Endocrine Abstracts

Introduction: rhPTH(1-84) replacement is the treatment of choice in adults with hypoparathyroidism not adequately controlled on standard therapy. Although increased bone turnover markers have consistently been reported in trials of safety and efficacy, marked elevations coupled with significant symptoms have been rare. We describe a case of increased treatment-induced bone turnover, necessitating significant therapeutic adjustments and monitoring.

Case report: A 26-year-old female suffered with severe hypoparathyroidism for 10 years, following total thyroidectomy and incidental parathyroidectomy (three glands) for papillary thyroid cancer (pT1N0). Laboratory values on calcium carbonate 4gr daily, alfacalcidol 3 mg daily, magnesium aspartate 60 mg bid and thyroxine 137 mg/d were as follows: TSH 0.33μIU/ml (0.27-4.7), thyroglobulin <0.1ng/ml (<1), anti-TG negative, corrected calcium 6.5 mg/dl (8.4-10.1), phosphate 6.6 mg/dl (2.7-4.5), Mg 1.61 mg/dl (1.6-2.6), Cr 0.7 mg/dl, ALP 55IU/l (23-104), PTH 5.1 pg/ml (15-65), 25(OH)D 34.9 ng/ml (20-50), 1,25(OH)₂D3 29 pg/ml (18-80). Kidney ultrasound revealed nephrocalcinosis bilaterally and 24h urinary calcium was 539.7 mg/24h (<250 mg/24h).Following referral, rhPTH(1-84) 50 mg daily was started and titrated to 100 mg daily within 6 months. The patient discontinued alfacalcidol and remained on 500 mg calcium carbonate and 1000IU cholecalciferol daily, with excellent response.Within a week on 100 mg/d the patient reported severe bone pain in the knee joints and back, paralleled with successive increase in serum ALP at 163IU/l, 221IU/l and 611IU/l (range 23-104IU/l) and bone markers: CTx 1.59ng/ml (0.04-0.6ng/ml), P1NP 623ng/ml (15-60 ng/ml) and osteocalcin 157ng/ml (5.4-59.1ng/ml). Liver function tests and liver ultrasound were normal. rhPTH(1-84) was reduced to 50 mg daily with gradual improvement in bone pain, but with immediate relapse of hypoparathyroid symptoms and worsened biochemical control. ALP levels normalized within 10 weeks to the upper normal range [113IU/l (46-116IU/l)]. Subsequently the dose was up titrated to 75 mg/d, together with calcium carbonate 500 mg bid, magnesium 60 mg bid and alfacalcidol 1 mg/d. She has remained stable clinically and biochemically for the past 6 months. ALP values increased again but are maintained within 10%ULN.

Conclusions: Elevation of bone turnover markers are anticipated by rhPTH(1-84) mechanism of action. However, they remain within normal range in the long term. The etiology for marked symptomatic increase in bone turnover in a minority of patients affecting treatment tolerability is unknown.

References: 1) Mannstadt M et al, J Clin Endocrinol Metab. 2019;104(11):5136-51472) 2) Mannstadt M et al, Lancet Diabetes Endocrinol. 2013;1(4):275-2833) 3) Rubin M et al, J Clin Endocrinol Metab. 2016; 101(7): 2742-27504) 4) Tay YD et al, J Clin Endocrinol Metab. 2019; 1;104(11):5601-5610.