Long-Term Safety and Efficacy of Recombinant Human Parathyroid Hormone (1-84) in Adults With Chronic Hypoparathyroidism

Abstract

Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled.

Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment.

Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices.

Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites.

Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.

Keywords: active vitamin D; bone turnover; calcium; hypoparathyroidism; mineral homeostasis; recombinant human parathyroid hormone (1-84).

Figure 1.

Flow diagram showing patients enrolled in the study. *One patient dropped out during optimization in REPLACE but met inclusion and exclusion criteria for RACE. ^†Among enrolled patients, 48 of 49 had chronic hypoparathyroidism that was not adequately controlled at baseline for RACE based on biochemical measurements. ^‡One patient discontinued at around month 72; however, the patient's last study visit fell within the analysis visit window for the month 72 visit, and the patient was therefore deemed to have completed the study. ITT = intent to treat.

Figure 2.

Change over time in (A) albumin-adjusted serum calcium, (B) 24-hour urinary calcium excretion corrected for body weight, (C) serum phosphorus, and (D) 24-hour urinary phosphorus excretion for the ITT and completer populations. Completers are patients who completed 72 months of treatment. ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

Figure 3.

Change over time in serum creatinine for the ITT and completer populations. Completers are patients who completed 72 months of treatment. ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

Figure 4.

Percentage change from baseline in dose of oral calcium and calcitriol over time for the ITT and completer populations. Completers are patients who completed 72 months of treatment. ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84). *n = 38 for the overall study (ITT) population.

Figure 5.

Change over time in serum 25(OH)D for the ITT and completer populations. Completers are patients who completed 72 months of treatment. ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

Figure 6.

Change over time in serum bone turnover markers (A) BAP, (B) P1NP, and (C) CTX for the ITT and completer populations. Completers are patients who completed 72 months of treatment. BAP, bone alkaline phosphatase; CTX, cross-linked C-telopeptide of type 1 collagen; ITT, intent to treat; P1NP, aminoterminal propeptide of type 1 collagen; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

Figure 6.

Change over time in serum bone turnover markers (A) BAP, (B) P1NP, and (C) CTX for the ITT and completer populations. Completers are patients who completed 72 months of treatment. BAP, bone alkaline phosphatase; CTX, cross-linked C-telopeptide of type 1 collagen; ITT, intent to treat; P1NP, aminoterminal propeptide of type 1 collagen; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

Figure 7.

Change from baseline in z score over time. Filled symbols with solid lines represent the ITT population, and open symbols with dashed lines represent the completer population. The table below the graph reports percentage change from baseline in BMD at month 72 and z score at baseline and month 72. Completers are patients who completed 72 months of treatment. BMD, bone mineral density; ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84). *Excludes results from 6 patients who were assessed by different dual-energy x-ray absorptiometry machines at baseline vs month 72 (Hologic and GE Lunar instruments, respectively).