ORF08-03 - Severe Hypocalcemia from Zoledronic Acid Administration in Adult with Multicentric Carpotarsal Osteolysis Syndrome and Recurrent Fractures

Background:
Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant skeletal dysplasia caused by mutations in the MAFB gene. It encodes transcription factor MafB (v maf avian musculoaponeurotic fibrosarcoma oncogene homolog B), which negatively regulates receptor activator of nuclear factor-κB ligand (RANKL) mediated osteoclastogenesis. Lower levels of MafB in MCTO individuals leads to upregulated osteoclast differentiation resulting in a high turnover skeletal state. Phenotypically, this syndrome is characterized by progressive osteolysis of carpal and tarsal bones, and chronic kidney disease (CKD) secondary to focal segmental glomerulosclerosis (FSGS).

Case:
A 23-year-old woman with MCTO (MAFB gene c.209C>T) and CKD stage 5 from FSGS requiring renal transplant at age 17 presented after multiple fragility fractures from falls. Fracture locations included humerus, femoral neck, tibia, and fibula. Her medications were calcitriol 0.25 mcg three times a week, calcium carbonate 1000 mg BID, and vitamin D3 1000 IU daily at initial consultation. Labs showed albumin-corrected calcium 9.1 (8.6-10.0 mg/dL), eGFR>100 (>60 mL/min/1.73m2), PTH 24 (15-65 pg/mL), 25 vitamin D 27.4 (10-50 ng/mL). Due to elevated bone resorption with C-telopeptide (CTX) 1871 (136-689 pg/mL), zoledronic acid 5 mg was given to reduce subsequent fracture risk. Four days after receiving zoledronic acid, she developed fatigue and weakness, found to have calcium of 6.1 mg/dL. Calcitriol was increased to 0.5 mcg BID and calcium carbonate to 1500 mg TID to achieve hypocalcemia resolution. With close lab monitoring and medication titration, she returned to her baseline doses of calcitriol and calcium 1 year after receiving zoledronic acid. Her 1-year post-infusion CTX level decreased to 1085. Serial DXA revealed that her bone mineral density (BMD) measurements of 1/3 distal radius increased from R: 0.287 gm/cm2 (Z-score -6.7) and L: 0.271 gm/cm2 (Z-score -7.0) at baseline to R: 0.299 gm/cm2 (+10.2%, Z-score -6.5), and L: 0.329 gm/cm2 (+14.5%, Z-score -6.0) 2-year post-infusion.

Conclusion:
To our knowledge, this is the first report describing biochemical and BMD response to zoledronic acid in an adult with MCTO, as existing literature is limited and focused primarily on pediatric patients. The profound and prolonged hypocalcemia was unexpected, and we propose it may have resulted from a unique “hungry bone”-type syndrome in the setting of MCTO and pre-existing kidney disease. Giving a bisphosphonate resulted in massive whole skeletal system mineral shift. This case report reveals that treating adult MCTO patients requires close lab monitoring following zoledronic acid. Empiric and prophylactic increases in calcium and calcitriol doses should be considered, particularly in adult patient with pre-existing kidney disease, to prevent the development of severe post-treatment hypocalcemia.