Teriparatide is a recombinant parathyroid hormone (PTH) fragment (PTH 1-34) composed of 34 amino acids, and its mechanism of action is mainly regulated by the activation of the PTH1 receptor (PTH1R), the N-terminal domain of teriparatide (amino acids 1-6) binds to the extracellular region of PTH1R, and activates downstream signals by triggering the receptor conformation to change it. Teriparatide has two unique signaling pathway regulatory networks, the classical cAMP/PKA pathway (including Gs protein activation and downstream effects) and the non-canonical pathway (β-arrestin-dependent EPK pathway and PLC/PKC pathway). It is this stability, tissue selectivity, dual pathway and other characteristics of teriparatide that make it play an important role in the fields of cell-level response and the regulation of bone metabolism homeostasis.

▌Scientific applications of teriparatide

• Activation of osteoblasts

Teriparatide promotes differentiation by upregulating the expression of alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (COL1A1), as well as enhanced matrix mineralization by the IGF-1 autocrine loop (JBMR, 2020). Researchers have used intermittent administration to inhibit osteoblast apoptosis, promote bone resorption, and continuously stimulate apoptosis to promote apoptosis to regulate the life cycle of bone cells.

• Targeting receptors and signaling pathways

Teriparatide plays a role in bone metabolism regulation through Gs/cAMP/PKA and β-arrestin/ERK dual pathways, because of its tissue-selective properties, teriparatide will mainly act on PTH1R high-expressing tissues such as bone and kidney, because of its weak effect on intestinal calcium absorption, it usually needs to rely on vitamin D to play a synergistic effect.

• Hypercalcemia monitoring and osteosarcoma risk

Hypercalcemia surveillance: the incidence of hypercalcemia is 11%, and this condition is more common in patients with CKD stage 3 to 4 (eGFR 30-59 ml/min) who are relieved by a combination of calcium > 1000 mg/day by suspending the dose until the serum calcium < 2.6 mmol/L, and then reducing the dose to 10 micrograms/day.

Osteosarcoma risk: Long-term high-dose (≥60 μg/kg/day) injection of teriparatide was found to cause osteosarcoma risk through experimental data in rats, while no increased risk was observed after 20 years of follow-up after 20 years of follow-up (J Bone Oncol, 2023).

▌Clinical application of teriparatide

• Research on osteoporosis

Postmenopausal osteoporosis (PMO): After an 18-24 month course of treatment, the researchers found that teriparatide reduced the risk of vertebral fractures by 65% and non-vertebral fractures by recording real-time detection of 20 μg of subcutaneous teriparatide per day (NEJM, 2001). In men, osteoporosis has been found to increase lumbar BMD by 5-8% (JBMR, 2003). Glucocorticoid-induced osteoporosis (GIOP) is indicated for patients who are at high risk of fracture with a long-term dose of prednisone equivalent ≥ 7.5 mg/day.

• Studies at high risk of fractures

The clinical application and research of teriparatide in people at high risk of fracture is a key direction in the field of osteoporosis treatment. By intermittently activating osteoblasts, significantly increasing trabecular bone thickness and connectivity, and improving bone microstructure (different from the "inhibition of osteoclasty" effect of anti-bone resorption drugs), teriparatide has been found to have a rapid miraculous effect under normal circumstances, and an increase in bone mineral density (BMD) can be observed within 3-6 months, thereby reducing the risk of early refracture.

▌Exploration of future research directions in clinical translation

• Exploration of precision treatment

Genotyping: Effect of PTH1R polymorphisms on efficacy (e.g., rs10500783 locus, the most promising biomarker); Artificial Intelligence Prediction: Individualized Approach Based on FRAX®+ Bone Turnover Marker; Multi-gene scoring system: integrate other SNPs (such as rs2141976 and rs1561570) to improve prediction accuracy. Gene editing intervention: CRISPR-Cas9 repairs splicing defects of TT genotype (in animal model validation); Dynamic monitoring technology: nanopore sequencing real-time detection of receptor mRNA isoforms.

• Development of new dosage forms

The long-acting injectable dosage form has a sustained-release microsphere formulation, which is based on the technical principle of encapsulating teriparatide in a biodegradable polymer material (such as polylactic acid-hydroxyacetic acid copolymer, PLGA) to make a microsphere formulation. After injection, the microspheres slowly release the drug to prolong the duration of action. It improves patient compliance by reducing the frequency of dosing (e.g., from once daily to weekly or monthly); Maintain a stable blood concentration and reduce side effects caused by fluctuations. The current R&D progress is that some companies have entered the clinical trial stage, and it is necessary to pay attention to the regulation of drug release rate, the stability of microspheres and biocompatibility.

The technical principle of long-acting nanoformulation is to use nanocarriers (such as liposomes, polymer micelles) to encapsulate the drug and achieve long-term release by prolonging the circulation time in the body. It has the advantage of improved drug stability, reduced injection site irritation, and targeted delivery by modifying the carrier surface to reduce systemic toxicity. The challenges we need to face are the particle size control of nanoparticles, the encapsulation efficiency of drugs, and the need to further optimize the large-scale production process.

Transdermal patches (in phase II clinical trials) to improve adherence in older patients. Local extended-release system: PTH-collagen composites for fracture repair。

▌Bibliography

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