▎Teriparatide Research
What is the definition of Teriparatide?
Teriparatide is a recombinant human parathyroid hormone (PTH) analog composed of the first 34 amino acids of human parathyroid hormone. It regulates bone metabolism by mimicking the physiological actions of endogenous parathyroid hormone. Teriparatide is the first synthetic anabolic drug approved for severe osteoporosis. Its structure exhibits high homology with endogenous PTH, enabling activation of the PTH receptor to modulate osteoclast metabolic activity.
What is the mechanism of action for Teriparatide?
Effects on osteoblasts:
Promotes osteoblast proliferation: Teriparatide stimulates the proliferation of osteoblast precursor cells, increasing osteoblast numbers. In animal studies, intermittent administration of teriparatide significantly accelerated the proliferation of mesenchymal stem cells capable of differentiating into osteoblasts in bone marrow. This enabled more cells to differentiate into mature osteoblasts, providing an ample cellular supply for bone formation. In vitro cell culture experiments demonstrated that the division rate of osteoblast precursor cells in the Teriparatide-treated group was significantly higher than in the control group, indicating that Teriparatide directly promotes the proliferation of osteoblast precursor cells[1,2].
Enhanced Osteoblast Activity: Teriparatide not only increases osteoblast numbers but also elevates their activity. It upregulates the expression of genes associated with bone matrix synthesis in osteoblasts, such as those encoding type I collagen and osteocalcin, which show significantly increased expression levels. Type I collagen, the primary organic component of the bone matrix, contributes to the formation of a more robust matrix framework through increased synthesis. Osteocalcin plays a crucial role in bone mineralization by promoting calcium ion deposition within the matrix, thereby enhancing bone mineralization. Through these mechanisms, osteoblasts synthesize and secrete bone matrix more efficiently, facilitating new bone formation [2,3].
Inhibition of osteocyte apoptosis: Under normal physiological conditions, osteocytes undergo apoptosis after completing specific bone formation tasks. Teriparatide suppresses this apoptotic process, prolonging osteocyte lifespan. Teriparatide activates relevant cellular signaling pathways, such as the PI3K/Akt pathway. Upon activation, this pathway suppresses the expression of apoptosis-related proteins, enabling osteoblasts to sustain their bone-forming functions and maintain the continuity and stability of bone formation[1,3].
Effects on Osteoclasts: Teriparatide's effects on osteoclasts are complex. During intermittent dosing, it influences osteoclasts through indirect mechanisms. It promotes osteoblast secretion of osteoprotegerin (OPG), a cytokine that competitively binds to the receptor activator of nuclear factor κB ligand (RANKL). RANKL is a key regulator of osteoclast differentiation and activation. When OPG binds to RANKL, RANKL cannot bind to the RANK receptor on the surface of osteoclast precursor cells, thereby inhibiting osteoclast differentiation and maturation and reducing bone resorption. In osteoporosis patients, where bone resorption exceeds formation leading to bone loss, teriparatide reduces osteoclast activity through this mechanism. This restores balance between resorption and formation, promoting bone gain[2,3].
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Figure 1 Sites of action for first-line osteoporosis treatments. Teriparatide, a recombinant fragment of parathyroid hormone, stimulates bone formation by increasing osteoblast activity and, to a lesser extent, inhibiting osteoclast recruitment[4].
Modulation of Bone Diabetes-Related Signaling Pathways:
Wnt/β-Catenin Signaling Pathway: The Wnt/β-catenin signaling pathway plays a crucial role in bone development and maintenance of bone homeostasis. Teriparatide activates this pathway, promoting intracellular accumulation and nuclear translocation of β-catenin. Nuclear β-catenin binds to associated transcription factors, initiating transcription of bone formation-related genes and enhancing expression of the osteoblast-specific transcription factor Runx2. Runx2 further regulates osteoblast differentiation and function, thereby promoting bone formation. Activation of this pathway also inhibits osteoblast differentiation toward adipocytes, ensuring greater differentiation of bone marrow mesenchymal stem cells toward the osteoblast lineage, thereby increasing bone mass[1,3].
PTH/PTHrP Receptor Signaling Pathway: Teriparatide, an analog of parathyroid hormone (PTH), primarily exerts its effects by binding to the PTH/PTHrP receptor. Upon binding, Teriparatide activates downstream signaling pathways such as the cAMP/PKA pathway and the PLC/PKC pathway. Activation of these pathways regulates osteoblast and osteoclast function, promoting bone formation. The cAMP/PKA pathway enhances expression of osteoblast-related genes by modulating transcription factor activity, while the PLC/PKC pathway influences cytoskeletal reorganization and cell motility, affecting osteoblast migration and function[2,5].
What are the applications of Teriparatide?
Osteoporosis Treatment
Postmenopausal Osteoporosis: Teriparatide is the first synthetic anabolic agent approved for treating postmenopausal women with severe osteoporosis. By stimulating bone formation, it increases bone mass, thereby reducing fracture risk. In postmenopausal women, daily teriparatide use increases bone mineral density, reducing the risk of vertebral fractures by 65% and non-vertebral fragility fractures by 53% compared to placebo. A meta-analysis of individual patient-level data demonstrated a 56% reduction in hip fracture risk compared to controls. Furthermore, compared to risedronate, Teriparatide reduced the risk of new vertebral and clinical fractures by 56% and 52%, respectively, in women with severe osteoporosis [3,6,7].
Male Osteoporosis: It is also approved for treating male osteoporosis. Quattrocchi E et al. demonstrated that in male osteoporosis patients, Teriparatide (20μg and 40μg daily injections) produced statistically significant increases in lumbar spine bone mineral density: 5.9% in the 20μg group and 9.0% in the 40μg group (both P < 0.001). At the femoral neck, bone density increased by 1.5% in the 20μg group (P = 0.021) and by 0.9% in the 40μg group (P < 0.001)[7].
Glucocorticoid-Associated Osteoporosis: Teriparatide is also used to treat glucocorticoid-induced osteoporosis in male and female patients with fractures, helping these patients increase bone mass and reduce bone loss and fracture risk associated with glucocorticoid use[8].
Fracture Healing Support: For fracture patients, transiently increasing bone formation at the fracture site is critical for repair, a role teriparatide can fulfill. It has been studied in both animal models and patients as a potential agent to enhance fracture healing. While further research is needed, existing explorations demonstrate its potential in promoting fracture healing[3].
Alveolar Bone Regeneration: Related studies indicate Teriparatide may be applicable for alveolar bone regeneration in conditions such as jawbone necrosis, chronic periodontitis, dental implant osseointegration, and orthodontic tooth movement, where it enhances alveolar bone formation. However, further human clinical trials are needed to validate its application and adverse effects across various oral bone diseases[9].
Pregnancy- and Lactation-Related Osteoporosis: In patients with pregnancy- and lactation-related osteoporosis (PLO), treatment with Teriparatide (20μg/day) combined with calcium and vitamin D resulted in significantly greater increases in lumbar spine bone mineral density at 12 and 24 months compared to calcium and vitamin D alone. At 12 months, the mean increase in lumbar spine bone mineral density was 20.9 ± 11.9% in the teriparatide group versus 6.2 ± 4.8% in the control group (P < 0.001). At 24 months, the mean increase in lumbar spine bone mineral density was 32.9 ± 13.4% in 7 patients treated with Teriparatide and 12.2 ± 4.2% in 6 control patients (P = 0.001). No new clinical fractures occurred during treatment[10].
Special Applications: Teriparatide has been reported in case studies for specific bone disorders, such as hypoparathyroidism-associated osteodystrophy (ABD) with hypercalcemia. A 51-year-old dialysis-dependent woman developed hypercalcemia post-parathyroidectomy, confirmed by bone biopsy as ABD. After 12 months of Teriparatide treatment, serum calcium levels normalized, representing the first documented case of Teriparatide resolving ABD-related hypercalcemia[11].
Conclusion
Teriparatide is effective for severe osteoporosis with high fracture risk. It is indicated for patients with a history of multiple osteoporotic fractures, extremely low bone mineral density, and limited response to conventional osteoporosis treatments.
About The Author
The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.
Scientific Journal Author
Susan V. Bukata is a researcher at the University of Rochester School of Medicine and Dentistry, specializing in orthopedics and musculoskeletal diseases. She has co-authored numerous publications focusing on bone biology, fracture healing, and the clinical applications of anabolic agents like teriparatide in orthopedic practice. Her work has contributed to the understanding of therapeutic strategies for enhancing bone repair and regeneration. Susan V. Bukata is listed in the reference of citation [1].
