Discontinuation of palopegteriparatide in chronic hypoparathyroidism without rebound hypocalcemia

Abstract

A woman with chronic hypoparathyroidism following total thyroidectomy was treated with palopegteriparatide, a long-acting parathyroid hormone replacement therapy, for more than 4 years. Previous reports have suggested that stopping parathyroid hormone therapy may lead to severe rebound hypocalcemia and increased calcium requirements due to a “hungry bone syndrome.” After discontinuation of palopegteriparatide, the patient resumed conventional treatment with calcium supplements and active vitamin D at doses similar to those used before starting hormone therapy; the alfacalcidol dose was subsequently reduced because of high-normal calcium levels. She remained clinically stable without symptoms of hypocalcemia or hungry bone syndrome, and repeated blood tests showed normal calcium levels throughout follow-up. This case suggests that discontinuation of palopegteriparatide may not necessarily result in major disturbances in calcium balance or increased treatment requirements. The findings provide reassurance that some patients with chronic hypoparathyroidism can transition safely back to conventional therapy after long-term palopegteriparatide treatment.

Introduction

Parathyroid hormone (PTH) is a calcium-mobilizing hormone. It increases plasma calcium levels by increasing bone resorption, decreasing renal calcium losses, and increasing the activity of the renal 1α-hydroxylase by which the intestinal absorption of calcium is increased. In hypoparathyroidism (HypoPT), PTH is lacking, or levels are too low to maintain normocalcemia. It most often occurs as a complication of surgery to the anterior part of the neck (eg, total thyroidectomy) with damage to the parathyroid glands.

Conventional therapy for HypoPT consists of an active vitamin D analog (calcitriol or alfacalcidol) in combination with supplements of elemental calcium with the aim of achieving normocalcemia. Because a lack of PTH is often associated with hypercalciuria and because stimulation of possible residual parathyroid function may be beneficial, it is recommended to aim for plasma calcium levels in the lower half of (or slightly below) the reference range (so-called “target range”) [1]. However, despite conventional treatment, plasma calcium levels often fluctuate unpredictably, causing intermittent symptomatic hypo- or hypercalcemia [2]. Furthermore, several epidemiological studies have demonstrated an increased risk of complications in patients with HypoPT treated with conventional therapy [1]. Due to these limitations of conventional therapy, studies over recent decades have investigated the feasibility of replacement therapy with “the missing hormone.” In 2013, the REPLACE study, a randomized, double-blind study of recombinant human PTH (1-84) (rhPTH(1-84)) in HypoPT, was published [3]. The study showed a greater reduction in the need for treatment with active vitamin D and calcium supplements, and the drug was subsequently marketed in the European Union and several countries outside the European Union (including the United States). Additional open-label studies have shown similar effects of treatment with synthetic PTH(1-34), which can also increase plasma calcium levels in HypoPT as expected, as both rhPTH(1-84) and PTH(1-34) contain the physiologically active (N-terminal) part of the PTH molecule [4]. However, despite increasing plasma calcium levels in HypoPT, treatment with rhPTH(1-84) and PTH(1-34) causes fluctuations in plasma calcium levels when administered once or twice daily [4, 5]. This is probably due to the relatively short duration of action of PTH when administered by subcutaneous injection. Furthermore, concerns have been raised regarding the effects on calcium homeostasis when PTH treatment for HypoPT is discontinued, as studies have suggested a rebound disturbance in calcium homeostasis, potentially resulting in hungry bone syndrome if treatment of HypoPT is changed from rhPTH(1-84) to PTH(1-34) or after discontinuation of PTH(1-34) [6, 7]. This may be related to the very low bone turnover associated with HypoPT, which increases during PTH treatment and may decrease after treatment discontinuation. Recently, palopegteriparatide (also known as TransCon PTH) has been approved by the US Food and Drug Administration, the European Commission, and regulatory authorities in other countries for the treatment of adults with chronic HypoPT, administered as a once-daily subcutaneous injection. It is a prodrug consisting of PTH(1-34) bound to an inert methoxypolyethylene glycol carrier via a TransCon linker. Upon exposure to physiological pH and temperature, autocleavage of the linker occurs and active PTH is released in a sustained manner, leading to PTH levels within the physiological range over a 24-hour period. Phase 2 and phase 3 trials have demonstrated superior effects of this treatment compared with conventional therapy [8, 9]. As no data are available on the effects of treatment in patients with severely impaired renal function (estimated glomerular filtration rate <30 mL/min [SI: <0.50 mL/s]) or in women who are pregnant or breastfeeding, treatment may have to be reconsidered in these special circumstances. Data on the effects of discontinuing palopegteriparatide are still very limited. Recently, a case report [10] described symptomatic hypocalcemia occurring ∼1 month after discontinuation of palopegteriparatide therapy in a patient with postsurgical HypoPT, suggesting that a rebound effect may occur in some patients.

Case presentation

A previously healthy woman underwent total thyroidectomy in 2016 (25 years old) due to multinodular nontoxic goiter causing hoarseness and a feeling of neck tightness. In addition to hypothyroidism, the patient developed HypoPT following the surgery.

Diagnostic assessment

Medical records were reviewed with a focus on plasma ionized calcium (P-Ca²⁺; reference range, 4.7-5.3 mg/dL [SI: 1.18-1.32 mmol/L]), intact PTH (reference range, 15-65 pg/mL [SI: 1.6-6.9 pmol/L]), and 25-hydroxyvitamin D, with a target level >20 ng/mL (SI: >50 nmol/L). All analyses were performed by standard laboratory methods at our department of biochemistry, Aarhus University Hospital, Denmark. The P-Ca²⁺ levels were adjusted to pH 7.4. Intact PTH was measured using a second-generation assay and 25-hydroxyvitamin D levels were measured by isotope-dilution liquid chromatography–tandem mass spectrometry.

Treatment

After being diagnosed with HypoPT, the patient was initially treated with alfacalcidol (a daily dose of 1.5-2.0 μg) and calcium supplements (on average 800 mg/day). In February 2020, she agreed to participate in the phase 2 clinical study of palopegteriparatide. Shortly thereafter, alfacalcidol and calcium supplements were discontinued, and after initial dose adjustments, the patient was treated with 12 μg of palopegteriparatide administered subcutaneously once daily. In February 2021, the dose was increased to 15 μg/day (notably, palopegteriparatide can only be dosed in intervals of 3 μg), which she continued until treatment discontinuation while maintaining stable plasma calcium levels. In February 2024, treatment was discontinued because she was moving to another country.

Outcome and follow-up

Changes in P-Ca²⁺ since the patient was diagnosed with HypoPT are shown in Fig. 1. The day after discontinuing palopegteriparatide, she started treatment with alfacalcidol 1.5 μg/day and calcium supplements at 400 mg twice daily, at doses similar to those used before initiation of palopegteriparatide. One week after discontinuation, P-Ca²⁺ remained in the target range (lower part of the reference range or slightly below), and the same doses of alfacalcidol and calcium supplements were continued. Two weeks after discontinuation, P-Ca²⁺ had increased to a high-normal level, and the alfacalcidol dose was reduced to 0.5 μg twice daily. Three weeks after discontinuation, plasma ionized calcium was within the target range, and she was feeling well. The last available plasma ionized calcium measurement was obtained on 15 March 2024, 3 weeks after discontinuation of palopegteriparatide. Shortly after the diagnosis of HypoPT and on 2 occasions after discontinuation of palopegteriparatide, intact PTH was measurable but remained below the lower limit of the reference interval, consistent with persistent HypoPT. Vitamin D status remained adequate (P-25OHD >20 ng/mL [SI: >50 nmol/L]) throughout the course of her disease.

Figure 1.

Plasma ionized calcium concentrations before, during, and after palopegteriparatide treatment. The shaded area indicates the reference range for plasma ionized calcium (1.18-1.32 mmol/L [4.7-5.3 mg/dL]). The vertical arrows indicate initiation and discontinuation of palopegteriparatide.

Discussion

The current case suggests that stopping palopegteriparatide after more than 4 years of treatment was not associated with marked disturbances in calcium homeostasis. Recently, however, a case report described the development of symptomatic hypocalcemia ∼1 month after discontinuation of palopegteriparatide therapy in a patient with postsurgical HypoPT, suggesting that a rebound effect may occur in some patients [10]. In contrast, our patient remained normocalcemic after discontinuation and could initially resume conventional therapy at doses similar to those used prior to initiation of palopegteriparatide. However, the alfacalcidol dose was subsequently reduced because of high-normal calcium levels. This finding contrasts with reports of hypocalcemia and increased requirements for calcium and active vitamin D following discontinuation of short-acting PTH replacement therapy [6, 7]. The rebound effect has been attributed to changes in bone remodeling, as chronic HypoPT is characterized by low bone turnover, whereas PTH replacement increases bone turnover. Treatment with palopegteriparatide has also been shown to increase bone turnover [8, 9]. However, our patient did not develop clinically apparent hypocalcemia after discontinuation. Importantly, palopegteriparatide is a prodrug of PTH(1-34) with an apparent half-life of ∼60 hours for the released PTH, compared with plasma half-lives of a few hours for synthetic PTH(1-34) and rhPTH(1-84). Thus, the physiological effects of palopegteriparatide may decline more gradually after discontinuation than those of short-acting PTH preparations.

A limitation of the generalizability of our findings is the relatively mild severity of HypoPT in this case. Only low doses were needed to achieve normocalcemia, and intact PTH was measurable in plasma, although below the lower limit of the reference interval. This suggests that some residual parathyroid function may have been present. Residual endogenous PTH secretion may have contributed to the favorable outcome by providing some PTH-mediated regulation of calcium homeostasis after discontinuation of palopegteriparatide, thereby reducing the risk of hypocalcemia. Thus, the absence of a rebound effect in this patient may not be representative of patients with complete absence of endogenous PTH secretion or more severe HypoPT. Bone turnover markers and urinary calcium measurements were not available around treatment discontinuation. Therefore, we cannot directly assess whether changes in bone turnover or renal calcium handling contributed to the observed calcium response. Further studies should evaluate the effects of treatment discontinuation in patients with more severe HypoPT and higher requirements for palopegteriparatide.

In conclusion, discontinuation of palopegteriparatide may not necessarily lead to clinically significant disturbances in calcium homeostasis, although hypocalcemia may occur in some patients. Further data are needed to determine whether these findings apply to patients with more severe HypoPT.

Learning points

• Discontinuation of palopegteriparatide after long-term treatment did not result in clinically significant hypocalcemia in this patient with chronic HypoPT.

• Conventional therapy with calcium supplements and active vitamin D could initially be restarted at doses similar to those used before initiation of palopegteriparatide.

• No clinical signs of rebound hypocalcemia or hungry bone syndrome were observed after stopping palopegteriparatide.

• The prolonged release and longer duration of action of palopegteriparatide may reduce the risk of rebound disturbances in calcium homeostasis compared with shorter-acting PTH therapies.

• Careful biochemical monitoring remains important when discontinuing PTH replacement therapy, as rebound hypocalcemia may still occur in some patients.

Contributors

L.R. and L.U. contributed to the conception and design of the case report, interpretation of the clinical data, and preparation and revision of the manuscript. Both authors approved the final version of the manuscript.

Abbreviations

HypoPT

hypoparathyroidism

P-Ca²⁺

plasma ionized calcium

PTH

parathyroid hormone

rhPTH(1-84)

recombinant human PTH (1-84)

Funding

No public or commercial funding.

Disclosures

The authors declare no financial conflicts of interest. L.R. and L.U. have been investigators in clinical trials of palopegteriparatide.

Informed patient consent for publication

Signed informed consent obtained directly from the patient.

Data availability

The data supporting the findings of this case report are available from the corresponding author upon reasonable request.