Parathyroid hormone (1-84)
rhPTH(1-84), recombinant human parathyroid hormone (1-84), full-length parathyroid hormone, parathormone, PTH(1-84)
Parathyroid hormone (1-84) is the complete, full-length human hormone made by recombinant DNA technology, rather than the 34-residue fragment used in teriparatide. It was licensed first in Europe for postmenopausal osteoporosis and later, on both sides of the Atlantic, as hormone replacement for chronic hypoparathyroidism. Manufacturing was discontinued at the end of 2024, so despite genuinely strong trial evidence the product is no longer available.
Mechanism
PTH(1-84) is identical in sequence to the hormone secreted by the parathyroid chief cells in response to a fall in ionised calcium sensed by the calcium-sensing receptor. It acts at the type 1 parathyroid hormone receptor (PTH1R), a class B G-protein-coupled receptor. The receptor-activating pharmacophore lies in the N-terminal 1-34 region, so the 1-84 and 1-34 forms share their principal signalling: Gs-coupled cyclic AMP and protein kinase A, with Gq/phospholipase C as a secondary route. In the kidney this increases distal tubular calcium reabsorption, inhibits sodium-phosphate cotransport in the proximal tubule to promote phosphaturia, and induces 1-alpha-hydroxylase so that 25-hydroxyvitamin D is converted to the active 1,25-dihydroxy form, which in turn raises intestinal calcium absorption. In bone, intermittent exposure recruits and preserves osteoblasts and suppresses osteocyte sclerostin; continuous exposure raises RANKL and drives resorption.
The 50 C-terminal residues are not inert. They are the site of proteolytic processing to C-terminal fragments that circulate at high concentration, and there is evidence for a distinct C-terminal PTH receptor with actions on osteocytes and chondrocytes that are not mediated through PTH1R, although its identity and physiological significance remain incompletely resolved. The practical consequence of full length is pharmacokinetic: a longer terminal half-life and a broader daily exposure profile than teriparatide. That is an advantage for hormone replacement in hypoparathyroidism, where the aim is to reproduce endogenous secretion, and arguably a disadvantage in osteoporosis, where the brief pulse that maximises the anabolic window is what is wanted.
What the research shows
In osteoporosis, the TOP trial randomised 2,532 postmenopausal women to PTH(1-84) 100 micrograms daily or placebo for 18 months. New or worsened vertebral fractures occurred in 1.4 per cent versus 3.4 per cent, a significant reduction, with greater gains in lumbar spine, total hip, femoral neck and trochanteric bone mineral density. The PaTH study examined combination and sequential strategies in 238 women and produced an instructive negative result: adding alendronate to PTH(1-84) blunted rather than augmented the anabolic bone density response, reinforcing the principle that antiresorptives and anabolics interfere with one another when given together. In hypoparathyroidism, the REPLACE trial randomised 134 adults to PTH(1-84) or placebo on a background of calcium and active vitamin D; 53 per cent of the treated group achieved the composite endpoint of at least a 50 per cent reduction in both oral calcium and active vitamin D while maintaining serum calcium, versus 2 per cent on placebo. Long-term open-label extension data over up to eight years showed sustained reductions in supplement burden.
The story since then is largely a regulatory and manufacturing one. The European osteoporosis product was authorised in 2006 and withdrawn from the market in 2014 for commercial rather than safety reasons. The hypoparathyroidism product was approved by the FDA in January 2015 and in the EU in April 2017. In September 2019 it was recalled in the US after rubber particulate was found to be shedding from cartridge septa. The manufacturer subsequently reported that reformulation and process changes had not resolved the particulate problem, and announced discontinuation of global manufacturing at the end of 2024, with remaining stock supplied until exhausted. Roughly 3,000 patients worldwide were affected. The therapeutic gap has since been addressed by a long-acting prodrug of PTH(1-34), palopegteriparatide, which is a different molecule and carries its own evidence base. It is worth noting for completeness that PTH(1-84) also carried the class osteosarcoma boxed warning derived from rodent data, and that this warning was a factor in its restricted positioning.
Evidence assessment
High-quality evidence
Two separate large randomised, placebo-controlled phase 3 programmes with fracture and hormone-replacement endpoints respectively, plus regulator-approved labelling in both the US and the EU. All four citations confirmed against PubMed. The tier reflects the quality of the trial evidence; the product is nonetheless no longer manufactured, which is a supply issue rather than an evidence issue.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial Preclinical only
New or worsened vertebral fractures occurred in 1.4 per cent on PTH(1-84) 100 micrograms daily versus 3.4 per cent on placebo, with significantly greater increases in lumbar spine, total hip, femoral neck and trochanteric bone mineral density.
Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study Preclinical only
53 per cent of patients receiving PTH(1-84) achieved at least a 50 per cent reduction in both oral calcium and active vitamin D while maintaining serum calcium, versus 2 per cent on placebo. This was the pivotal trial for the hypoparathyroidism indication.
The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis Preclinical only
A key negative result: concurrent alendronate blunted rather than enhanced the anabolic response to PTH(1-84), with trabecular bone density gains by quantitative CT largest in the PTH-alone group. Established the principle that antiresorptives interfere with concurrent anabolic therapy.
Long-term safety and efficacy of recombinant human parathyroid hormone (1-84) in adults with chronic hypoparathyroidism Preclinical only
Sustained reductions in oral calcium and active vitamin D requirements with maintained serum calcium over several years of continuous treatment, with no new safety signals attributable to the hormone itself. Being open-label and uncontrolled, it cannot separate drug effect from natural history or management changes.
Safety
The adverse effect profile is dominated by disturbances of calcium balance. Hypercalcaemia and hypocalcaemia both occur, the latter particularly if the dose is interrupted or stopped abruptly, when severe symptomatic hypocalcaemia and seizures have been reported. This is the basis for the requirement in hypoparathyroidism labelling that treatment is never withdrawn without immediate replacement of calcium and active vitamin D. Other commonly reported effects include paraesthesia, nausea, headache, hypercalciuria and injection-site reactions. Antibodies to PTH(1-84) develop in a proportion of treated patients; their clinical relevance has not been established. The product carried the class boxed warning for potential osteosarcoma based on lifetime rat carcinogenicity studies, and in the US was distributed only through a restricted programme. A separate and ultimately decisive safety problem was mechanical rather than pharmacological: rubber particulate shedding from the delivery cartridge septum, which triggered the 2019 US recall and, after unsuccessful attempts at reformulation, the 2024 discontinuation of manufacturing. This entry is educational and describes no dosing or administration procedures.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Available through the EU centralised authorisation from April 2017 for chronic hypoparathyroidism, and previously from 2006 for postmenopausal osteoporosis before that product was withdrawn from the market in 2014. Following the manufacturer's announcement, production ceased at the end of 2024 and supply was maintained only until existing stock was depleted. The product is not currently obtainable in the UK. |
| United States | FDA-approved January 2015 as an adjunct to calcium and vitamin D in adults with chronic hypoparathyroidism not well controlled on standard therapy, with a boxed warning for potential osteosarcoma and availability restricted through a risk evaluation and mitigation strategy. Recalled in September 2019 because of rubber particulate contamination of cartridges. Manufacturing was discontinued globally at the end of 2024 and the product is no longer supplied. It was never FDA-approved for osteoporosis. |
| WADA (sport) | Not named on the WADA Prohibited List. Parathyroid hormone acts on calcium homeostasis and bone rather than on muscle, tendon or ligament, so the S2.2 growth factor catch-all does not capture it. Athletes should verify against the current list. |
Questions
For hormone replacement in hypoparathyroidism the goal is to reproduce what the parathyroid glands would have secreted, and the full-length molecule with its longer roughly three-hour half-life gives a broader daily exposure than the roughly one-hour profile of teriparatide. For osteoporosis the reverse logic applies: a sharper, briefer pulse widens the anabolic window, which is one reason the 1-34 fragment came to dominate that indication.
No. Manufacturing was discontinued globally at the end of 2024 after several years of supply problems caused by rubber particulate shedding from the delivery cartridges. The European osteoporosis product had already been withdrawn in 2014 for commercial reasons, and the US hypoparathyroidism product was recalled in 2019. Remaining stock was supplied until exhausted.
They are not required for PTH1 receptor activation, but they are not simply filler. They are the substrate for proteolytic processing into abundant circulating C-terminal fragments, and there is evidence for a distinct C-terminal receptor with effects on osteocytes and chondrocytes independent of PTH1R. The physiological importance of that pathway is still unsettled.
In hypoparathyroidism the drug is replacing an absent hormone. Abrupt withdrawal without simultaneously restoring calcium and active vitamin D supplementation can precipitate severe symptomatic hypocalcaemia, including tetany and seizures. This is a documented labelling warning rather than a theoretical concern.
A long-acting prodrug of PTH(1-34), palopegteriparatide, was authorised in the EU in November 2023 and approved by the FDA in August 2024 for chronic hypoparathyroidism, and has largely taken over that role. It is a chemically distinct product with its own trial programme, not a substitute formulation of PTH(1-84).