Abaloparatide 3mg*10vials

▎Abaloparatide Structure

▎Abaloparatide Research

What is the research background of abaloparatide?

Osteoporosis is a common multifactorial systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue. This leads to increased bone fragility and susceptibility to fractures, with hip and spinal fractures being common consequences. It significantly impacts patients' quality of life and increases disability and mortality rates. With the accelerating global aging population, the incidence of osteoporosis continues to rise. It is estimated that 42%-56% of women and 27%-29% of men over 50 years old will experience osteoporotic fractures, making it an urgent public health issue. Traditional osteoporosis treatments, such as bisphosphonates and selective estrogen receptor modulators (SERMs), primarily maintain bone density by inhibiting osteoclast-mediated bone resorption. However, their efficacy is limited for patients with severely reduced bone mass and high fracture risk. Although parathyroid hormone (PTH) 1-34 fragment (teriparatide) was the first anabolic agent approved by the U.S. Food and Drug Administration (FDA), effectively increasing bone density and reducing fracture risk, its long-term use carries limitations including enhanced bone resorption, hypercalcemia, and a potential increased risk of osteosarcoma.

Against this backdrop, developing novel drugs that combine potent anabolic effects while avoiding these drawbacks is imperative. As a parathyroid hormone-related peptide (PTHrP) analog, abaloparatide retains strong anabolic activity while reducing impact on bone resorption and minimizing serum calcium fluctuations, making it useful for osteoporosis.

What are the mechanisms of action for abaloparatide?

Interaction with Parathyroid Hormone Receptor 1 (PTH1R)

Receptor Selective Activation: Abaloparatide is a selective agonist of the parathyroid hormone receptor 1 (PTH1R). PTH1R is widely expressed on the surface of cells in tissues such as bone and kidney, playing a key role in regulating bone metabolism. Abaloparatide specifically binds to PTH1R, initiating a series of intracellular signaling pathways to regulate bone metabolism. Upon binding, it activates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) production to modulate cellular function and metabolism^[1,2].

Differences from other ligands: Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) also bind to PTH1R. Although PTH, PTHrP, and Abaloparatide all signal through PTH1R, their downstream signaling pathways differ. PTH and PTHrP exhibit similar affinities for the R^G (GTPγS-sensitive) state of PTH1R. Teriparatid (TPTD, i.e., 1–34 PTH) has four times higher affinity for the R^0 (GTPγS-insensitive) state than PTHrP, resulting in prolonged cAMP signaling induced by TPTD. In contrast, abaloparatide, derived from PTHrP(1–34), is engineered for enhanced stability and overcomes issues such as loss of the anabolic window and hypercalcemia associated with TPTD use. Because the dissociation rate of the PTHrP-PTH1R complex is faster than that of the PTH-PTH1R complex, the osteogenic effects of PTHrP are accompanied by less absorption and hypercalcemia than TPTD. Abaloparatide inherits this relative advantage^[1,2,3].

Regulation of Bone Metabolism

Promotion of Osteogenesis: Abaloparatide stimulates osteoblast activity, increasing synthesis and deposition of bone matrix to promote bone formation. Osteoblasts synthesize and secrete bone matrix components like collagen and osteocalcin, which gradually mineralize to form new bone tissue. Studies indicate that in treating postmenopausal osteoporosis, abaloparatide significantly increases bone mineral density (BMD) at sites including the total hip, femoral neck, and lumbar spine. By stimulating the expression of osteoblast-related genes, it upregulates the synthesis of key proteins such as osteocalcin and type I collagen. This promotes trabecular thickening and cortical strengthening, enhancing skeletal strength and quality while reducing fracture risk^[1,2,3].

Inhibition of Bone Resorption: While Abaloparatide primarily acts as an anabolic agent, it also exhibits some inhibitory effects on bone resorption. It modulates the differentiation and activity of osteoclasts—cells responsible for bone resorption that dissolve bone mineral and organic matrix by releasing acidic substances and proteolytic enzymes. Abaloparatide may reduce bone resorption rates by decreasing the differentiation of osteoclast precursor cells into mature osteoclasts or shortening the lifespan of mature osteoclasts. Concurrently, it modulates signaling between osteoblasts and osteoclasts, maintaining the dynamic equilibrium between bone formation and resorption. For instance, it reduces osteoclast activation and resorptive activity by decreasing osteoblast-secreted receptor activator of nuclear factor κB ligand (RANKL). Unlike teriparatide, abaloparatide does not excessively increase RANKL production, thereby preventing the loss of the anabolic window that occurs when resorption overtakes formation in later stages^[1,2,3].

Figure 1 Model of parathyroid hormone (PTH)/teriparatide and PTH-related peptide (PTHrP/abaloparatide activation of parathyroid hormone type 1 receptor (PTH1R))^[4].

Effects on Cartilage Metabolism (in Osteoarthritis-Related Studies)

Promotes Cartilage Matrix Synthesis: Studies in osteoarthritis (OA) have demonstrated that abaloparatide exerts a protective effect on cartilage. Articular chondrocytes express PTH1R, and Abaloparatide activates this receptor, stimulating chondrocytes to synthesize components of the cartilage matrix. For example, studies indicate Abaloparatide increases lubricin (Prg4) expression, an important extracellular matrix protein in cartilage that is crucial for maintaining joint lubrication and reducing friction. It also promotes synthesis of type II collagen, the primary component of cartilage matrix, which helps maintain cartilage structural and functional integrity. By increasing synthesis of these cartilage matrix components, Abaloparatide aids in repairing and protecting damaged cartilage tissue, slowing the progression of osteoarthritis^[5].

Inhibiting chondrocyte hypertrophy and degeneration: Abaloparatide can suppress the hypertrophic differentiation process of chondrocytes. During osteoarthritis progression, chondrocytes undergo hypertrophic differentiation, characterized by increased cell volume and elevated expression of specific hypertrophy markers such as type X collagen (Col10). This process leads to degradation of the cartilage matrix and cartilage degeneration. Studies indicate that Abaloparatide treatment alleviates the upregulation of Col10 expression in cartilage tissue while reducing the number of large hypertrophic-like cells. This suggests it can slow chondrocyte hypertrophic differentiation, maintain the normal chondrocyte phenotype, thereby protecting cartilage and delaying osteoarthritis progression^[5].

What are the applications of Abaloparatide?

Osteoporosis Treatment

Postmenopausal Osteoporosis: Abaloparatide, a selective agonist of the parathyroid hormone receptor 1 (PTHR1), is indicated for treating osteoporosis, particularly in postmenopausal women at fracture risk or unresponsive to other therapies. It significantly increases bone mineral density and reduces the incidence and risk of new vertebral and non-vertebral fractures in postmenopausal women.

Male Osteoporosis: In Chandler H's study on male osteoporosis using orchidectomized rats (ORX rats, a male osteoporosis model), Abaloparatide treatment resulted in greater increases in BMD measured by dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) at sites including the total body, lumbar spine, femur, and tibia. It significantly improved trabecular formation, bone volume, and microarchitecture without increasing osteoclast numbers. This suggests Abaloparatide holds potential therapeutic benefits for male osteoporosis^[6].

Post-Traumatic Osteoarthritis (PTOA) Treatment: Following knee PTOA induction via medial meniscus destabilization (DMM) surgery in 16-week-old male C57BL/6 mice, daily subcutaneous injections of 40 μg/kg Abaloparatide (or saline as control) were administered starting 2 weeks post-surgery for 6 weeks. Tissue analysis was performed at 8 weeks. Results showed that compared to the saline-treated group, the Abaloparatide-treated group exhibited reduced DMM-induced articular cartilage loss and preserved tibial surface cartilage tissue. Immunohistochemical analysis revealed that Abaloparatide treatment mitigated the upregulation of type X collagen (Col10) in cartilage, increased lubricin (Prg4) expression in non-calcified cartilage areas, and reduced the number of large hypertrophic cells. suggesting that Abaloparatide slows hypertrophic differentiation and exerts a chondroprotective effect in mouse PTOA, offering a novel therapeutic strategy for PTOA^[5].

Alveolar Bone Regeneration: Post-extraction alveolar bone resorption severely impedes subsequent orthodontic tooth movement (OTM) or implant placement. Tan B synthesized biodegradable, bifunctional bioactive calcium phosphate nanoblossoms (NFs) loaded with Abaloparatide (ABL), termed ABL@NFs. This material exhibits a porous layered structure, high drug encapsulation efficiency, and excellent biocompatibility. ABL was initially released to recruit stem cells, followed by sustained release of Ca⊃2;⁺ and PO₄⊃3;⁻ for in situ interfacial mineralization. This successfully restored morphologically and functionally active alveolar bone without compromising OTM ^[7].

Refractory Hypoparathyroidism (HPT): Chamseddin R reported a 39-year-old female with iatrogenic HPT who failed to achieve normal serum calcium levels despite high-dose vitamin D, calcium supplements, and recombinant PTH (rPTH) injections. Following subcutaneous administration of abaloparatide via the Simplicity patch with close monitoring and personalized dosing, her serum calcium remained stable at 9 mg/dL after 2 months. By 4 months, she maintained normal serum calcium without hypocalcemia episodes while gradually reducing oral calcium and vitamin D supplementation^[3].

Promoting Spinal Fusion: In cervical-thoracic revision surgery, abaloparatide was used to promote spinal fusion in patients with a history of cervical instability and multiple failed cervical surgeries. Parikh S et al. reported a 66-year-old female patient who initiated daily 80 mcg Abaloparatide treatment two weeks postoperatively for a planned 12-week course. Cervical CT scans at 3 and 6 months demonstrated well-healed cervical-thoracic fusion with no signs of nonunion^[8].

Conclusion

Abaloparatide's clinical application centers on osteoporosis treatment. It is indicated for postmenopausal women with osteoporosis at high fracture risk or unresponsive to other therapies, significantly increasing bone mineral density (BMD) and reducing vertebral and non-vertebral fracture risk. For male osteoporosis, animal studies demonstrate increased BMD at multiple sites and improved bone microarchitecture, indicating potential therapeutic value. In post-traumatic osteoarthritis, it reduces cartilage loss and inhibits chondrocyte hypertrophy to protect cartilage. In alveolar bone regeneration, ABL@NFs materials loaded with this drug promote bone regeneration, offering a solution for post-orthodontic bone repair. Research also supports its use in refractory hypoparathyroidism and spinal fusion promotion.

About The Author

The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.

Scientific Journal Author

Bin T is a researcher at the Department of Chemistry, Peking University, specializing in nanomaterials and their applications in biomedical engineering. His work focuses on the design and synthesis of functional nanostructures for targeted drug delivery and tissue regeneration. Tan has co-authored numerous publications in leading scientific journals, contributing to advancements in nanomedicine and regenerative therapies. Bin T is listed in the reference of citation [7].

▎Relevant Citations

[1] Shirley M. Abaloparatide: First Global Approval. Drugs 2017; 77(12): 1363-1368.DOI: 10.1007/s40265-017-0780-7.

[2] Sleeman A, Clements JN. Abaloparatide: A new pharmacological option for osteoporosis. American Journal of Health-System Pharmacy 2019; 76: 130-135.https://api.semanticscholar.org/CorpusID:59338650.

[3] Chamseddin R, Mathew A, Alzohaili O. Abstract #1407986: Abaloparatide Administration Through the Simplicity Patch: A Therapeutic Option for Refractory Hypoparathyroidism Post-thyroidectomy. Endocrine Practice 2023; 29: S57-S58.DOI: 10.1016/j.eprac.2023.03.131.

[4] Thompson JC, Wanderman N, Anderson PA, Freedman BA. Abaloparatide and the Spine: A Narrative Review. Clinical Interventions in Aging 2020; 15: 1023-1033. DOI:10.2147/CIA.S227611.

[5] Landgrave S, Ishii T, Maynard R, et al. 302 Abaloparatide as a novel therapy for posttraumatic osteoarthritis. Journal of Clinical and Translational Science 2022; 6: 53. DOI:10.1017/cts.2022.166.

[6] Chandler H, Lanske B, Varela A, et al. Abaloparatide, a novel osteoanabolic PTHrP analog, increases cortical and  trabecular bone mass and architecture in orchiectomized rats by increasing bone  formation without increasing bone resorption. Bone 2019; 120: 148-155.DOI: 10.1016/j.bone.2018.10.012.

[7] Tan B, Wu Y, Wang R, et al. Biodegradable Nanoflowers with Abaloparatide Spatiotemporal Management of Functional Alveolar Bone Regeneration. Nano Letters 2024. https://api.semanticscholar.org/CorpusID:267655299.

[8] Parikh S, Lubitz SE, Sharma A. MON-365 Novel Use of Abaloparatide to Augment Spinal Fusion in Patient Undergoing Cervicothoracic Revision Surgery. Journal of the Endocrine Society 2020; 4(Supplement_1): 365.DOI: 10.1210/jendso/bvaa046.108.

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