Transient secondary hyperparathyroidism following intravenous infusion of zoledronic acid

Abstract

Dear Editor, We have read with interest the paper of Sayin and Yazici [1], describing a case of secondary hyperparathyroidism following multiple intravenous zoledronic acid (ZOL) infusions in a patient with stomach lymphoma and bone metastases. The authors supported that serum parathyroid hormone (PTH) continued to increase, despite serum calcium and vitamin D normalization, until ZOL infusions were stopped. Hypocalcemia has been described after ZOL, as well as after other bisphosphonates (BPs), in various conditions, including bone metastases, Paget’s disease of bone (PDB), and osteoporosis. Transient secondary hyperparathyroidism after a single ZOL infusion has previously been observed in a cohort of nine patients with active PDB [2]. These patients had normal serum calcium, magnesium, and vitamin D and no evidence of hyperparathyroidism or hypoparathyroidism at baseline. They had received calcium carbonate (1,500 mg) and vitamin D (400 IU) daily for 10 days before, as well as after the infusion, until serum calcium was normalized. ZOL effectively restricted PDB activity, as it was shown by the significant reduction in total serum alkaline phosphatase (322±211 IU/L at baseline vs. 101±36 IU/L at 3 months vs. 93±42 IU/L at 12 months) and in the scintigraphic index of involvement, a dimensionless marker for the per patient activity of the disease (14.4±7.6 vs. 7.2±1.8 vs. 5.5±2.5, respectively) and the scintigraphic ratio, a dimensionless marker for the per lesion activity of the disease (12.8±7.7 vs. 7.0±2.9 vs. 5.8±3.0, respectively) [2]. Other bone turnover markers, such as bone-specific serum alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen (CTX), follow a similar pattern of reduction, as it has been shown elsewhere [3]. However, a significant hypocalcemia [decrease of 10% (range 4–23%) in the mean serum calcium] on the third day (2.43±0.13 vs. 2.18±0.10 mmol/L at baseline, p<0.05) was observed accompanied by a mild but not statistically significant hypophosphatemia. No patient experienced symptoms or signs of hypocalcemia. Interestingly, PTH remained significantly increased by 90% (range 20–252%) 3 months (11.6±8.7 vs. 6.8±5.7 pmol/L at baseline, p<0.05) after ZOL infusion and returned to baseline levels at 12 months (7.5±4.8 pmol/L, p=ns vs. baseline), although calcium was normalized by the tenth day (2.35±0.13 mmol/L, p=ns vs. baseline) in all patients [2]. It seems that PTH increase after treatment is compensatory in order to maintain normocalcemia. The ability of the parathyroid gland to react prevents long-term hypocalcemia, by increasing renal reabsorption of calcium and vitamin D production and by stimulating osteoclasts. The effect of PTH on osteoclasts is restricted in patients taking BPs, depending on the potency of the BP. The newer more potent aminobisphosphonates, such as ZOL, initially create a bone remodeling imbalance by strongly suppressing bone S. A. Polyzos Second Medical Clinic, Medical School, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece