abaloparatide

**Mechanism of action:** Abaloparatide is a 34-amino-acid synthetic peptide analog of PTHrP (1-34). It is a selective agonist of the PTH1 receptor (a Gs-coupled GPCR, which raises cAMP). It preferentially binds the transient (RG) conformation of the receptor. This produces a brief signal that favors bone formation over resorption. Intermittent (daily) dosing is anabolic: osteoblast activity rises, which increases bone mineral density and strength. Continuous PTH exposure, as in primary hyperparathyroidism, is catabolic and increases osteoclast-mediated resorption.

**Indications:** - Postmenopausal women with osteoporosis at high risk of fracture (history of osteoporotic fracture, multiple risk factors, or failure/intolerance of other therapy). - Men with osteoporosis at high fracture risk (approved later, based on the ATOM trial).

**Dosing:** 80 mcg subcutaneously once daily (abdomen). Before 2021 the lifetime limit was 2 years. Current labeling no longer states a hard cumulative limit, but the usual approach is a finite course followed by an antiresorptive. Stopping an anabolic agent without follow-on therapy leads to loss of the BMD gains.

**Evidence:** In the ACTIVE trial, abaloparatide reduced new vertebral fractures (~86%) and nonvertebral fractures versus placebo. It increased BMD more than teriparatide at some sites, such as the total hip. It also caused less hypercalcemia than teriparatide.

**Adverse effects:** - Orthostatic hypotension, dizziness, and tachycardia/palpitations. Give the first doses where the patient can sit or lie down. - Hypercalcemia (mild) and hypercalciuria. Nephrolithiasis is possible. - Hyperuricemia. - Nausea, headache, injection-site reactions. - Osteosarcoma was seen in rats, which prompted a boxed warning. The boxed warning was removed in 2021 because no increased risk has been seen in humans.

**Contraindications/cautions:** Use caution in patients with a history of urolithiasis or hypercalcemia. Avoid it in patients at increased risk of osteosarcoma: Paget disease of bone, open epiphyses (children, young adults), prior skeletal radiation, or bone metastases or skeletal malignancy. Hyperparathyroidism needs caution.

**Boards high-yield comparison:** - **Teriparatide:** PTH (1-34) analog, also anabolic, with the same daily subcutaneous dosing. It requires refrigeration, while abaloparatide does not need refrigeration after first use. - **Romosozumab:** anti-sclerostin monoclonal antibody. It is anabolic and also decreases resorption. It has a boxed warning for MI, stroke, and CV death. - **Antiresorptives:** bisphosphonates (first line, inhibit osteoclasts), denosumab (RANKL inhibitor), SERMs (raloxifene), calcitonin. - **Sequencing:** In very high-risk patients (e.g., T-score < -3.0 or recent vertebral fracture), consider an anabolic agent first, then an antiresorptive. - **Mnemonic:** Anabolic = "build" (teriparatide, abaloparatide, romosozumab). Antiresorptive = "block breakdown."

**Clinical pearl:** Monitor serum calcium if hypercalcemia is a concern. A patient with osteoporosis who has a new fracture despite bisphosphonate therapy is a classic case for switching to an anabolic agent.