Pitfalls of using denosumab preoperatively to treat refractory severe hypercalcaemia

Abstract

A 40-year-old man, with a history of metastatic parathyroid carcinoma, status post primary tumour resection and lung metastasectomy, was hospitalised for persistent severe hypercalcaemia and elevated parathyroid hormone levels despite conventional management and escalating doses of cinacalcet. A single dose (120 mg) of denosumab was given and his calcium level plummeted from 14.8 mg/dL to 5.5 mg/dL. After second lung metastasectomy, he developed prolonged hypocalcaemia that required calcium and vitamin D supplements for more than 3 years. In patients with severe hypercalcaemia refractory to conventional therapies, denosumab has been used off-label with some success. A known side effect of denosumab is hypocalcaemia, which is often short-lived. The risk of prolonged hypocalcaemia should be fully evaluated before using denosumab preoperatively, especially in patients with renal insufficiency, prolonged hyperparathyroidism or anticipated tumour debulking surgery.

Background

Primary hyperparathyroidism (PHPT) is a common endocrine disorder. A rare cause of PHPT is parathyroid carcinoma. Germline mutation in the CDC73 (cell division cycle 73) gene is a known genetic risk factor for parathyroid carcinoma. Parathyroid carcinoma, which is most commonly hormonally active, secretes parathyroid hormone (PTH) and leads to hypercalcaemia. Persistent hypercalcaemia and PHPT can lead to a wide array of complications in the renal, neurological, cardiovascular, musculoskeletal and gastrointestinal organ systems. Parathyroid carcinoma is not sensitive to radiation and has a low response rate to chemotherapy as well. Currently, there is no effective targeted therapy. The goal of medical management of parathyroid carcinoma is to control hypercalcaemia. Management of hypercalcaemia secondary to malignancy or PHPT has been discussed in two recent reviews,^{1 2} and is summarised in table 1. Specifically, both calcitonin and bisphosphonate are effective in controlling hypercalcaemia, and the former drug has more rapid onset of action than the latter one. However, tachyphylaxis limits usage of calcitonin while bisphosphate needs to be dose-reduced/avoided in patients with renal insufficiency. Glucocorticoids are effective in hypercalcaemia associated with 1,25(OH)₂D (1,25-dihydroxyvitamin D) overproduction, such as in multiple myeloma, leukaemia and lymphoma. It may also be used with calcitonin as it could boost the expression of calcitonin receptor on osteocytes and thus delay tachyphylaxis. Cinacalcet has been approved by the US Food and Drug Administration (FDA) in patients with hypercalcaemia associated with PHPT (including parathyroid carcinoma), but it only has moderate effect.

Table 1.

Conventional and non-conventional therapy for hypercalcaemia of malignancy

Therapies	Mechanism	Indications	Precautions	Onset15 16	Duration15 16	Dosage15 16
Isotonic saline hydration	Offset calcium-induced urinary salt wasting; replete intravascular volume; increase renal perfusion and calcium excretion	Hypovolaemia with hypercalcaemia	Heart failure, oedema, severe renal insufficiency	Hours	During infusion	200 mL/hour to maintain urine output 100 mL/hour
Loop diuretics	Inhibit kidney calcium resorption and increase urinary calcium excretion	Fluid overload with hypercalcaemia	Electrolytes abnormality	Hours	During therapy	Various
Calcitonin	Primarily decrease rate of bone resorption. Also increase calcium urinary excretion. Approved by FDA for hypercalcaemia	Early treatment of hypercalcaemia emergency	Hypersensitivity	1 hour	6–8 hours while on treatment	4 international units/kg intramuscularly every 12 hours; maximal 8 international units/kg every 6 hours
Zoledronate or pamidronate (bisphosphonates)	Inhibits osteoclast-mediated bone resorption. Approved by FDA for hypercalcaemia of malignancy	Hypercalcaemia of malignancy	Deterioration in renal function; pregnancy category D	24–72 hours	2–4 weeks	Zoledronate: 4 mg single intravenous infusion over no less than 15 min Pamidronate: 60–90 mg single intravenous infusion over 2–24 hours; minimum 7 days before retreat
Prednisone (glucocorticoids)	Inhibit endogenous 1,25(OH)2D production. Approved by FDA for hypercalcaemia of malignancy. May boost expression of calcitonin receptor on osteoclasts and delay tachyphylaxis of calcitonin	Patients with multiple myeloma, leukaemia or lymphoma	Various	2–5 days	Days to weeks	20–40 mg daily
Denosumab	Inhibit bone resorption through inhibition of RANKL. FDA approved for prevention of skeletal-related events in patients with bone metastases form solid tumours	Can be used in renal insufficiency	Osteonecrosis of jaw, hypocalcaemia, hypophosphataemia, foetal harm	2–4 days	4–15 weeks	120 mg SubQ every 4 weeks if used in FDA approved indications
Cinacalcet (calcimimetics)	Bind to calcium sensing receptor and reduce PTH production and secretion. FDA approved for secondary hyperparathyroidism, hypercalcaemia in primary hyperparathyroidism and parathyroid carcinoma	Primary and secondary hyperparathyroidism as indicated, parathyroid carcinoma	Hypocalcaemia, adynamic bone disease, hepatic impairment	2–3 days	During therapy	30 mg once daily, up to 90 mg four times per day
Dialysis	Reduce calcium by using low or no calcium dialysate	Severe malignancy-associated hypercalcaemia with renal insufficiency or heart failure	Various	Hours	During treatment	Various

FDA, Food and Drug Administration; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor kappa-Β ligand; SubQ, subcutaneously.

Denosumab is a humanised monoclonal antibody that binds to receptor activator of nuclear factor kappa-Β ligand and inhibits osteoclast formation, function and survival.³ It is approved by the FDA for preventing skeletal complications in patients with solid tumours and bone metastases. Off-label use of denosumab to treat refractory hypercalcaemia was first reported in a patient with parathyroid carcinoma in 2013. Since then, multiple cases/case series have been reported in literature (table 2). However, perioperative use of denosumab in patients with refractory hypercalcaemia and its potential complications has rarely been reported. We report herein a case of protracted hypocalcaemia that developed postoperatively after a single preoperative dose of denosumab. Literature is reviewed on using denosumab to treat hypercalcaemia secondary to parathyroid carcinoma.

Table 2.

Literature review of using denosumab to treat refractory hypercalcaemia caused by parathyroid carcinoma

Patient number	Age* (years)	Gender	Other therapy tried before denosumab	Denosumab dose and frequency	Other comorbidities	Effects on calcium after first dose of denosumab	Follow-up after first dose of denosumab	Calcium (mg/dL) before dosing	Calcium (mg/dL) after dosing	PTH level before dosing	PTH level after dosing	Reference	Comments
1	26	F	Saline, acute haemodialysis, calcitonin, bisphosphonate, cinacalcet	120 mg, every 4–8 weeks	Vit D deficiency, renal tubular acidosis, osteoporosis, acute pancreatitis, cardiac arrhythmias	Calcium normalised on day 3. Symptomatic hypocalcaemia developed on the day 7 requiring calcium and vit D supplements	Patient deceased at 6 months after first dose of denosumab	12	7–8	n/a	n/a	Tong et al4 5	There was no PTH level available during denosumab treatment. She developed hypocalcaemia with a history of vit D deficiency and renal disease. No details regarding duration of hypocalcaemia. It was likely transient since the patient had continued denosumab dose every 4–8 weeks
2	77	M	Fluid, bisphosphonate	120 mg, monthly	n/a	Calcium dropped from 12.56 to 10.96 mg/dL in 4 days, and remained same level for 4 months	4 months	12.56	10.96	16 pmol/L (1.1–6.9)	n/a	Nadarasa et al6	No hypocalcaemia
3	48	M	Fluid, bisphosphonate, cinacalcet	120 mg, once	n/a	Calcium dropped within a week to 9.84 mg/dL	n/a	16.88	9.84	145 pmol/L (1.1–6.9)	n/a	Nadarasa et al6	At end of case, the author mentioned the patient underwent resection of a likely solitary skeletal metastasis. He required a low dose of alfacalcidol to maintain normocalcaemia. No detail was given regarding PTH or calcium level before and after surgery. No further follow-up information available
4	31	F	Bisphosphonate, calcitonin cinacalcet, diuretic, somatostatin analogue	60 mg every 3 months to every month, then 120 mg	n/a	Did not achieve normocalcaemia. Patient had a gradual decrease of response	n/a	n/a	n/a	n/a	n/a	Baretić7	Persistent hypercalcaemia with decreased response to repeated doses of denosumab. No PTH level was available
5	32	F	Bisphosphonate, calcitonin, cinacalcet, diuretic, somatostatin analogue	60 mg every 3 months to every month, then 120 mg	n/a	Did not achieve normocalcaemia. Patient had a gradual decrease of response	n/a	n/a	n/a	n/a	n/a	Baretić7	Persistent hypercalcaemia with decreased response to repeated doses of denosumab. No PTH level was available
6	39	M	Fluids, pamidronate, cinacalcet	120 mg once, then 60 mg given as needed, then 120 mg monthly	B/l patellar tendon rupture	Calcium normalised, then dropped to 6.9 mg/dL after surgical resection of neck mass. Hypercalcaemia recurred	>24 months	14.2	6.9	1541–590 pg/mL (12–65)	Persistently elevated and trended up	Vellanki et al8	PTH dropped from 1541 to 590 after surgical resection of neck mass. Patient developed hypocalcaemia at 6.9 mg/dL after surgery. Both PTH and calcium level trended up in couple of months, and patient continued denosumab therapy
7	46	M	Fluids, zoledronic acid, cinacalcet, chemotherapy	120 mg, day 1, 8, 15, then monthly, then based on the calcium level	n/a	Calcium dropped to 10.64 mg/dL on day 8. Calcium normalised at 9.32 mg/dL on day 15, and remained to be normalised for total 4 months	Deceased at 1 year	Persistently >12	9.32	203 pmol/L (0.7–7)	433 pmol/L (0.7–7)	Bowyer et al9	PTH persistently elevated through the treatment. No hypocalcaemia developed
8	50	M	Fluids, pamidronate then zoledronate, cinacalcet	60 mg monthly for two times then 120 mg monthly	Renal insufficiency	Calcium dropped from 14.16 to 11.72 mg/dL on day 10	5 months	14.16	11.72	73 pmol/L (1.3–7.6)	PTH trended up	Karuppiah et al10	PTH persistently elevated and trended upwards. No hypocalcaemia developed
9	71	M	Fluid, cinacalcet, zoledronate	120 mg, monthly	n/a	Calcium normalised at 8.6 mg/dL on day 5, and remained in normal range for 11 months	11 months	13.7	8.6	1272 pg/mL (12–65)	2976 pg/mL (12–65)	Fountas et al11 12	PTH continued to rise possibly because of tumor progression. No hypocalcaemia
10	39	F	Cinacalcet, zoledronate	120 mg, monthly for 3 months, reduced frequency to once every 2 to 4 months	n/a	Calcium dropped to 10.1 mg/dL on day 10, remained between 8.5 and 12.6 mg/dL for 2 months	14 months	15.1	10.1	1921 pg/mL (10–65)	4130 pg/mL (10–65)	Itoshima et al13	PTH continued to rise due to metastatic parathyroid cancer. No hypocalcaemia
11	71	M	Fluid, furosemide, zoledronate, cinacalcet	60 mg, a total of 9 doses	Pulmonary embolism	Calcium normalised on day 1, remained between 10.4 and 10.8 mg/dL for 4 months	26 months	12.4	10.4–10.8	>200 pg/mL (12–65)	PTH fluctuated and trended up	Jumpertz von Schwartzenberg et al14	PTH persistently elevated and trended up during treatment. No hypocalcaemia

* Age when patients received denosumab

B/L, bilateral; n/a, not available; 1,25(OH)₂D, 1,25-dihydroxyvitamin D; PTH, parathyroid hormone; Vit D, vitamin D.

Case presentation

In September 2012, a 40-year-old man with a history of recurrent metastatic parathyroid carcinoma, presented with weight loss and dehydration. The workup showed total serum calcium of 13.3 mg/dL (normal <10.2 mg/dL), intact PTH of 1114 pg/mL (normal <65 pg/mL) and serum creatinine of 2.57 mg/dL (normal <1.2 mg/dL) with estimated glomerular filtrate rate of 30 mL/min/1.73 m² by the Modification of Diet in Renal Disease (MDRD) method, which met the criteria of stage 3B moderate chronic kidney disease.

In October 2000, at 28 years of age, he was diagnosed with metastatic parathyroid carcinoma. At that time, he was found to have elevated total calcium (12.9 mg/dL), PTH (584 pg/mL) and creatinine (3.2 mg/dL). Biopsies of a parathyroid mass and lung nodule revealed parathyroid carcinoma with lung metastasis. Renal biopsy showed acute interstitial nephritis. His father and one of two brothers had hypercalcaemia; however, they lived in Vietnam and no further details were available. On 5 December 2000, he underwent an en bloc left parathyroid mass resection and left hemithyroidectomy with a 2.5 cm primary parathyroid carcinoma removed, as well as a wedge resection of left upper lung with a 1.2 cm pulmonary metastasis removed. He received radiation therapy postoperatively (dose unknown). His postoperative PTH was 58 pg/mL and calcium ranged from 7.8 to 8.2 mg/dL. Between 2000 and 2012, during which time the patient was poorly compliant with follow-up, his serum calcium and PTH levels steadily increased (figure 1). A series of CT and positron emission tomography (PET)/CT scans revealed three slowly growing subcentimetre nodules in right lung. Cinacalcet was started, but his serum calcium and PTH levels continued to rise, despite of increasing dose up to 90 mg three times a day.

Figure 1.

PTH (intact PTH) and serum total calcium levels between 2011 and 2016. PTH, parathyroid hormone.

During his hospitalisation in 2012, his calcium and intact PTH rose to 14.8 mg/dL and 2509 pg/mL, respectively. His other lab results included phosphate of 3.6 mg/dL (normal 2.5–4.5 mg/dL) and 25(OH)D (25-hydroxyvitamin D) of 40.1 ng/mL (normal 20–50 ng/mL). Dialysis and off-label use of denosumab were both offered, and the latter treatment was selected because of patient’s preference. After obtaining an informed consent, a single dose of denosumab 120 mg was given subcutaneously. Thirteen days after the initial denosumab dose, he was symptomatic from hypocalcaemia and his calcium level plummeted to 5.5 mg/dL. He required treatment with intravenous calcium infusion and subsequently with a regimen of oral calcium and calcitriol supplementation. In the next month, he had wedge resection of three metastases in the right lung. Postoperatively, his PTH decreased from 3065 pg/mL to 144 pg/mL (figure 1).

Outcome and follow-up

One month after surgery, his calcium level went down to 6.1 mg/dL, ionised calcium to 3.3 mg/dL (normal 4.8–5.6 mg/dL) and phosphate to 2.9 mg/dL (normal 2.5–4.5 mg/dL). Four years following his surgery, his PTH levels remained relatively stable and multiple imaging scans showed stable post-surgical changes without evidence of recurrent disease. He continued to require calcitriol 0.5 μg two to three times a day and calcium carbonate 3000 mg–4000 mg a day to maintain his serum calcium level in normal or low normal range. As of his last visit on April 2017, the patient was still on calcitriol and calcium supplementation.

In 2013, after his second surgery, he was referred to the National Institutes of Health for germline genetic testing, and was found to have a germline non-sense CDC73 c.226C>T (p.Arg76*) mutation.

Discussion

Hypercalcaemia secondary to locally invasive or metastatic parathyroid carcinoma is frequently severe and refractory to medical therapy. As observed in our patient as well as in the 11 patients reported in the literature (table 2),^4–14 standard-of-care therapies including saline, calcitonin, bisphosphonates and cinacalcet provide limited benefit, commonly because of progression of metastatic disease that leads to worsening of hypercalcaemia. This is clearly documented in our patient (figure 1) that his hypercalcaemia worsened in connection with radiological progression of his metastatic disease and an increase in circulating PTH level, despite increments in the dose of cinacalcet up to 90 mg three times a day.

Denosumab is approved by the FDA for preventing skeletal complications in patients with solid tumours and bone metastases.^{15 16} The documented efficacy in the prevention and treatment of hypercalcaemia and skeletal complications in patients with bone metastasis has prompted off-label use of this drug for the treatment of hypercalcaemia secondary to parathyroid carcinoma. Even though such patients may not have bone metastasis, the mechanism of hypercalcaemia is similarly due to increased bone resorption because of excess PTH secretion. Review of the reported cases in the literature (table 2) shows that normalisation of calcium following denosumab administration occurred in 5 out of 11 patients (45%) in a duration up to 11 months.

Our patient is unique for the severity of hypocalcaemia (5.5 mg/dL) that he developed 13 days following the administration of the initial and only dose of denosumab. A milder degree of hypocalcaemia (7–8 mg/dL) was reported in one patient (#1, table 2) 7 days following the administration of the same dose of denosumab. Although details of follow-up was scarce, it appears that her hypocalcaemia was transient since she received additional doses of denosumab. Of interest, in common with our patient she had coexiting renal insufficiency. Two patients, whose calcium normalised after administration of denosumab, developed hypocalcaemia following surgical resection of metastasis. In one patient (#3, table 2) the degree of hypocalcaemia was not mentioned and no follow-up of its duration was provided. In another patient (#6, table 2), the calcium transiently dropped to 6.9 mg/dL after surgical resection of the neck mass, but subsequently rose because of progression of his disease. Within this context, the unique severity of hypocalcaemia and its prolonged duration observed in our patient raised a few considerations when considering denosumab in the treatment of hypercalcaemia secondary to parathyroid carcinoma. Renal insufficiency appears to be a risk factor for development of severe hypocalcaemia after denosumab. Both our patient and patient #1 in table 2 had renal insufficiency, and severe hypocalcaemia appeared to be more common in patients on haemodialysis.^{17 18} However, because the pharmacokinetics of denosumab are not altered by renal function, it is possible that these patients with renal insufficiency are more dependent on bone turnover to maintain serum calcium level which is targeted by denosumab. Another possibility is that patients with renal insufficiency typically have decreased 1-hydroxylase activity, which can affect synthesis of 1,25(OH)₂D and, therefore, calcium homoeostasis. Unfortunately, our patient did not have 1,25(OH)₂D level measured around his second operation, despite his 25(OH)D level was in normal range. His postoperative supplementation of calcitriol appeared to help control his hypocalcaemia.

Another unique finding in our patient is that he continues to have no demonstrable evidence of recurrence 4 years after surgical resection of his pulmonary metastasis. In line with this finding his hypocalcaemia persisted and he continued to require relatively high dose of calcitriol and calcium supplement. The origin of his residual PTH secretion is likely from residual normal parathyroid tissue on the right side since he only had en block left parathyroid mass resection and left hemithyroidectomy. It appears that the residual normal parathyroid tissue is insufficient to maintain normal calcium level in the absence of calcitriol and calcium supplementation.

Denosumab is an effective rescue therapy for refractory hypercalcaemia of malignancy in patients who have failed conventional therapies. Denosumab can cause short-term as well as protracted hypocalcaemia. Risk factors for developing protracted hypocalcaemia after denosumab may include renal insufficiency and anticipated tumour debulking surgery. If denosumab needs to be given, a lower dose (60 mg or lower) should be initiated with careful monitoring of serum calcium level.

Learning points.

• For treating severe hypercalcaemia of malignancy, conventional therapies, including intravenous saline, loop diuretics, bisphosphonates, steroids, calcitonin and cinacalcet, have limited long-term efficacy.

• Denosumab is an effective rescue therapy for refractory hypercalcaemia of malignancy in patients who have failed conventional therapies.

• Denosumab can cause short-term as well as protracted hypocalcaemia. Risk factors for developing protracted hypocalcaemia after denosumab may include renal insufficiency, prolonged hyperparathyroidism or anticipated tumour debulking surgery.