Palopegteriparatide: A Once-Daily Parathyroid Hormone Replacement for Hypoparathyroidism

Table of Contents

1. Hypoparathyroidism in Brief
2. Why Calcium and Active Vitamin D Alone Fall Short
3. A Hormone Fragment on a Slow-Release Carrier
4. How the Label Starts and Adjusts the Dose
5. What the 26-Week PaTHway Trial Found
6. Results at One, Two and 3.5 Years
7. Warnings on the US Label
8. Side Effects Recorded in the Trial
9. Missed Doses, Interruptions and Stopping
10. What Is Not Yet Known
11. Key Research Papers
12. Connections
13. Featured Videos

Hypoparathyroidism in Brief

Four small parathyroid glands in the neck make parathyroid hormone. The hormone keeps blood calcium steady in three ways: it releases calcium from bone, it tells the kidneys to hold on to calcium and let phosphate go, and it switches on the kidney step that turns vitamin D into its active form, which in turn raises calcium absorption from food. The US label for palopegteriparatide describes these same actions.

In hypoparathyroidism there is too little of the hormone. Blood calcium falls, phosphate rises, and the kidneys lose more calcium into the urine than normal. The most common cause is damage to the glands during neck surgery: in the PaTHway trial, 85% of the 82 adults had hypoparathyroidism acquired from neck surgery, and the rest had idiopathic, autoimmune or genetic forms. Low calcium causes tingling, muscle cramps and, when severe, seizures. The Hypocalcemia page describes the symptoms, and the calcium control animation shows the hormone loop at work.

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Why Calcium and Active Vitamin D Alone Fall Short

For decades the standard treatment, called conventional therapy, has been calcium tablets plus an active form of vitamin D such as calcitriol. This raises blood calcium but does not replace the hormone. The 26-week PaTHway report puts it plainly: conventional therapy aims to relieve low calcium “but fails to restore normal parathyroid hormone (PTH) physiology.”

The gap matters most in the kidneys. Without parathyroid hormone, the kidneys cannot hold back calcium, so much of the swallowed calcium passes into the urine. Two long-running studies measured the result:

• Boston, 120 patients (1988–2009). Of those who had a 24-hour urine calcium test, 38% had at least one result over 300 mg a day. Of those who had kidney imaging, 31% had calcium deposits in the kidneys, and 52% of those who had head imaging had calcium deposits in the basal ganglia of the brain. Rates of chronic kidney disease stage 3 or worse were 2 to 17 times higher than expected for age. The authors concluded that “renal abnormalities are particularly common.”
• Denmark, 688 patients after neck surgery. Compared with matched people from the general population, people with post-surgical hypoparathyroidism had a higher risk of kidney complications (hazard ratio 3.67) and of hospital stays for seizures (hazard ratio 3.82). The same study found no increased risk of heart rhythm problems, heart disease or death.

The 2022 Second International Workshop guideline lists the complications linked with hypoparathyroidism: kidney calcium deposits and stones, reduced kidney function, cataracts, seizures, heart rhythm problems, ischemic heart disease, depression and a higher risk of infection. Its panel suggests conventional therapy as first-line treatment (a weak recommendation based on low-quality evidence) and considers parathyroid hormone when conventional therapy is unsatisfactory. Palopegteriparatide was developed for that second step. The Kidney Stones page covers stones more broadly.

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A Hormone Fragment on a Slow-Release Carrier

Natural parathyroid hormone is a chain of 84 amino acids. The working part is the first 34 of them, a fragment sold on its own for many years as teriparatide, an osteoporosis drug described on the osteoporosis drugs page.

Palopegteriparatide is that same 34-amino-acid fragment attached, through a linker, to a large inert carrier made of polyethylene glycol (40 kilodaltons, two branches of 20). The label calls it a prodrug: in the body the linker breaks on its own and slowly frees the active fragment. The aim is a steady level of hormone through the whole day instead of a short spike after each injection.

• Half-life. The label gives the apparent half-life of the released hormone as about 60 hours. The first-in-human trial in healthy adults also measured an effective half-life of about 60 hours and described an “infusion-like” profile.
• Peak and steady state. The released hormone peaks at a median of 4 hours after the injection (range 4 to 8 hours), and steady state is reached after 7 days of daily doses, according to the label.
• Strength. Each millilitre contains 3,456 micrograms of palopegteriparatide, which equals 300 micrograms of teriparatide. Doses on the label are written as micrograms of the active fragment.
• Kidney function. In a dedicated study, mild, moderate and severe kidney impairment did not change total hormone exposure in a clinically significant way; the label lists no dose change for an estimated glomerular filtration rate (a measure of kidney filtering) of 15 or above. It also states that no studies were done in people with hypoparathyroidism who have severe kidney impairment.

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How the Label Starts and Adjusts the Dose

The dose is set person by person, guided by blood calcium. The US prescribing information describes this scheme:

• Before starting. Within two weeks before the first dose, the label calls for a normal 25-hydroxy vitamin D level and an albumin-corrected blood calcium of at least 7.8 mg/dL. The titration scheme was only tested in adults who first reached that calcium level on calcium and active vitamin D.
• Starting dose. 18 micrograms once daily, injected under the skin of the abdomen or front of the thigh, with the site rotated daily. The trial gave the same 18-microgram starting dose.
• Cutting back the old pills. On the first day, the label’s table cuts calcitriol by at least half or stops it, depending on blood calcium and the current calcitriol dose, and reduces or stops calcium tablets in people not taking active vitamin D. Calcium enough to meet dietary needs (600 mg a day of elemental calcium or less) may continue.
• Steps. The dose moves up or down in 3-microgram steps, no more often than every 7 days for an increase and every 3 days for a decrease. The labelled range is 6 to 30 micrograms once daily, and 30 micrograms is the maximum.
• Blood tests. Calcium is measured 7 to 10 days after the first dose and after any change in palopegteriparatide, active vitamin D or calcium, and at least every 4 to 6 weeks once the maintenance dose is reached.
• Very high calcium. If albumin-corrected calcium is 12 mg/dL or higher, the label withholds the drug for 2 to 3 days and rechecks.
• One injection a day. The label states that using two injections to make up one daily dose increases the variability of the delivered dose and can cause unintended high or low calcium.

The goal written into the label is normal blood calcium without active vitamin D and without therapeutic calcium doses (more than 600 mg a day of elemental calcium). The label also notes that some people need a higher dose over time to keep the same effect. The Serum Calcium Test page explains albumin-corrected calcium.

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What the 26-Week PaTHway Trial Found

Before the main trial, a phase 2 trial called PaTH Forward enrolled 59 adults. By week 26, 91% of those on the drug no longer needed active vitamin D and took 500 mg of calcium a day or less, and average 24-hour urine calcium fell from 415 mg to 178 mg (in the 44 people measured), while blood calcium stayed normal.

The phase 3 PaTHway trial then randomized 84 adults (82 received study drug) 3 to 1 to once-daily palopegteriparatide, started at 18 micrograms, or a placebo injection, both alongside conventional therapy. Doses were adjusted by a set algorithm guided by blood calcium. The main goal combined three things at week 26: normal albumin-adjusted blood calcium (8.3 to 10.6 mg/dL), no active vitamin D and 600 mg of calcium a day or less, and no dose increase in the last 4 weeks.

• Main goal (published report). 79% (48 of 61) on the drug met it, against 5% (1 of 21) on placebo.
• Main goal (US label). The label uses a stricter version that also requires no missing data and a dose of 30 micrograms or less throughout. By that measure, 68.9% (42 of 61) on the drug met it, against 4.8% (1 of 21) on placebo.
• Free of the old pills. 93% (57 of 61) on the drug no longer needed conventional therapy. In the label’s table, 95.1% were free of active vitamin D and 86.9% were free of therapeutic calcium doses.
• Urine calcium. Treatment brought average 24-hour urine calcium into the normal range.
• Quality of life. Scores on a hypoparathyroidism symptom and impact scale improved more than on placebo, as did the physical functioning score of a general health survey.

A smaller single-arm trial in Japan, PaTHway Japan, enrolled 13 adults, most with idiopathic hypoparathyroidism. 92% (12 of 13) met the combined goal at week 26, and 92% (11 of 12) at week 52. The trial had no placebo group.

The PaTHway trial was funded by the manufacturer, and several authors of each report are its employees, as the papers’ author lists state.

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Results at One, Two and 3.5 Years

After 26 weeks, everyone in PaTHway, including those first given placebo, received palopegteriparatide in an open-label extension (no placebo, and everyone knows what they are taking) planned for 156 more weeks.

• Week 52. 78 of 82 adults completed the first year. 81% (63 of 78) had normal calcium while free of conventional therapy, 95% (74 of 78) were free of conventional therapy, and none needed active vitamin D. Average 24-hour urine calcium fell from 376 mg a day at the start to 195 mg a day. Bone mineral density scores moved down toward the levels expected for age and sex. None of the side effects led anyone to leave the trial during the extension.
• Kidney filtering at one year. In a later analysis of the same data (a post hoc analysis), the estimated glomerular filtration rate rose by an average of 9.3 mL/min/1.73 m², and 43% gained 10 or more. In people who started below 60, the average rise was 11.5. One kidney stone was reported in the placebo group during the blinded period and none on the drug through week 52.
• Week 104. 76 of 82 (93%) were still in the trial. Of those, 82% had normal calcium and 97% were free of conventional therapy. The average kidney filtering rate was 9.0 above the starting value. Average 24-hour urine calcium was 158.8 mg, and no treatment-related kidney stones were reported. This analysis was also post hoc.
• Week 182 (3.5 years). 73 adults completed. 96% (70 of 73) were free of therapeutic calcium doses, 100% (73 of 73) were free of active vitamin D, and 89% (65 of 73) had normal blood calcium. Markers of bone turnover rose and then stayed above their starting levels; bone density scores trended toward age- and sex-matched norms while staying above zero. The early fall in urine calcium, the gain in kidney filtering and the better quality-of-life scores held through week 182. Most side effects were mild to moderate.

The US label reports the same extension with a stricter yardstick. Counting everyone first randomized to the drug and applying the trial’s full endpoint, including “no dose increase,” 68.9% (42 of 61) met it at week 26 and 39.3% (24 of 61) at both week 52 and week 78. When dose increases were allowed, 64% (39 of 61) at week 52 and 66% (40 of 61) at week 78 kept normal calcium without active vitamin D or therapeutic calcium. The difference shows that many people needed their dose raised over time.

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Warnings on the US Label

The current US prescribing information (revised August 2026) lists these warnings and precautions:

• Serious high calcium. Serious events of high blood calcium needing a hospital stay have been reported. The label states the risk is highest when starting or raising the dose but may occur at any time. One trial participant who accidentally injected about three times the prescribed dose for more than 7 days reached an albumin-corrected calcium of 16.1 mg/dL and was hospitalized.
• Serious low calcium. Serious events of low blood calcium have been seen with parathyroid hormone products, including this one. The label states the risk is highest when the drug is stopped abruptly, but may occur at any time, even on a stable dose.
• Two injections for one dose. Splitting one daily dose across two injections increases variability and can cause unintended high or low calcium.
• Possible risk of osteosarcoma. Osteosarcoma, a bone cancer, increased in rats given parathyroid hormone analogs including teriparatide, depending on dose and duration. Osteosarcoma has been reported in people after teriparatide went on sale, though observational studies in humans have not found an increased risk, and data beyond 2 years of teriparatide use are limited. The label states palopegteriparatide is not recommended in people at increased risk: those with open growth plates, Paget’s disease of bone or other metabolic bone diseases, unexplained high alkaline phosphatase, bone metastases or past bone cancer, past radiation therapy involving the skeleton, or inherited conditions that predispose to osteosarcoma. See the Osteosarcoma page.
• Low blood pressure on standing (orthostatic hypotension). Signs may include dizziness, a racing or pounding heart, near-fainting or fainting. The label states that early doses are given while the person can sit or lie down, and that symptoms can be managed by dosing at bedtime while reclining.
• Digoxin. Because the drug raises calcium, high calcium can predispose to digoxin toxicity, and low calcium may reduce digoxin’s effect; the label calls for routine calcium and digoxin levels when both are used. Other drugs that affect calcium may change the response, and the label calls for more frequent calcium checks around them.
• Allergic reactions. Anaphylaxis, angioedema (swelling of the face, lips or throat) and hives have been reported after approval. A history of severe allergy to the drug or its inactive ingredients is the label’s one contraindication. Hospitals treat throat swelling and trouble breathing as emergencies.

The label describes daily watching for clinical signs and symptoms of both low and high calcium. The Hypoparathyroidism page lists the signs of low calcium.

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Side Effects Recorded in the Trial

The label’s table lists reactions seen in at least 5% of people on the drug, and at least 2 percentage points more often than placebo, during the 26-week blinded period (61 on drug, 21 on placebo):

• Injection site reactions (bruising, redness, rash): 39% on the drug, 5% on placebo.
• Vasodilatory signs and symptoms (drop in blood pressure on standing, dizziness, palpitations, near-fainting, fainting, vertigo): 28% on the drug, 0% on placebo.
• Headache: 21% versus 10%.
• Diarrhea: 10% versus 5%.
• Back pain: 8% versus 0%.
• High blood calcium: 8% versus 0%.
• Throat pain: 7% versus 0%.

Looking at blood tests rather than reported symptoms, 54.1% of people on the drug had at least one albumin-corrected calcium above 10.6 mg/dL after starting, against 9.5% on placebo, and 13.1% had at least one value above 12 mg/dL, against none on placebo. Symptomatic high calcium occurred in 8%, all within the first 3 months.

The published 26-week report counted any adverse event, related or not: 82% (50 of 61) on the drug and 100% (21 of 21) on placebo, most mild (46%) or moderate (46%), with no withdrawals caused by the study drug. Across clinical studies, the label reports that 1 of 139 people developed low-level antibodies against the hormone and 7 of 139 developed antibodies against the polyethylene glycol carrier; 3 people had carrier antibodies before treatment that briefly affected drug levels and calcium, and calcium was brought back under control by dose adjustment.

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Missed Doses, Interruptions and Stopping

The label gives these rules for gaps in treatment:

• A dose missed by less than 12 hours is taken as soon as possible; a dose missed by more than 12 hours is skipped, and the next dose is taken as scheduled.
• After a gap of 3 days or more, the label calls for checking for low-calcium signs and considering a calcium test; calcium and active vitamin D may be restarted or raised, and the drug is resumed at the previous dose with a calcium test 7 to 10 days later.
• The label states the risk of serious low calcium is highest when the drug is stopped abruptly.

A 2025 case report shows what that can look like. A 62-year-old man with hypoparathyroidism after neck surgery stopped palopegteriparatide after three years. He restarted calcium at 25% less than his pre-treatment dose and calcitriol at double his pre-treatment dose. One week later his calcium and phosphorus were stable. One month later he had symptoms of low calcium, with an albumin-adjusted calcium of 7.4 mg/dL and phosphorus of 5.1 mg/dL, and his oral calcium was increased. Six months later his levels were stable on calcium and calcitriol doses lower than before he had started the drug. The authors describe a “potential rebound effect” and note that information on stopping the drug is limited. It is one case: it shows that low calcium can appear weeks rather than days after stopping, but it cannot say how often this happens.

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What Is Not Yet Known

• Hard outcomes. The trials measured blood and urine calcium, kidney filtering, bone density and quality-of-life scores. None of the reports cited here measured kidney stones, kidney failure, fractures, cataracts or survival as main outcomes over many years.
• Kidney benefit. The rises in kidney filtering come from post hoc analyses of a trial whose comparison with placebo ended at week 26; the authors call for further study.
• Cancer risk over decades. The label states that long-term animal studies of the drug’s cancer-causing potential have not been done, and the osteosarcoma warning rests on rat studies of related drugs.
• Bone over the long run. In a 26-week study in rats, the drug caused net bone loss at some doses and net bone gain at higher doses, according to the label. In people, bone turnover markers stayed above their starting levels through 3.5 years; what that means for fractures is unknown.
• Who was studied. The label states the drug was not studied for sudden hypoparathyroidism straight after surgery, its safety and effectiveness are not established in children, there were too few people aged 65 or older to tell whether they respond differently, pregnancy data are insufficient to identify a drug-related risk, and there are no data on breast milk. In PaTHway, 93% of participants were white.
• Stopping the drug. Apart from the label’s general statement and one case report, there is little published on how to come off the drug.
• Comparison with other hormone treatments. None of the studies cited here compares palopegteriparatide directly with full-length recombinant parathyroid hormone (1-84) or with teriparatide given on its own; the trials compared it with placebo on top of conventional therapy.

Decisions about starting, adjusting or stopping a hormone treatment belong with the clinician managing it. The Parathyroid Hormone Test page explains how the hormone is measured.

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Key Research Papers

1. Khan AA, Rubin MR, Schwarz P, Vokes T, Shoback DM, Gagnon C, et al. Efficacy and Safety of Parathyroid Hormone Replacement With TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial. J Bone Miner Res. 2023;38(1):14-25. PubMed PMID: 36271471
2. Clarke BL, Khan AA, Rubin MR, Schwarz P, Vokes T, Shoback DM, et al. Efficacy and Safety of TransCon PTH in Adults With Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial. J Clin Endocrinol Metab. 2025;110(4):951-960. PubMed PMID: 39376010
3. Khan AA, Clarke BL, Rubin MR, Schwarz P, Shoback DM, Gagnon C, et al. Palopegteriparatide in Adults With Hypoparathyroidism: 3.5-Year Results From the Phase 3 PaTHway Trial. J Clin Endocrinol Metab. 2026 (online ahead of print):dgag440. PubMed PMID: 42935168
4. Rejnmark L, Gosmanova EO, Khan AA, Makita N, Imanishi Y, Takeuchi Y, et al. Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial. Adv Ther. 2024;41(6):2500-2518. PubMed PMID: 38691316
5. Rejnmark L, Gosmanova EO, Khan AA, Sprague S, Shoback DM, Kohlmeier L, et al. Sustained improvement in renal function with palopegteriparatide in adults with chronic hypoparathyroidism: 2-year results from the phase 3 PaTHway-trial. J Bone Miner Res. 2026;41(9):922-933. PubMed PMID: 42166177
6. Khan AA, Rejnmark L, Rubin M, Schwarz P, Vokes T, Clarke B, et al. PaTH Forward: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of TransCon PTH in Adult Hypoparathyroidism. J Clin Endocrinol Metab. 2022;107(1):e372-e385. PubMed PMID: 34347093
7. Karpf DB, Pihl S, Mourya S, Mortensen E, Kovoor E, Markova D, Leff JA. A Randomized Double-Blind Placebo-Controlled First-In-Human Phase 1 Trial of TransCon PTH in Healthy Adults. J Bone Miner Res. 2020;35(8):1430-1440. PubMed PMID: 32212275
8. Ashida K, Nomura M, Makita N, Imanishi Y, Kanamoto N, Zhao C, et al. Palopegteriparatide in Japanese adults with hypoparathyroidism: 52-week results from the phase 3 PaTHway Japan trial. Endocr J. 2026;73(2):275-289. PubMed PMID: 41260697
9. Naciu AM, Sargentini E, Tsourdi E, Palermo A, Tabacco G. Rebound Effect Following the Discontinuation of Palopegteriparatide. Calcif Tissue Int. 2025;116(1):121. PubMed PMID: 40956444
10. Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab. 2012;97(12):4507-14. PubMed PMID: 23043192
11. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. J Bone Miner Res. 2013;28(11):2277-85. PubMed PMID: 23661265
12. Khan AA, Bilezikian JP, Brandi ML, Clarke BL, Gittoes NJ, Pasieka JL, et al. Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop. J Bone Miner Res. 2022;37(12):2568-2585. PubMed PMID: 36054621
13. US National Library of Medicine, DailyMed. Palopegteriparatide injection, for subcutaneous use — full prescribing information (revised 8/2026). DailyMed: palopegteriparatide

PubMed Topic Searches

1. PubMed: palopegteriparatide
2. PubMed: parathyroid hormone replacement in hypoparathyroidism
3. PubMed: kidney complications of conventional therapy
4. PubMed: urine calcium in hypoparathyroidism

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Connections

• Drugs — the parent section for every drug page
• Hypoparathyroidism — the disease this drug treats
• Hypocalcemia (Low Calcium) — the problem the hormone corrects
• Serum Calcium Test — the test that guides every dose change
• Parathyroid Hormone Test — how the missing hormone is measured
• Calcium Control Animation — the hormone loop shown step by step
• Denosumab, Romosozumab and Teriparatide — the same hormone fragment used for osteoporosis
• Kidney Stones — a complication of high urine calcium
• Osteosarcoma — the bone cancer named in the label warning

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