Abaloparatide

What is Abaloparatide?#

Abaloparatide is a 34-amino-acid synthetic analog of human parathyroid hormone-related protein (PTHrP) developed by Radius Health (now Ipsen). It is marketed under the brand name Tymlos and was FDA-approved in April 2017 for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In January 2023, the FDA expanded the indication to include men with osteoporosis at high risk for fracture.

Abaloparatide has 76% homology to native human PTHrP(1-34) and 41% homology to parathyroid hormone (PTH)(1-34). It contains several non-native amino acid substitutions in the C-terminal region that optimize receptor binding selectivity and pharmacological profile. Like teriparatide, it is an osteoanabolic agent that stimulates new bone formation, but its distinct receptor binding properties result in differences in bone resorption stimulation and calcium handling.

Mechanism of Action#

Abaloparatide activates the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor expressed on osteoblasts and osteocytes. PTH1R exists in two conformational states:

• RG conformation: Generates transient cAMP signaling that promotes bone formation
• R0 conformation: Generates prolonged cAMP signaling associated with both bone formation and bone resorption, as well as calcium mobilization

Abaloparatide preferentially binds the RG conformation of PTH1R, producing more transient receptor activation compared to teriparatide (which activates both RG and R0 conformations more equally). This selective binding profile is believed to explain abaloparatide's favorable ratio of bone formation to bone resorption stimulation, resulting in:

• Robust stimulation of osteoblast-mediated bone formation
• Less stimulation of osteoclast-mediated bone resorption compared to continuous PTH exposure
• Lower incidence of hypercalcemia than teriparatide (3.4% vs 6.4% in the ACTIVE trial)
• Potentially greater net bone accrual, particularly at cortical sites such as the hip

When administered as a brief daily subcutaneous pulse, abaloparatide produces an anabolic window favoring bone formation over resorption. This intermittent exposure pattern is critical -- continuous PTH1R activation (as in hyperparathyroidism) leads to net bone loss.

Research Overview#

The clinical evidence for abaloparatide centers on the ACTIVE (Abaloparatide Comparator Trial In Vertebral Endpoints) and ACTIVExtend programs, which together enrolled over 2,000 postmenopausal women and provided up to 43 months of follow-up data.

In the ACTIVE trial, abaloparatide demonstrated statistically significant reductions in vertebral fractures (86% relative risk reduction vs placebo), nonvertebral fractures (43% risk reduction), and major osteoporotic fractures (70% risk reduction) over 18 months. Notably, abaloparatide showed statistically superior increases in total hip bone mineral density compared to the active comparator teriparatide, while demonstrating lower rates of hypercalcemia.

The ACTIVExtend trial showed that sequential therapy with abaloparatide followed by alendronate maintained and extended fracture protection and BMD gains for an additional 24 months, establishing the clinical paradigm of anabolic-to-antiresorptive sequencing.

Important Considerations#

• Prescription medication requiring medical supervision
• Originally limited to 2 years of cumulative use (based on teriparatide class precedent), though the boxed warning for osteosarcoma was removed from the teriparatide label in 2020
• Most common adverse effects are injection site reactions, hypercalcemia, dizziness, and nausea
• Contraindicated in patients at increased risk for osteosarcoma (Paget disease, unexplained alkaline phosphatase elevation, prior radiation to the skeleton, open epiphyses, pre-existing hypercalcemia)
• Should be followed by antiresorptive therapy to maintain BMD gains

Key Research Findings#

Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial (ACTIVE), published in JAMA (Miller PD et al., 2016; PMID: 27533157):

• The study showed new vertebral fractures of 0.58% abaloparatide vs 4.22% placebo
• The study showed nonvertebral fractures of 2.7% vs 4.7% placebo
• The study showed major osteoporotic fractures of 70% risk reduction vs placebo
• The study showed total hip BMD increase of 2.90% abaloparatide vs 2.04% teriparatide
• The study showed lumbar spine BMD increase of 9.2% abaloparatide vs 10.5% teriparatide
• The study showed hypercalcemia of 3.4% abaloparatide vs 6.4% teriparatide

Related Reading#

• Abaloparatide research studies and evidence
• Abaloparatide dosing protocols
• Abaloparatide side effects profile
• Teriparatide research guide