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Torregrosa reports a rare case of dramatic increase in intact parathyroid hormone (iPTH) and hypocalcaemia after administration of denosumab in a kidney-transplanted patient [1]. However, the author does not comment on another important finding of this case which is the unusually prolonged hypocalcaemia. In the only study to have investigated this issue so far, Block et al. report that in the chronic kidney disease (CKD) 4 subgroup, adjusted serum calcium (ACa) levels return to normal within 15 days [2], but in Torregrosa's report the patient still remains hypocalcaemic 6 months after denosumab [1].  We report a similar case of a 64-year-old female with an allogeneic renal transplant 3 years prior to presenting to the clinic with stable CKD4 and tertiary hyperparathyroidism, and presented with sustained multiple fragility fractures secondary to osteoporosis. Her medication included alfacalcidol 500 ng daily, cinacalcet 60 mg daily, tacrolimus, and prednisolone. Biochemistry was as follows: ACa 2.37 mmol/L (9.48 mg/dL) (always within the normal range in the last year), estimated glomerular filtration rate (eGFR) 16 mL/min/1.73 m2, iPTH >190 pmol/L (1.79 ng/dL) and 25(OH)vitamin D 34.2 nmol/L (13.7 ng/mL). Following administration of denosumab 60 mg, ACa concentrations decreased to 1.96 mmol/L (7.84 mg/dL) at Day 16, returning to normal at Day 93. iPTH remained persistently elevated at >100 pmol/L (943 pg/mL). Throughout this period, the patient had adequate dietary calcium intake and did not change medication. Block also reports that in the CKD 5 subgroup, ACa returns to normal by Day 60 after denosumab [2].  We report an unusually prolonged (almost 5 months) and poor response to treatment for hypocalcaemia following administration of 60 mg denosumab in a patient with CKD5. A 64-year-old female presented with osteoporosis and a femoral fragility fracture. Past medical history included CKD5 secondary to IgA nephropathy, 11 years of haemodialysis treatment, tertiary hyperparathyroidism and treated non-metastatic breast cancer. Medication included cinacalcet 60 mg daily, alfacalcidol 1 µg daily and letrozole (all taken long term in an unchanged dose). Biochemistry was as follows: ACa 2.45 mmol/L (9.8 mg/dL) (always within the normal range in the last 12 months), eGFR 9 mL/min/1.73 m2 and PTH 54.8 pmol/L (517 pg/dL). Following denosumab, ACa decreased to 1.97 mmol/L (7.88 mg/dL) at Day 30 and remained low for the following 3 months [2.04 mmol/L (8.16 mg/dL) at Day 91]. Similarly to Torregrosa's case, iPTH rose from 54.8 to 108 pmol/L (1.02 ng/dL) at the nadir of hypocalcaemia. Throughout this period, medication and dialysis settings were not changed and the patient had adequate dietary calcium intake. On Day 91, alfacalcidol was increased to 4 µg daily and cinacalcet was reduced to 30 mg daily, but this resulted in only a modest improvement in ACa to 2.26 mmol/L (9.04 mg/dL) at Day 139.  From our two cases and from Torregrosa's case, it appears that hypocalcaemia following denosumab can be more prolonged than previously thought even with adequate calcium and vitamin D supplementation. We hypothesized that in our two cases, the prolonged hypocalcaemia was due to the combined effect of denosumab and cinacalcet, both of which are known to lower serum calcium levels. However, Torregrosa's case points out that there might be other possible causes and there is scope for further studies.

clinical kidney journal

Prolonged hypocalcaemia following a single dose of 60 mg denosumab in two patients with CKD 4/5 on cinacalcet treatment for tertiary hyperparathyroidism