# Functionally-selective parathyroid hormone analogs as therapeutics in metabolic bone disease

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2020 · —

## Abstract

Osteoporosis is an aging related condition characterized by progressive loss of bone mass and increasing
bone fragility that affects many Veteran men and women. Given the tremendous morbidity and excess
mortality associated with osteoporosis-related fracture, it is vital to the VA healthcare mission to explore novel
strategies to reduce fracture risk. The only current FDA-approved anabolic therapy for severe osteoporosis is
teriparatide [hPTH(1-34)], a conventional agonist of the type 1 parathyroid hormone receptor (PTH1R). While
effective at stimulating osteoblastic bone formation, its clinical utility is limited by unfavorable pharmacokinetics
necessitating daily injection, its propensity to promote hypercalcemia, a lack of efficacy in states where
endogenous PTH is elevated, and the rapid loss of accrued bone mass upon discontinuation of treatment. The
‘ideal’ anabolic agent for osteoporosis would circumvent these limitations, i.e. it would be capable of stimulating
osteoblastic bone formation with prolonged exposure, and would ‘uncouple’ increased bone formation rates
from accelerated bone resorption and renal calcium retention. One approach that has shown early promise is
the use of ‘biased’ PTH1R agonists that stimulate receptor signaling through non-G protein effectors, e.g.
arrestins, while antagonizing receptor coupling to heterotrimeric G proteins. ‘Biased’ ligands are novel
pharmacological entities that possess the unique ability to engender ‘mixed’ agonist-antagonist effects in vivo
that cannot be attained through conventional agonism or antagonism. In preliminary work, we have
demonstrated that a modified bovine PTH derivative, [D-Trp12,Tyr34]-bPTH(7-34), can bias PTH1R in a manner
that dissociates heterotrimeric G protein-dependent signaling from non-canonical arrestin-dependent signaling.
In vivo, [D-Trp12,Tyr34]-bPTH(7-34) promotes osteoblast differentiation and survival leading to increased bone
formation in eugonadal male and female mice, while antagonizing the G protein-mediated signals that lead to
osteoclast activation and calcium retention. Functional genomic analysis of bone from mice treated with
conventional and biased PTH1R agonists indicates that despite targeting the same receptor, [D-Trp12,Tyr34]-
bPTH(7-34) and hPTH(1-34) have distinct mechanisms of action. The overall objective of this proposal is to
determine whether an arrestin pathway-selective ‘biased’ PTH1R ligand affords specific advantages over
teriparatide in terms of reduced side effects and retained efficacy in settings where a conventional PTH1R
agonist is ineffective or contraindicated. Our central hypothesis is that a ‘biased’ ligand that uncouples
arrestin-dependent PTH1R signals that increase osteoblast number/activity from G protein-mediated signals
that stimulate osteoclastic bone resorption, will likewise uncouple the beneficial effects of PTH1R activation on
bone formation from its adverse effects on bone resorption and renal calcium retention in ...

## Key facts

- **NIH application ID:** 9814683
- **Project number:** 5I01BX003188-04
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** LOUIS M LUTTRELL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814683

## Citation

> US National Institutes of Health, RePORTER application 9814683, Functionally-selective parathyroid hormone analogs as therapeutics in metabolic bone disease (5I01BX003188-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9814683. Licensed CC0.

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