normal salineExpands volume, enhances filtration and excretion of Ca++6 hMay worsen CHF
Bisphosphonates (IV)Inhibits osteoclast action and bone resorption24 – 48 hNephrotoxicity, fever, ONJ, hypocalcemia
Calcitonin (IM)Inhibits bone resorption, increases Ca++ excretion, decreases GI reabsorption of Ca++2 hHypocalcemia, tachyphylaxis
GlucocorticoidsInhibits vitamin D conversion to calcitriol, potentiates action of calcitonin1 – 2 hImmunosuppression
Denosumab (SC)Inhibits osteoclast formation and bone resorption9 daysONJ, hypocalcemia, nausea
Abbreviations: Ca++=calcium; CHF=congestive heart failure; GI=gastrointestinal; IM=intramuscular; IV=intravenous; ONJ=osteonecrosis of the jaw; SC=subcutaneous.

Denosumab products and indications

Denosumab is a human monoclonal antibody that binds receptor activator of nuclear factor-kappa ligand (RANKL).10,11 Once bound, RANKL cannot interact with its receptor (RANK) located on osteoclast surfaces. The inhibition prevents osteoclast formation resulting in decreased bone resorption, increased bone mass, and decreased tumor bone destruction. In giant cell tumors of the bone expressing RANK and RANKL, denosumab inhibits tumor growth.

There are 2 Food and Drug Administration (FDA)-approved formulations of denosumab: Prolia® and Xgeva®.10,11 Each brand has a specific indication and recommended dosing (Table 2). Prolia® is approved for use in patients with a high risk for fractures, such as patients with osteoporosis or taking certain medications that results in the weakening of bone.10  Xgeva® is approved for the prevention of skeletal related events (eg, spinal cord compression, fractures) in adults with bone metastases from solid tumors or multiple myeloma, treatment of giant cell tumor of bone that is unresectable, and treatment of HCM refractory to bisphosphonate therapy.11 Though the medications contain the same active and inactive ingredients, the specific formulation prescribed should be consistent with the labeled indication to ensure accurate billing and reimbursement.

Table 2. Comparison of denosumab products.10,11
Brand NameIndicationUsual Dosing
Prolia®Treatment for patients with a high risk for fracture including:

·         Postmenopausal women with osteoporosis

·         Men with osteoporosis

·         Men and women with glucocorticoid-induced osteoporosis

·         Men receiving androgen deprivation therapy for nonmetastatic prostate cancer

·         Women receiving adjuvant aromatase inhibitor therapy for breast cancer		60 mg subcutaneously every 6 months
Xgeva®·         Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors

·         Treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable

·         Treatment of HCM refractory to BP therapy		120 mg subcutaneously every 4 weeks

(additional 120 mg doses on days 8 and 15 of the first month are recommended in giant cell tumor of bone and HCM)
Abbreviations: BP=bisphosphonate; HCM=hypercalcemia of malignancy.

Denosumab for prevention and treatment of hypercalcemia of malignancy

Overall, the evidence for denosumab in the treatment and prevention of HCM is limited (Table 3). The approval of denosumab in the treatment of HCM is based on a single, prospective, open-label trial in patients refractory to bisphosphonates.12 A small number of case reports6,13 and a single retrospective chart review also document the efficacy of denosumab.14 For the prevention of HCM and skeletal muscle related events (SREs), denosumab was compared with zolendronic acid (ZA) in a post-hoc analysis of data combined from 2 phase III trials of advanced cancer patients (with metastases) or multiple myeloma.15 Treatment with denosumab resulted in a statistically significant delay in the time to first HCM event and reduced risk of recurrent HCM. Adverse events in the denosumab and ZA groups were similar in the full study population. In patients that experienced more than 1 HCM event (N = 84) there were 2 reports of osteonecrosis of the jaw with denosumab versus no reports with ZA. In this subgroup, pneumonia and renal failure were more frequent with denosumab, but these values were not tested for significance.

Table 3. Select literature evaluating denosumab (Xgeva®) for the treatment or prevention of HCM.12,14,15
Study DesignSubjectsInterventionsEndpointsConclusion
Treatment
Hu12

2014

Phase II, OL, MC, MN, SA		N=33 patients with hypercalcemia refractory to BP

Median follow-up time: 56 days		Denosumab 120 mg SC on days 1, 8, 15, and 29, then every 4 weeks thereafterEfficacy:

At day 10, 21 patients (64%) reached CSC ≤ 11.5 mg/dL, and 12 patients (33%) reached CSC ≤ 10.8 mg/dL

At the completion of the study, 23 patients (70%) reached CSC ≤ 11.5 mg/dL, and 21 patients (64%) reached CSC ≤ 10.8 mg/dL

Estimated median response duration was 104 days

Safety:

SAEs reported included hypercalcemia worsening (5 patients, 5%) and dyspnea (3 patients, 9%)		Denosumab lowered serum calcium in 64% of patients within 10 days that were previously refractory to BP therapy.
Dietzek14

2015

R, CR		N=7 patients that received denosumab for HCM in the study period (June 2010 – January 2013)Denosumab 60 mg (N=2) or 120 mg (N=5) SCEfficacy:

Mean CSC decreased significantly between admission and last known in-house value (13.7 mg/dL vs 9.92 mg/dL, P = 0.0016)

Safety:

1 patient developed hypocalcemia 86 hours after denosumab 60 mg was administered		Denosumab effectively lowered calcium concentrations; however, the cost and safety concerns may limit expanded use for HCM.
Prevention
Diel15

2015

Combination of 2 Phase III,  DB, AC, RCT		N=3822 patients with advanced cancer and bone metastases or with multiple myelomaDenosumab 120 mg SC (N=1912) or ZA 4 mg IV (N=1910) every 4 weeksEfficacy:

Time to first HCM was lower with denosumab versus ZA (HR, 0.63; 95% CI: 0.41 to 0.98; P = 0.042)

Risk of recurrent HCM was lower with denosumab versus ZA (RR, 0.48; 95% CI: 0.29 to 0.81; P = 0.006)

Fewer patients with denosumab experienced HCM events (1.7% vs 2.7%; P = 0.028)

Safety:

The overall rates of AEs and SAEs were similar between the treatment groups in the full study population		Denosumab was more efficacious than ZA in delaying or preventing HCM in patients with advanced cancer and bone metastases or with multiple myeloma.
Abbreviations: AE=adverse event; BP=bisphosphonate; CR=chart review; CSC=corrected serum calcium; HCM=hypercalcemia of malignancy; HR=hazard ratio; MC=multicenter; MN=multinational; OL=open label; R=retrospective; RR=rate ratio; SA=single-arm; SAE=serious adverse event; SC=subcutaneous; ZA = zolendronic acid.

Denosumab in renal impairment

Unlike bisphosphonates, denosumab is not renally eliminated, providing an additional therapeutic option in patients with renal dysfunction.9 Furthermore, in a systematic review and meta-analysis of 6 randomized trials (N=13,733) denosumab was associated with a significantly lower risk of renal events (26%) when compared with ZA; however, there was also higher risk of hypocalcemia with denosumab use.16 The prescribing information for denosumab acknowledges a possible increased risk of hypocalcemia, especially in renal impairment.10,11 A reduced 60 mg dose of denosumab was effective and well tolerated in a patient with HCM and renal dysfunction in a case report.17 The reduced dose, however, may still result in adverse events. For example, in a 4-patient case series, a single 60 mg dose of denosumab in 1 patient with multiple myeloma and renal impairment resulted in prolonged hypocalcemia requiring IV calcium supplementation.18 Subsequent patients in this series with renal dysfunction were administered a weight-based dose of denosumab (0.3 mg/kg), resulting in normalized CSC for those responding to therapy (N = 2). Authors of this report recommended implementing a weight-based strategy of denosumab administration in patients with renal dysfunction and adjusting based on CSC concentrations reached after 1 week. Until more experience is gained with denosumab in this patient population, patients should be monitored frequently for development of adverse effects, like hypocalcemia.18,19

Conclusion

Denosumab is an additional treatment option for hypercalcemia that has demonstrated a sustained response when evaluated in a single clinical trial.12 At this time, there are no published criteria for choosing denosumab over other agents for management of hypercalcemia. Some considerations of denosumab therapy include the associated costs of acquiring and administering a monoclonal antibody. Additionally, the longer onset of action, compared with other calcium-lowering medications, may preclude widespread use in emergency management of HCM.4 Currently, denosumab is recommended in patients refractory to bisphosphonates or where bisphosphonate therapy may be contraindicated (eg, renal impairment).10,11 In an open-label trial, denosumab was initiated if serum calcium continued to be elevated (> 12.5 mg/dL) despite bisphosphonate treatment within 7 to 30 days.12 Though recommended as an alternative to bisphosphonates in patients with renal impairment, denosumab dosing has not been established in this population. Notably, the American Society of Clinical Oncology (ASCO) continues to recommend dose-reduced pamidronate for patients with extensive bone disease in the setting of multiple myeloma and severe renal impairment.20 Given the possibility of an increased risk of hypocalcemia in patients with renal impairment, some studies report empiric dose reductions with no change in efficacy.14,17,18 These criteria may be an important tool for institutions to consider when developing guidelines for use.

References

  1. Rizzoli R, Body J-J, Brandi M-L, et al. Cancer-associated bone disease. Osteoporos Int. 2013;24(12):2929-2953.
  2. Pai A. Disorders of calcium and phosphorus homeostasis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th New York, NY: McGraw-Hill; 2017. http://accesspharmacy.mhmedical.com. Accessed October 14, 2019.
  3. DeVita VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.
  4. Dellay B, Groth M. Emergency management of malignancy-associated hypercalcemia. AdvEmerg Nurs J. 2016;38(1):15-25.
  5. Feldenzer KL, Sarno J. Hypercalcemia of malignancy. J Adv Pract Oncol. 2018;9(5):496-504.
  6. Freeman A, El-Amm J, Aragon-Ching JB. Use of denosumab for renal cell carcinoma-associated malignant hypercalcemia: a case report and review of the literature. Clin Genitourin Cancer. 2013;11(4):e24-26. doi:10.1016/j.clgc.2013.06.002
  7. Boikos SA, Hammers H-J. Denosumab for the treatment of bisphosphonate-refractory hypercalcemia. J Clin Oncol. 2012;30(29):e299. doi:10.1200/JCO.2012.41.7923
  8. Carrol MF, Schade DS. A practical approach to hypercalcemia. Am Fam Physician. 2003;67(9):1959-1966.
  9. Thosani S, Hu MI. Denosumab: a new agent in the management of hypercalcemia of malignancy. Future Oncol. 2015;11(21):2865-2871. doi:10.2217/fon.15.232
  10. Prolia [package insert]. Thousand Oaks, CA: Amgen Inc.; 2019.
  11. Xgeva [package insert]. Thousand Oaks, CA: Amgen Inc.; 2019.
  12. Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014;99(9):3144-3152.
  13. Rajan R, Cherian KE, Kapoor N, Paul TV. Denosumab as a bridge to surgery in a patient with severe hypercalcemia due to primary hyperparathyroidism in the setting of renal dysfunction. Indian J Endocrinol Metab. 2019;23(2):269-270.
  14. Dietzek A, Connelly K, Cotugno M, Bartel S, McDonnell AM. Denosumab in hypercalcemia of malignancy: a case series. J Oncol Pharm Pract. 2015;21(2):143-147.
  15. Diel IJ, Body J-J, Stopeck AT, et al. The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer. 2015;51(11):1467-1475.
  16. Chen F, Pu F. Safety of denosumab versus zoledronic acid in patients with bone metastases: a meta-analysis of randomized controlled trials. Oncol Res Treat. 2016;39(7-8):453-459.
  17. Bech A, de Boer H. Denosumab for tumor-induced hypercalcemia complicated by renal failure. Ann Intern Med. 2012;156(12):906-907.
  18. Cicci JD, Buie L, Bates J, van Deventer H. Denosumab for the management of hypercalcemia of malignancy in patients with multiple myeloma and renal dysfunction. Clin Lymphoma Myeloma Leuk. 2014;14(6):e207-211.
  19. Hu M. Response letter to the editor. J Clin Endocrinol Metab. 2015;100(1):L7.
  20. Anderson K, Ismaila N, Flynn PJ, et al. Role of bone-modifying agents in multiple myeloma: American Society of Clinical Oncology clinical practice guideline update. JCO. 2018;36(8):812-818.

Prepared by:
Lauren Endriukaitis, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

November 2019

The information presented is current as October 16, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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