MON-779 - Rebound Hypercalcemia after Denosumab Interruption

Background:
Hypercalcemia with suppressed parathyroid hormone (PTH) and elevated parathyroid related peptide (PTHrP) classically suggests humoral hypercalcemia of malignancy. In advanced chronic kidney disease/ end stage renal disease (CKD/ESRD) however, PTHrP results should be interpreted cautiously, as measured levels can be higher in renal failure, even with modern assays. This can result in unnecessary evaluation for malignancy.¹
Clinical

Case:
A 66-year-old woman with ischemic cardiomyopathy, papillary thyroid cancer s/p thyroidectomy, osteoporosis on long-term denosumab, and newly declared ESRD was admitted for expedited heart–kidney transplant evaluation. During hospitalization, serum calcium increased from 10.8 mg/dL to 12.2 mg/dL (ref 8.5–10.2) prompting further evaluation. Outpatient record review showed intermittent mild hypercalcemia with elevated PTH (most recent 145 pg/mL ~3 months prior (ref 15-65 pg/mL). In contrast, repeat inpatient PTH was inappropriately normal at 20 pg/mL, supporting a non–PTH-mediated process. Vitamin A and vitamin D metabolites were normal, and evaluation for plasma cell dyscrasia was unrevealing. PTHrP was elevated at 9.7 pmol/L (ref 0.0–3.4 using ARUP LC-MS/MS mid-region peptide assay), raising concern for malignancy. However, the patient was up to date on cancer screening, and whole-body PET did not identify any malignancy. Given the negative malignancy evaluation and recognition of the limited specificity of PTHrP in ESRD, we shifted focus to alternative etiologies and revisited the medication timeline.¹ Review of her medication schedule revealed a lapse in denosumab therapy (last injection ~9 months prior; scheduled dose missed ~3 months prior). With timing consistent with reported adult rebound hypercalcemia after denosumab interruption, hypercalcemia was attributed to denosumab ‘rebound,’ and serum calcium normalized over the subsequent weeks.2

Conclusion:
In ESRD, elevated PTHrP should be interpreted cautiously because renal failure may be associated with higher measured PTHrP in the absence of malignancy. Denosumab interruption is a rare but important cause of delayed, PTH-suppressed hypercalcemia and should be actively assessed during evaluation to avoid unnecessary malignancy workup.

References:
1. Kroner G et al. J Endocr Soc. 2020;4(Suppl 1):SAT-LB70.
2. Schmitt L et al. Arch Endocrinol Metab. 2024;68:e240035.

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