Abaloparatide
BA058, BIM-44058, PTHrP(1-34) analogue, abaloparatide acetate
Abaloparatide is a synthetic 34-amino-acid analogue of parathyroid hormone-related protein, not of parathyroid hormone itself. Like teriparatide it is a daily injectable bone-building treatment for osteoporosis, but it was engineered to bias signalling towards bone formation with less calcium-raising effect. It has been licensed in the US since 2017 and in the EU and UK since 2022.
Mechanism
Abaloparatide is derived from parathyroid hormone-related protein (PTHrP) 1-34 rather than parathyroid hormone. Eight residues in the 22-34 region are substituted (including glutamate at 22 and 25, leucine at 23, 28 and 31, lysine at 26 and 30, and the helix-stabilising non-natural residue 2-aminoisobutyric acid at position 29), and the C-terminus is amidated. These changes were selected to stabilise the amphipathic helix and to alter how the peptide engages its receptor.
Both abaloparatide and teriparatide act at the same target, the type 1 parathyroid hormone receptor (PTH1R), producing Gs-coupled cyclic AMP generation, protein kinase A activation, increased osteoblast recruitment and survival, and suppression of osteocyte sclerostin with de-repression of Wnt signalling. The proposed difference is conformational selectivity. PTH1R exists in a high-affinity, long-lived state (R0) that supports prolonged signalling from internalised receptor, and a transient, G-protein-dependent state (RG). Teriparatide binds both, whereas abaloparatide binds RG with relatively greater selectivity and R0 more weakly, giving a shorter-lived signalling event. In principle this should shift the balance towards formation with less of the resorptive and renal calcium-raising response that follows sustained R0 occupancy. The clinical correlate is a lower observed rate of hypercalcaemia than with teriparatide, and less rise in the bone-resorption marker CTX early in treatment. It is worth being clear that the R0/RG account is a well-supported pharmacological hypothesis rather than a settled explanation for every clinical difference between the two drugs.
What the research shows
The pivotal ACTIVE trial randomised 2,463 postmenopausal women with osteoporosis to abaloparatide 80 micrograms daily, placebo, or open-label teriparatide 20 micrograms daily for 18 months. New vertebral fractures occurred in 0.58 per cent on abaloparatide versus 4.22 per cent on placebo, an 86 per cent relative reduction, with a 43 per cent reduction in non-vertebral fractures. Hypercalcaemia was less common on abaloparatide (3.4 per cent) than on teriparatide (6.4 per cent). In the ACTIVExtend follow-on, women who had received abaloparatide and then moved to weekly alendronate showed sustained reduction in new radiographic vertebral fracture relative to the placebo-then-alendronate arm; the first published analysis covered 18 months of abaloparatide plus 6 months of alendronate, and the full 24-month extension has since been reported separately. A phase 3 trial in men with osteoporosis (ATOM) supported the bone density indication granted in the US in 2022, and the Japanese phase 3 ACTIVE-J study confirmed spine and hip bone density gains in an East Asian population.
Several caveats belong alongside those numbers. ACTIVE was not powered for hip fracture, and no abaloparatide trial has demonstrated hip fracture reduction; the non-vertebral benefit is a composite. The teriparatide arm was open-label, so the head-to-head comparison of the two anabolics is not a blinded contest and no formal superiority claim on fractures was made. Both ATOM and ACTIVE-J used bone mineral density, not fracture, as the primary endpoint. Palpitations and tachycardia were more frequent than on placebo, and a modest transient rise in heart rate after dosing is a consistent finding. A transdermal microneedle patch formulation did not reproduce the bone density gains achieved by subcutaneous injection and was not carried forward, which is a relevant null result for anyone assuming route-switching is straightforward with this class. The EU regulatory path was also not smooth: an initial application was withdrawn in 2018 before approval was eventually granted in December 2022. As with teriparatide, gains are not maintained after discontinuation without a sequenced antiresorptive.
Evidence assessment
High-quality evidence
A large placebo-controlled phase 3 trial with a radiographic vertebral fracture primary endpoint, a pre-specified extension, a supporting phase 3 trial in men, a separate phase 3 in a Japanese population, and marketing authorisations with approved labelling in the US, EU and UK. All five citations have now been confirmed against PubMed, including two that the draft had left unverified.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial Preclinical only
New vertebral fractures occurred in 0.58 per cent on abaloparatide versus 4.22 per cent on placebo (86 per cent relative reduction); non-vertebral fractures fell 43 per cent. Hypercalcaemia was less frequent on abaloparatide (3.4 per cent) than teriparatide (6.4 per cent).
Eighteen months of treatment with subcutaneous abaloparatide followed by 6 months of treatment with alendronate in postmenopausal women with osteoporosis: results of the ACTIVExtend trial Preclinical only
Sequential abaloparatide followed by alendronate maintained a substantial reduction in new radiographic vertebral fracture relative to placebo followed by alendronate, supporting the value of sequencing an antiresorptive after anabolic therapy.
Fracture and bone mineral density response by baseline risk in patients treated with abaloparatide followed by alendronate: results from the phase 3 ACTIVExtend trial Preclinical only
Fracture risk reduction with sequential abaloparatide-then-alendronate was consistent across baseline risk strata, including women with and without prevalent vertebral fracture and across bone mineral density categories.
The efficacy and safety of abaloparatide-SC in men with osteoporosis: a randomized clinical trial Preclinical only
Abaloparatide increased lumbar spine, total hip and femoral neck bone mineral density significantly more than placebo in men, supporting the US indication extension granted in 2022. The trial was powered for bone density, not fractures.
Abaloparatide increases lumbar spine and hip BMD in Japanese patients with osteoporosis: the phase 3 ACTIVE-J study Preclinical only
Abaloparatide produced significant gains in lumbar spine and hip bone mineral density versus placebo in Japanese patients, extending the ACTIVE findings to an East Asian population. Bone density, not fracture, was the primary endpoint.
Safety
The most frequently reported adverse effects are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, abdominal pain and injection-site reactions. Orthostatic hypotension can occur in the hours after a dose, most often at the start of treatment. A small transient increase in heart rate after dosing is a consistent pharmacological finding and palpitations and sinus tachycardia were reported more often than on placebo, so caution is described for people with pre-existing tachyarrhythmias. Hypercalcaemia occurs but at a lower rate than with teriparatide. Serum uric acid rises modestly. Labelling advises against use where there is pre-existing hypercalcaemia, severe renal impairment, metabolic bone disease other than osteoporosis, unexplained alkaline phosphatase elevation, skeletal malignancy or bone metastases, prior skeletal radiotherapy, or open epiphyses. As with teriparatide, the rodent osteosarcoma finding has not been borne out in human surveillance and the boxed warning was withdrawn, though the risk statement remains in the warnings section. Bone density gains regress after discontinuation unless followed by an antiresorptive. This entry is educational and contains no dosing or administration guidance.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Authorised for postmenopausal women at increased risk of fracture. The EU marketing authorisation was granted on 12 December 2022 after an earlier application had been withdrawn in 2018. NICE technology appraisal TA991, published in 2024, recommends abaloparatide as an option for treating osteoporosis after menopause only in people at very high risk of fracture and subject to a commercial arrangement, and advises choosing the least expensive suitable option where abaloparatide, teriparatide and romosozumab are all appropriate. The exact publication date of TA991 could not be independently verified for this entry, so current NICE guidance should be checked directly. |
| United States | FDA-approved April 2017 for postmenopausal women with osteoporosis at high risk of fracture; indication extended in 2022 to increase bone density in men with osteoporosis at high fracture risk. The original osteosarcoma boxed warning and the cumulative lifetime duration limit were removed in a subsequent labelling revision, aligning it with the revised teriparatide labelling. |
| WADA (sport) | Not named on the WADA Prohibited List. The S2.2 growth factor provisions target agents acting on muscle, tendon or ligament; abaloparatide acts on bone via PTH1R. Athletes should verify against the current list. |
Questions
Teriparatide is a fragment of parathyroid hormone; abaloparatide is an engineered analogue of parathyroid hormone-related protein with eight substitutions and a C-terminal amide. Both act at the PTH1 receptor, but abaloparatide favours the transient RG receptor conformation over the long-lived R0 state. Clinically this correlates with less hypercalcaemia and a smaller early rise in bone resorption markers.
Aib is a non-natural, doubly methylated amino acid that strongly favours helical geometry. Placing it in the C-terminal region stabilises the amphipathic helix that docks into the receptor's extracellular domain, improving conformational stability and resistance to proteolysis. It is a common tactic in peptide drug design and is also found in several incretin analogues.
No. The ACTIVE trial was powered for radiographic vertebral fracture and reported a composite non-vertebral fracture reduction. Hip fracture events were too few for a meaningful analysis, and no abaloparatide trial has been designed to answer that question. This is a genuine gap rather than a technicality.
A microneedle patch formulation was developed to avoid daily injections, but in comparative testing it did not reproduce the bone mineral density gains achieved with the subcutaneous route and was not taken forward to approval. It is a useful reminder that for peptides the delivery route is part of the drug, not a detail.
It is licensed in the UK, and NICE guidance TA991 from 2024 recommends it as an option only for people at very high risk of fracture after menopause, subject to a commercial arrangement. Where abaloparatide, teriparatide and romosozumab are all clinically suitable, NICE directs prescribers to the least expensive option. Current guidance should be checked directly.