Parathyroid Hormone (1-84)

Full-length 84-amino-acid human parathyroid hormone, the body's principal calcium-regulating hormone; its recombinant form (Natpara) was FDA approved in 2015 for hypoparathyroidism but has since been discontinued worldwide after unresolved manufacturing problems.

Also referenced as: Natpara, Natpar, Preotact, rhPTH(1-84), rhPTH 1-84, PTH(1-84), PTH 1-84, recombinant human parathyroid hormone (1-84), full-length parathyroid hormone, parathormone, Preos, NPSP558, ALX1-11

Also appears in: Longevity

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What is Parathyroid Hormone (1-84)?

Parathyroid hormone (PTH) is the 84-amino-acid peptide hormone secreted by the chief cells of the parathyroid glands (molecular weight 9,425 Da), and it is the body’s minute-to-minute regulator of extracellular calcium. This page covers both the native hormone and its full-length recombinant drug form, rhPTH(1-84), which is produced in E. coli and was approved by the FDA on January 23, 2015 as Natpara, the first hormone-replacement therapy for hypoparathyroidism; the same molecule was authorized in the European Union as Preotact (2006, osteoporosis) and Natpar (2017, hypoparathyroidism). The N-terminal fragment PTH(1-34) is a different drug, teriparatide, and has its own profile, as do the PTHrP analog abaloparatide and the long-acting PTH(1-34) prodrug palopegteriparatide. Full-length PTH(1-84) appears only rarely in the research-peptide market, where “PTH” vials are almost always PTH(1-34); the 1-84 protein is sold mainly as a recombinant reagent for assay and standards work.

How it works

PTH acts through a single receptor to coordinate calcium release from bone, calcium retention by the kidney, and calcium absorption from the gut. Its skeletal effect depends on exposure pattern: brief daily pulses are anabolic, while sustained elevation is catabolic.

• Receptor pharmacology — PTH binds the PTH/PTHrP type 1 receptor (PTH1R), a family B G protein-coupled receptor expressed on osteoblast-lineage cells and renal tubular cells, signaling mainly through Gs/cAMP/PKA with a secondary Gq/phospholipase C arm; the receptor-activating determinants reside in the N-terminal 1-34 region, which is why the truncated fragment reproduces most acute actions of the full hormone (Gardella and Vilardaga, Pharmacological Reviews, 2015;67(2):310–337)
• Calcium and phosphate homeostasis — PTH secretion is suppressed by the calcium-sensing receptor as serum calcium rises; the hormone increases distal tubular calcium reabsorption, promotes renal phosphate excretion, induces renal 1α-hydroxylase (CYP27B1) to convert 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D for intestinal calcium absorption, and raises bone turnover to release calcium into the circulation (Potts, Journal of Endocrinology, 2005;187(3):311–325; Mannstadt et al., Nature Reviews Disease Primers, 2017;3:17080)
• Anabolic versus catabolic — intermittent exposure favors osteoblast recruitment and survival and net bone formation, whereas continuous exposure, as in hyperparathyroidism, drives osteoclast-mediated resorption through RANKL; this divergence is the basis for both the osteoporosis and the hypoparathyroidism programs with the same molecule (Silva and Bilezikian, Current Opinion in Pharmacology, 2015;22:41–50)
• Replacement in hypoparathyroidism — in patients lacking endogenous PTH, once-daily rhPTH(1-84) restores abnormally low bone turnover and reduces the need for oral calcium and active vitamin D; in the Danish randomized trial, bone-turnover markers rose several-fold and bone mineral density initially fell at the hip and spine from an over-mineralized baseline (Sikjaer et al., Journal of Bone and Mineral Research, 2011;26(10):2358–2370)

Research status

rhPTH(1-84) has a complete phase 3 program and years of extension data in hypoparathyroidism, a large but troubled osteoporosis program that never produced a US approval, and a product history that ended in global discontinuation.

• REPLACE (pivotal, hypoparathyroidism) — Mannstadt et al., Lancet Diabetes Endocrinol, 2013;1(4):275-83 (NCT00732615, Phase 3, NPS/Shire). 134 adults with hypoparathyroidism of at least 18 months’ duration were randomized 2:1 to rhPTH(1-84) 50 mcg daily (titratable to 75 and 100 mcg) or placebo for 24 weeks at 33 sites in eight countries. The primary endpoint, a 50% or greater reduction in oral calcium and active vitamin D while holding serum calcium in range, was met by 53% of the treated group versus 2% on placebo. Hypocalcemia, muscle spasm, paresthesia, headache, and nausea were the most common adverse events, with similar serious-adverse-event rates in both arms (11% versus 9%). This trial was the basis of the January 2015 FDA approval and the April 2017 EU conditional authorization.
• Independent randomized trial — Sikjaer et al., J Bone Miner Res, 2011;26(10):2358-70: 62 patients randomized to 100 mcg daily or placebo for 24 weeks as add-on to conventional therapy. Daily calcium and active vitamin D doses fell by 75% and 73%, but hypercalcemia was frequent during down-titration, and BMD decreased at the hip (-1.6%) and lumbar spine (-1.8%).
• Long-term extension — RACE (NCT01297309, open-label, 12 US centers): Mannstadt et al., J Clin Endocrinol Metab, 2019;104(11):5136-5147 reported a 5-year interim analysis in 49 adults, 40 of whom completed 60 months. Serum calcium stayed between 8.2 and 8.7 mg/dL, 24-hour urinary calcium and serum phosphate declined, estimated GFR was unchanged, and 70% of the 40 completers (28 patients) met the composite efficacy outcome at month 60; treatment-emergent adverse events occurred in 98% (hypocalcemia 36.7%, muscle spasms 32.7%, paresthesia 30.6%). A separate single-center prospective cohort followed patients for 8 years (Tay et al., J Clin Endocrinol Metab, 2019;104(11):5601-5610), with companion analyses of skeletal microstructure over 4 years (Cusano et al., J Bone Miner Res, 2020;35(7):1274-1281) and quality of life (Tabacco et al., J Clin Endocrinol Metab, 2019;104(7):2748-2756). None of these is a controlled comparison against conventional therapy, and no trial was powered for renal or fracture outcomes.
• Guideline position — the Second International Workshop guidelines (Khan et al., J Bone Miner Res, 2022;37(12):2568-2585) position PTH therapy as an option for patients not adequately controlled on calcium and active vitamin D, not as first-line replacement.
• Osteoporosis (never approved in the US) — the TOP trial (NCT00172081), Greenspan et al., Ann Intern Med, 2007;146(5):326-39, randomized 2,532 postmenopausal women at 168 centers to 100 mcg daily or placebo for 18 months. New or worsened vertebral fractures were reduced (relative risk 0.42 under the primary assumption, but 0.60-0.62 under alternative assumptions about the many dropouts; only 67% completed), spine BMD rose 6.9% and hip BMD 2.1% versus placebo, forearm BMD fell, and hypercalciuria, hypercalcemia, and nausea were each 14-24 percentage points more common than placebo. An earlier dose-ranging study (Hodsman et al., J Clin Endocrinol Metab, 2003;88(11):5212-5220) and the PaTH trial (Black et al., N Engl J Med, 2003;349(13):1207-1215, 238 women) established the BMD effect and showed no synergy with alendronate, which appeared to blunt the anabolic response. The EU authorized Preotact for postmenopausal osteoporosis on April 24, 2006 (vertebral, not hip, fracture reduction; labeled for up to 24 months of use) and withdrew the authorization on May 16, 2014 at the holder’s request for commercial reasons. The parallel US application under the name Preos drew an approvable letter in March 2006 that cited hypercalcemia at the proposed dose and the reliability of the injection device; NPS then dropped proprietary osteoporosis development and the drug never gained US approval for that use.
• Discontinuation — Natpara was recalled in the US on September 5, 2019 (all four strengths) because rubber fragments could shed from the cartridge septum into the drug during the 14 daily punctures; US patients were thereafter supplied only through a Special Use Program. Takeda’s August 2021 supplement proposing a new septum and needle drew an FDA Complete Response Letter on March 22, 2022. On October 4, 2022 Takeda announced it would stop manufacturing globally at the end of 2024, citing both protein-particle formation in the formulation and its conclusion, after the Complete Response Letter, that the rubber-particle problem could not be fixed; it also said it would not re-commercialize the product in the US. Manufacturing ended in December 2024, the US Special Use Program closed on December 31, 2025, and the European Commission withdrew the Natpar authorization on July 1, 2026.

Common dosage forms

Natpara was supplied as a multiple-dose, dual-chamber glass cartridge holding lyophilized rhPTH(1-84) (0.4, 0.8, 1.21, or 1.61 mg) and a 1.13 mL m-cresol-preserved diluent, in four strengths delivering 25, 50, 75, or 100 mcg per fixed 71.4 µL dose; each cartridge gave 14 daily subcutaneous doses through a reusable Q-Cliq pen after reconstitution in a separate mixing device, and cartons held two cartridges. Natpar in the EU used the same four strengths. Preotact for osteoporosis was a pre-filled pen holding a dual-chamber cartridge of 1.61 mg hormone, delivering 14 doses of 100 mcg each, packed two pens per carton. None of these products is manufactured anymore. Outside the clinic, recombinant human PTH(1-84) is sold as lyophilized protein in microgram quantities by life-science reagent suppliers for assay calibration and cell-culture work; the “PTH” products listed by research-peptide vendors are nearly always PTH(1-34), not the full-length hormone.

Key considerations

• Regulatory status — The FDA Approved status reflects that an approved drug product containing the molecule exists (BLA 125511, Natpara, approved January 23, 2015), even though the product has been discontinued. Natpara was approved as an orphan product, the label was last revised in April 2022 (S-028), and Drugs@FDA still lists the four strengths as prescription products with no 2025-2026 regulatory actions. The only post-approval FDA action of note was the March 2022 Complete Response Letter on the cartridge-redesign supplement, which blocked a US relaunch. In practice the drug is unavailable: manufacturing stopped in December 2024, the US Special Use Program shipped its last doses by December 31, 2025, and the EU authorization was withdrawn on July 1, 2026. The only FDA-approved PTH therapy for hypoparathyroidism now on the market is palopegteriparatide (Yorvipath, approved August 2024), to which the closing Takeda letter directed prescribers.
• Boxed warning and REMS — the Natpara label carries a boxed warning for osteosarcoma, based on dose- and duration-dependent tumors in rats at 3 to 71 times the human exposure from a 100 mcg dose, and restricts the drug through the NATPARA REMS Program to patients who cannot be controlled on calcium and active vitamin D. Unlike teriparatide, whose boxed warning was removed in November 2020 after the 15-year postmarketing surveillance study, rhPTH(1-84) never accumulated enough human exposure for a comparable reassessment; the label also warns of severe hypocalcemia on interruption, severe hypercalcemia on initiation or dose change, digoxin toxicity, and hypersensitivity reactions (anaphylaxis, dyspnea, angioedema, urticaria, rash).
• Manufacturing, not efficacy, ended the product — the 2019 recall concerned rubber particulate from the cartridge septum, and the 2022 discontinuation decision concerned both that unresolved device problem and protein-particle formation in the formulation; Takeda stated that released product still met quality standards and that the safety profile had not changed. Neither issue was a new safety finding about the hormone itself, but both left patients on a drug whose abrupt withdrawal causes severe hypocalcemia with no supply, a situation that shaped the push for successor PTH therapies.
• Evidence gaps — the pivotal endpoint was a reduction in supplement burden over 24 weeks, a surrogate; there is no controlled evidence that rhPTH(1-84) reduces kidney stones, nephrocalcinosis, or chronic kidney disease, and BMD falls initially as over-mineralized bone remodels. Natpara was not studied in hypoparathyroidism caused by calcium-sensing receptor mutations or in acute postsurgical hypoparathyroidism, and the osteoporosis trials had high dropout and showed no hip-fracture benefit.
• Naming confusions — “parathyroid hormone” on the Natpara label means full-length PTH(1-84); teriparatide is PTH(1-34), abaloparatide is a PTHrP(1-34) analog, and palopegteriparatide is a PEGylated PTH(1-34) prodrug, each with different pharmacology, indications, and labels. Preos, Preotact, Natpar, Natpara, NPSP558, and ALX1-11 all refer to the same 1-84 molecule. Laboratory “intact PTH” assays measure the endogenous hormone and cross-react with the drug, and PTH-related protein (PTHrP), the tumor-associated hypercalcemia peptide, is a separate gene product.