Abaloparatide

Abaloparatide activates the parathyroid hormone type 1 receptor (PTH1R) on bone cells, which raises the messenger molecule cAMP inside them. Short, intermittent bursts of this signal favor new bone formation, while continuous signaling tips the balance toward bone breakdown and higher blood calcium.

In cell experiments, abaloparatide bound more selectively than PTH(1-34), the fragment used in teriparatide, to one receptor shape (the RG conformation) and produced shorter-lived cAMP responses. The researchers proposed this as a plausible explanation for its bone-building profile, which in earlier animal studies came with less calcium-raising effect¹. The FDA label describes stimulation of bone-forming cells on both spongy (trabecular) and outer (cortical) bone surfaces, and in rats and monkeys, gains in bone mineral density that tracked with stronger bone⁴.

In the ACTIVE phase 3 trial, 2,463 postmenopausal women with osteoporosis were randomized to abaloparatide, placebo, or open-label teriparatide for 18 months. New vertebral fractures were less frequent with abaloparatide than with placebo (0.6% versus 4.2% in the label's analysis), nonvertebral fractures were also reduced, and bone density at the spine and hip rose more; high blood calcium was less common than with teriparatide (3.4% versus 6.4%)^2,4.

In the ATOM trial, 228 men with osteoporosis had larger 12-month bone density gains at the spine, total hip and femoral neck than with placebo; fractures were not the main endpoint³. In rats treated for most of their lifespan, abaloparatide caused dose- and time-dependent bone tumors (mostly osteosarcoma), similar to a parathyroid hormone fragment at comparable exposure; the label states it is unknown whether this happens in people^4,5.

The FDA approved abaloparatide (Tymlos) in 2017 for postmenopausal women with osteoporosis at high risk of fracture, and in 2022 added an indication to increase bone density in men with osteoporosis at high risk of fracture⁴.

In the women's trial, the most common reactions were raised urine calcium, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo; in men, injection-site redness, swelling and pain, dizziness and joint pain led the list. The label warns about allergic reactions including anaphylaxis, osteosarcoma (it advises avoiding use when baseline risk is raised, such as Paget's disease or prior skeletal radiation), dizziness or low blood pressure on standing, high blood calcium, and kidney stones⁴.

1. Hattersley et al., Endocrinology 2016PubMed
2. Miller et al., JAMA 2016PubMed
3. Czerwinski et al., J Bone Miner Res 2022PubMed
4. FDA label: TymlosFDA label (DailyMed)
5. Jolette et al., Regul Toxicol Pharmacol 2017PubMed