Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

RANK ligand storm – rebound severe hypercalcaemia and bone loss following long-term denosumab discontinuation (#405)

Arunan Sriravindrarajah 1 2 3 4 5 , Albert Kim 1 3 5 6 , Christian Girgis 1 3 , Jacqueline R Center 2 5 6
  1. Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  2. St Vincent’s Hospital, Sydney, NSW, Australia
  3. Westmead Hospital, Sydney, NSW, Australia
  4. Blacktown Hospital, Sydney, NSW, Australia
  5. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia
  6. Garvan Institute of Medical Research, Sydney, Australia

Denosumab binds and inhibits RANK ligand, leading to inhibition of osteoclast differentiation and bone resorption[1]. Discontinuation of denosumab leads to rapid loss of effect and rebound increase in bone turnover[2].

A 66-year-old caucasian female was referred for hypercalcaemia CCa2+ 3.18mmol/L (2.15-2.55) with polyuria, polydipsia and 4kg weight loss. She had a background of osteoporosis on teriparatide 20mcg daily and Caltrate 600mg daily. She was treated with denosumab 60mg six-monthly for 11 years and transitioned to teriparatide four months prior due to non-union of a metatarsal fracture causing significant pain and impairment.

Investigations demonstrated PTH-independent hypercalcaemia (CCa2+ 2.90mmol/L, PTH <0.8pmol/L [2-9], 25-OHD 87nmol/L [50-150], 1-25-OHD 34nmol/L [60-200]) with elevated bone turnover (CTx 2,422ng/L [50-800], P1NP 511ug/L [8-84)) and absence of hypocalciuria (calcium-creatinine clearance ratio 0.035). Multiple myeloma screen was negative and cortisol, TFTs, ACE, LDH and PTH-rp were within normal range. CT Chest, Abdomen and Pelvis and 18FFDG PET/CT did not identify malignancy. 99mTc bone scintigraphy demonstrated diffusely increased activity in the skull and bilateral long bones cortices suggestive of metabolic bone disease.

Teriparatide and Caltrate were ceased, and she was treated with fluid rehydration. CCa2+ downtrended to 2.58mmol/L but bone turnover remained markedly elevated (CTx 2,420ng/L, P1NP 229ug/L). DEXA scan demonstrated a 12.5% decline in total mean hip and 2.7% decline in the L1-L4 spine bone mineral density in the 6 months post commencement of teriparatide (Tables 1-2). She received a rescue dose of denosumab 60mg to reduce hyper-resorption and prevent further bone loss. Blood tests six weeks post-denosumab administration showed hypocalcaemia (CCa+ 2.11mmol/L, PTH 19.7pmol/L) with rapid suppression of bone turnover (CTx <70ng/L from 2,420ng/L, P1NP 229ug/L from 524ng/L).

This case demonstrates hypercalcaemia secondary to significant bone turnover following cessation of long-term denosumab and transition to osteoanabolic therapy with teriparatide. Caution is needed when considering ceasing denosumab.

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  1. Kim AS, Taylor VE, Castro-Martinez A, et al. Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition. J Bone Miner Res. 2024;39(4):484-497. doi:10.1093/jbmr/zjae023
  2. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96(4):972-980. doi:10.1210/jc.2010-1502