Hungry bone syndrome like presentation following single-dose denosumab for hypercalcaemia secondary to sarcoidosis with IgA nephropathy
- 1 Department of Endocrinology, Army Hospital Research and Referral, Delhi, India
- 2 Department of Nephrology, Army Hospital Research and Referral, Delhi, India
- Correspondence to Dr Amit Nachankar; anasvini@gmail.com
Abstract
A woman in her mid-50s with IgA nephropathy, sarcoidosis and steroid-induced diabetes mellitus presented with generalised paraesthesia and spontaneous tetany. She had received denosumab 60 mg subcutaneously 8 weeks previously for parathyroid hormone independent hypercalcaemia.
At admission, she had severe hypocalcaemia (5 mg/dL), hypophosphataemia (1.9 mg/dL), hypomagnesaemia (1.4 mg/dL) and elevated serum creatinine (1.48 mg/dL) with prolonged QTc (corrected QT interval) on electrocardiograph. She initially received intravenous calcium and magnesium followed by oral calcium carbonate and calcitriol. Her prednisolone dose was tapered to 5 mg/day. Evaluation showed secondary hyperparathyroidism (1474 pg/mL) and elevated 1,25-dihydroxy vitamin D (195 pg/mL). After 1 week of oral calcium carbonate (3000 mg/day) and calcitriol (1.5 µg/day), she achieved normocalcaemia (8.1 mg/dL).
To conclude, denosumab for hypercalcaemia with renal insufficiency causes prolonged severe symptomatic hypocalcaemia and hypophosphataemia mimicking hungry bone syndrome. It is important to periodically monitor for hypocalcaemia after denosumab.
Background
Denosumab is a monoclonal antibody against a receptor activator of nuclear factor kappa B ligand (RANK-L), used in the treatment of osteoporosis subcutaneously every 6 months even in the presence of renal impairment compared with bisphosphonates requiring intravenous use and dose modification in renal impairment.1 It is also used in the emergency management of hypercalcaemia especially with severely impaired renal function where intravenous bisphosphonates are contraindicated.2 A number of case reports related to prolonged hypocalcaemia following denosumab therapy especially when used in the treatment of solid tumours or in the presence of renal impairment have been published.3–5 We report here a case of severe symptomatic hypocalcaemia and hypophosphataemia mimicking hungry bone syndrome after 8 weeks of subcutaneous denosumab administration for parathyroid hormone independent hypercalcaemia.
Case presentation
A woman in her mid-50s was a known case of chronic kidney disease due to IgA nephropathy, sarcoidosis stage 2 and steroid-induced secondary diabetes mellitus. She presented to the emergency department with paraesthesia of the whole body and spontaneous tetany without any hyperventilation. She had no previous history of neck surgery or hypoparathyroidism. Prior to this admission, she was on tablet prednisolone 20 mg/day, tablet pantoprazole 40 mg once a day, tablet ramipril 10 mg once a day, tablet linagliptin 5 mg/day, tablet atorvastatin 20 mg at night and cholecalciferol sachet 60 000 U once a month.
Eight weeks prior to this admission, she had developed parathyroid hormone independent hypercalcaemia (serum calcium 12.04 mg/dL with parathyroid hormone 18.6 pg/mL, serum 25-hydroxy vitamin D 12 ng/mL and serum 1,25-dihydroxy vitamin D 137 pg/mL) when she was on oral prednisolone 40 mg/day with a deranged serum creatinine 3.9 mg/dL (estimated glomerular filtration rate (eGFR) 12 mL/min/1.73 m2). That episode was then managed with intravenous fluids and diuretics. She also received a single dose of subcutaneous injection denosumab 60 mg in view of underlying osteoporosis and persistent hypercalcaemia despite saline rehydration and loop diuretics. After achieving normocalcaemia, she was discharged with advice to follow up weekly but she did not follow up.
At this admission, she had a pulse of 94 beats/min with blood pressure of 146/98 mm Hg associated with cardinal signs of hypocalcaemia in the form of grade II Chvostek’s sign (alae nasi twitch) and grade IV Trousseau’s sign (spontaneous carpopedal spasm). Urgent evaluation revealed severe hypocalcaemia (corrected serum calcium 4.96 mg/dL) with serum albumin (3.3 g/dL), hypophosphataemia (1.9 mg/dL) and hypomagnesaemia (1.4 mg/dL). She also had a deranged serum creatinine (1.48 mg/dL) with eGFR of 39 mL/min/1.73 m2 suggestive of chronic kidney stage 3. Her urine pH was 6.5 with urine anion gap of 23 mEq/L, while her serum pH was 7.33 with serum bicarbonate level of 21 mEq/L and serum anion gap of 8 mEq/L at this admission. She had prolonged corrected QT (0.49 s) on electrocardiograph without any arrhythmia.
The laboratory parameters of serial calcium and vitamin D are shown in table 1.
Serial calcium and vitamin D profile
| Parameters | Normal value | 8 weeks before | Day 1 | Day 2 | Day 5 | Day 6 | Day 7 | Day 12 |
| Serum calcium | 8.1–10.3 mg/dL | 12.04 ↑ | 4.96 ↓ | 5.36 ↓ | 6.02 ↓ | 7.88 ↓ | 6.10 ↓ | 7.82 ↓ |
| Serum phosphorus | 3.0–4.5 mg/dL | – | 1.9 ↓ | – | 1.6 ↓ | – | – | 3.1↔ |
| Serum magnesium | 2.0–3.5 mg/dL | – | 1.4↓ | – | – | – | – | 2.5↔ |
| Serum alkaline phosphatase | 50–100 IU/L | – | 173↔ | – | – | – | – | – |
| Serum 25-hydroxy vitamin D | 30–100 ng/mL | 12.0↓ | – | 9.37↓ | – | – | – | – |
| Serum 1,25-dihydroxy vitamin D | 15–70 pg/mL | 137↑ | – | – | – | – | – | – |
| Serum creatinine | 0.5–1.3 mg/dL | 3.9 ↑ | 1.48 ↑ | – | – | 1.58 ↑ | – | 1.53 ↑ |
| Urine pH | 6–7.5 | 6.5 | – | – | – | – | – | – |
-
*Abnormal values are shown in bold, decreased (↓), increased (↑) or in range (↔).
Treatment
Initially, she received intravenous calcium gluconate 20 mL (180 mg of elemental calcium) in 50 mL 5% dextrose over 15 min followed by continuous calcium gluconate infusion (11 ampoules of 10 mL total containing total 990 mg of elemental calcium in of 5% dextrose to make 1 liter of fluid infused at 100 mL/hour over 10 hours) with addition of oral calcium carbonate 500 mg tablet (containing 200 mg of elemental calcium) every 6 hours orally, along with tablet calcitriol 0.5 µg orally two times per day. She was also managed with intravenous magnesium initially in the intensive care unit. Her steroid doses were tapered to 5 mg prednisolone per day with insulin therapy for steroid-induced secondary diabetes mellitus. She was found to have secondary hyperparathyroidism with markedly elevated serum parathyroid hormone (1474 pg/mL) and markedly low 25-hydroxy vitamin D (9.37 ng/mL). After 1 week of oral calcium carbonate (3000 mg/day) and calcitriol (1.5 µg/day), she had near normalisation of serum calcium (8.1 mg/dL).
Outcome and follow-up
At the discharge, we diagnosed her as a case of severe hypocalcaemia secondary to denosumab therapy for parathyroid hormone independent hypercalcaemia due to sarcoidosis associated with chronic kidney disease due to IgA nephropathy. During follow-up after 1 month, she was asymptomatic with normal serum calcium (8.6 mg/dL), normal serum phosphorus (3.0 mg/dL) with elevated serum creatinine (1.8 mg/dL) and normal serum 1,25-dihydroxy vitamin D (67 pg/mL) while on treatment with oral calcium (2000 mg/day) and calcitriol (1.0 µg/day). She was scheduled to be followed up every 3 months to monitor for delayed hypocalcaemia and s waadvised to report back in case of any symptoms suggestive of hypocalcaemia.
Discussion
A number of case reports related to prolonged hypocalcaemia following denosumab therapy especially when used in the treatment of solid tumours or in the presence of renal impairment have been published.3–5 The risk factors for denosumab-induced hypocalcaemia are vitamin D deficiency, renal insufficiency and increased bone turnover. Here our patient initially received denosumab for parathyroid hormone independent hypercalcaemia due to sarcoidosis-mediated hypervitaminosis D (increased 1-alpha hydroxylase activity) with underlying impaired renal function due to IgA nephropathy. Eventually after 8 weeks, she reported with severe symptomatic hypocalcaemia for which denosumab is the aetiology.
Mechanism of denosumab-mediated hypocalcaemia
Denosumab is a full-length IgG2 subtype human monoclonal antibody which binds and inhibits RANK-L, similar to the action of native osteoprotegerin. After subcutaneous therapy, it shows a non-linear, dose-dependent pharmacokinetics achieving peak levels in 7–21 days.6 It is not excreted through renal route being an IgG antibody, and so it needs no renal dose modification.2 Denosumab causes rapid and sustained reduction in bone resorption with 85% reduction in serum C-telopeptide of type I collagen in 3 days and a peak reduction in 1 month. Hence, its potent and long-lasting effect on bone remodelling results in high risk for hypocalcaemia.
A marked hypocalcaemia was detected in renal impaired subjects in the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) Extension study at approximately day 10.7 The earliest report of denosumab-induced hypocalcaemia was as early as day 4 post administration of denosumab,8 and in one case, the protracted hypocalcaemia and hypophosphataemia lasted for 5 months.3 In patients with chronic kidney disease, the first presentation of hypocalcaemia after the denosumab injection was from 2 to 12 weeks with a median of 8 weeks and mean of 6.6 weeks, similar as in our case.9 This rapid and sustained hypocalcaemia induced by denosumab in the presence of severe renal impairment has an accentuating effect in the presence of secondary hyperparathyroidism as in our case due to available huge load of active osteoblasts. Denosumab by inhibiting osteoclastic activity allows excess unopposed osteoblastic activity, thereby resulting in severe prolonged hypocalcaemia.10 Similarly, our patient had hypocalcaemia, hypomagnesaemia and hypophosphataemia which mimicked hungry bone syndrome,11 which is defined as the rapid, profound and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone levels, which usually follows parathyroidectomy in patients with severe primary hyperparathyroidism and preoperative high bone turnover. This prolonged hypocalcaemia itself further causes elevated parathyroid hormone, thereby worsening secondary hyperparathyroidism as in our case with parathyroid hormone level of 1474 pg/mL.
The hypocalcaemia in our patient persisted for a prolonged period despite intravenous and oral calcium along with 1-hydroxy vitamin D supplementation. Her 25-hydroxy vitamin D deficiency was persistent in the presence of chronic kidney disease, and her serum parathyroid hormone was very high due to secondary hyperparathyroidism. However, her serum 1,25-dihydroxy vitamin D was elevated above the normal range. This indicates that her 25-hydroxy vitamin D deficiency was not responsible for persistent hypocalcaemia. Elevated parathyroid hormone often causes rapid loss of 25-hydroxy vitamin D stores via accelerated conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D, increases clearance of 25-hydroxy vitamin D and promotes hepatic inactivation of 25-hydroxy vitamin D to 24,25-dihydroxy vitamin D.12 13 In our case also, parathyroid hormone was high, secondary to hypocalcaemia, and serum 1,25-dihydroxy vitamin D levels were high due to elevated parathyroid hormone. However, denosumab restricted the effect of parathyroid hormone to achieve normocalcaemia by inhibiting bone resorption, thereby leading to prolonged hypocalcaemia.3
The risk factors for denosumab-induced hypocalcaemia are vitamin D deficiency, secondary hyperparathyroidism, renal insufficiency, increased bone turnover states, hypomagnesaemia and simeltaneous use of hypocalcaemic agents like steroids, calcimimetics and bisphosphonates.14 The eGFR cutpoint is 30 mL/min/1.73 m2 below which there is increased risk of hypocalcaemia and hypophosphataemia leading to hungry bone syndrome like picture following denosumab administration.10 Hence, those with chronic kidney disease stages 4 and 5 or those on any form of dialysis are at the greatest risk in view of underlying chronic kidney disease-associated mineral bone disease especially secondary hyperparathyroidism.
Learning points
-
Denosumab treatment for hypercalcaemia in the presence of impaired renal function results in prolonged severe symptomatic hypocalcaemia and hypophosphataemia after a few weeks mimicking hungry bone syndrome.
-
The presence of vitamin D deficiency, secondary hyperparathyroidism, renal insufficiency (chronic kidney disease stages 4 and 5), increased bone turnover states, hypomagnesaemia and simultaneous use of hypocalcaemic agents like steroids, calcimimetics and bisphosphonates are the risk factors for denosumab-induced hypocalcaemia.
-
Denosumab prevents the recovery from hypocalcaemia by inhibiting parathyroid hormone-mediated bone resorption, thereby blocking calcium mobilisation into blood.
-
Aggressive intravenous and oral calcium along with calcitriol supplementation for a prolonged period is needed in denosumab-induced hungry bone syndrome like picture to increase intestinal calcium absorption thereby restoring normocalcaemia.
-
It is important to monitor patients after denosumab therapy initially every 2–4 weeks for 3 months and later at the end of 6 months for development of hypocalcaemia or hungry bone syndrome like picture in patients at high risk.
Ethics statements
Patient consent for publication
Acknowledgments
We acknowledge the assistance contributed by the nursing staff and laboratory staff in the management of the case.
Footnotes
-
Contributors AN had substantial contributions to the conception or design of the work; AK had substantial contribution to the acquisition, analysis or interpretation of data for the work; NB had substantial contribution to the final approval of the version to be published. AB revised it critically for important intellectual content.
-
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
-
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
-
Competing interests None declared.
-
Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
Use of this content is subject to our disclaimer