Rat parathyroid hormone fragment: lab version of Forteo (PTH 1-34)
The rat form of a natural bone-regulating hormone fragment, used in rodent studies of how bone cells build and remodel bone. Research tool only, the human version (Forteo) is FDA-approved for osteoporosis.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Parathyroid hormone fragment (1-34), or PTH(1-34), is the biologically active N-terminal piece of the 84-amino-acid parathyroid hormone — the calcium-regulating hormone secreted by the four small parathyroid glands in the neck. This card covers the rat form of the fragment, whose 34-residue sequence differs from the human version at five positions, making it the species-matched reagent used in rodent bone-biology research. The human equivalent — sold as Forteo and, in biosimilar form, as Bonsity — was FDA-approved in November 2002 as the first anabolic (bone-building) treatment for osteoporosis. PTH(1-34) acts on the PTH type-1 receptor (PTH1R), a class B G-protein-coupled receptor present on osteoblasts and kidney tubule cells, and its effects on bone depend critically on whether it is delivered as brief daily pulses or as a continuous signal.
History
Parathyroid hormone was first isolated in 1925 by James Collip, who used crude glandular extracts to reverse the life-threatening muscle spasms (tetany) that follow parathyroid removal. The polypeptide structure was defined by Rasmussen and Craig in the early 1960s. The amino-terminal 34-residue sequence of human PTH was determined by Potts, Niall, and colleagues at Massachusetts General Hospital — the 1972 proposal was later refined, with the sequence published in PNAS (1972) becoming the basis for synthetic work. By the mid-1970s, largely through the efforts of British pharmacologist John Parsons, researchers had established that single daily injections of PTH(1-34) dramatically increased bone mass in several mammalian species — a key observation that reversed decades of focus on PTH's calcium-mobilizing (resorptive) actions and identified it as a potential bone-building drug (Marcus 2011). The rat form of PTH(1-34) is distinguished from the human form by five amino acid substitutions; it shows 8–10-fold greater potency than human PTH(1-34) in canine and rat adenylate cyclase systems, and is therefore the preferred ligand in rodent experimental models. The 1998 paper by Gray and colleagues used the rat sequence to demonstrate that PTH(1-34) suppresses appositional bone formation in cultured rat cranial osteoblasts — an important model result for understanding the context-dependent anabolic and anti-anabolic actions of the fragment (Gray et al. 1998).
What it does
PTH(1-34) tells bone-building cells (osteoblasts) to become more active and to survive longer, ultimately increasing bone mass and improving bone architecture. Crucially, this anabolic action only emerges with intermittent, short-duration receptor activation — the kind produced by a once-daily injection. When PTH(1-34) is present continuously (as in primary hyperparathyroidism, or with sustained drug infusion), the net effect flips: bone-resorbing osteoclasts are upregulated more than osteoblasts, leading to net bone loss. This dose-timing paradox has made understanding PTH(1-34) signaling a central preoccupation of bone biology. In the kidney, PTH(1-34) increases tubular reabsorption of calcium and promotes conversion of vitamin D to its active form, supporting overall calcium homeostasis (Lee et al. 2009).
Evidence
- Human: The pivotal Fracture Prevention Trial (Neer et al., NEJM 2001) enrolled 1,637 postmenopausal women with prior vertebral fractures and showed that the 20 µg daily dose of human PTH(1-34) reduced the risk of new vertebral fractures by 65% and non-vertebral fractures by 53% over 18 months compared with placebo, with lumbar spine bone mineral density increasing by approximately 9%. A separate randomized Japanese trial (TOWER) confirmed vertebral fracture reduction in a weekly-dosing regimen. Multiple systematic reviews have since confirmed the anti-fracture efficacy across male and postmenopausal female osteoporosis populations.
- Animal: Appositional bone formation in rat cranial osteoblast cultures is suppressed by PTH(1-34) at pharmacologically relevant concentrations (Gray et al. 1998). Rodent ovariectomy models have extensively validated intermittent PTH(1-34) as a bone-anabolic agent, with numerous studies showing increased trabecular bone volume and bone mineral density; these models used the rat sequence at matched doses.
- In vitro: PTH(1-34) is a full agonist at PTH1R in osteoblast-lineage cell lines, stimulating cAMP accumulation via Gαs coupling. Differential signaling through β-arrestin and G-protein pathways has been characterized in cell-based assays (Gesty-Palmer et al. 2009; Sutkeviciute et al. 2019).
Known effects
- Vertebral and non-vertebral fracture reduction — Phase III evidence (human PTH 1-34, Neer 2001)
- Increased bone mineral density (spine, hip) — Phase III and multiple RCTs
- Stimulation of osteoblast differentiation and survival — Preclinical, mechanistic
- Suppression of appositional bone formation at high/continuous exposures — Preclinical (rat cranial osteoblast model, Gray et al. 1998)
- Calcium reabsorption in kidney — Mechanistic, supported by clinical observations
Safety signals
Transient hypercalcemia occurs in approximately 11% of patients receiving the 20 µg human dose, peaking at 4–6 hours after injection and resolving within 16–24 hours. Mild nausea, headache, dizziness, and limb pain were reported in the Fracture Prevention Trial. The original FDA approval for Forteo in 2002 carried a boxed warning about osteosarcoma based on rat carcinogenicity studies in which high-dose teriparatide caused dose- and duration-dependent bone tumors; however, a 15-year FDA-mandated post-marketing surveillance study covering approximately 2.47 million teriparatide-treated patients found no increase in osteosarcoma incidence above background population rates (Krege et al. 2022). The FDA removed the boxed warning and the 2-year cumulative lifetime use restriction in November 2020. Rat bones grow throughout life (unlike human bones), which likely explains the species-specific carcinogenicity signal.
Regulatory status
- US: The human PTH(1-34) drug teriparatide (Forteo, Eli Lilly; Bonsity biosimilar, Alvogen) is FDA-approved as a prescription anabolic agent for osteoporosis. The original 2-year lifetime treatment limit was lifted in November 2020.
- EU: Teriparatide (Forsteo) received EMA approval in June 2003; biosimilar versions (Terrosa, Movymia) are also approved.
- Research use: The rat PTH(1-34) fragment on this card (AVSEIQLMHNLGKHLASVERMQWLRKKLQDVHNF) is a research reagent used in rodent bone-biology experiments; it is not a clinical drug and is not separately regulated as a pharmaceutical.
- WADA: PTH and its fragments are listed under the WADA Prohibited List (S2, peptide hormones and related substances).
Mechanism
PTH(1-34) binds the extracellular domain of PTH1R, a class B (secretin-family) GPCR whose principal endogenous ligands are full-length PTH (1-84) and the related peptide PTHrP. Receptor engagement initiates Gαs-mediated activation of adenylyl cyclase, generating cAMP and activating protein kinase A (PKA); this PKA signal is the primary driver of the anabolic response in osteoblasts. PTH1R also signals through Gαq/11 (IP3/Ca²⁺) and, via β-arrestin recruitment, through G-protein-independent endosomal pathways. A biased agonist study showed that β-arrestin-selective PTH1R activation can stimulate bone formation independently of G-protein signaling, suggesting the two arms of the receptor's output can be pharmacologically separated (Gesty-Palmer et al. 2009).
PTH1R exists in at least two conformational states — a G-protein–coupled RG state and a G-protein–uncoupled R0 state. Teriparatide (human PTH 1-34) binds preferentially to the R0 conformation, producing a prolonged cAMP signal that persists from endosomes after receptor internalization. Abaloparatide, a PTHrP-based analog, binds the RG conformation more selectively, generating a more transient signal that results in less accompanying bone resorption and hypercalcemia (Hattersley et al. 2016; Sutkeviciute et al. 2019). The rat PTH(1-34) fragment shares the same receptor-activation mechanism but differs at five residues, yielding approximately 8–10-fold higher potency in rodent adenylate cyclase assays compared with the human peptide.
The CaSR (calcium-sensing receptor) modulates PTH1R signaling in skeletal development: CaSR-null models display dysregulated PTH1R activity, underlining an interplay between the two receptor systems in coordinating bone formation and calcium homeostasis (Santa Maria et al. 2016).
Related peptides
- Teriparatide (human PTH 1-34) — the human-sequence version of this fragment; the approved drug form. See /card/pep-10509 if available, or search "teriparatide" on the platform.
- Abaloparatide — a PTHrP(1-34) analog that preferentially engages the RG conformation of PTH1R, showing reduced hypercalcemia relative to teriparatide; reviewed in Brent (2021) and Leder (2017).
- Full-length PTH (1-84) — the intact hormone; the (1-34) fragment retains full receptor-activation capacity because residues 1–34 carry both the receptor-binding and the activation domains.
- PTHrP (1-36) — parathyroid hormone-related protein, the other endogenous PTH1R ligand; shares the (1-34) binding pharmacophore with structural divergence at the C-terminal end; basis for abaloparatide design.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Does the rat version of this peptide trigger a different mix of bone-building versus bone-breakdown signals than the human drug Forteo?
If true, it would explain why bone treatments that look powerful in rats sometimes disappoint in human trials, and could help researchers pick a better lab model for testing future osteoporosis drugs. Patients waiting for the next generation of bone therapies could benefit from faster, more accurate preclinical screening.
If a protein called beta-arrestin2 is what flips the bone-building drug into a bone-destroying one during continuous exposure, could blocking that protein make a slow-release patch or implant safe?
Forteo currently requires daily injections for up to two years, limiting patient compliance. If this mechanism holds, a slow-release implant delivering PTH continuously could become safe, meaning osteoporosis patients could receive months of treatment from a single procedure instead of hundreds of self-injections.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8666156530380249 | openfold3-mlx |
| ranking score | 0.9935994148254395 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.823 | global PDE — lower = better |
| disorder | 0.337 | ! high disorder |
| chain pair ipTM (A, B) | 0.867 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 755s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10508,
sequence = {AVSEIQLMHNLGKHLASVERMQWLRKKLQDVHNF},
target = {pth1r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}