teriparatide

Teriparatide is a recombinant, biologically active fragment (amino acids 1-34) of human parathyroid hormone (PTH), administered via daily subcutaneous injection. It is FDA-approved for severe osteoporosis (postmenopausal women and men) at high fracture risk, glucocorticoid-induced osteoporosis, and in patients who have failed or cannot tolerate other osteoporosis therapies (e.g., bisphosphonates).

Mechanism: PTH physiologically has dual effects on bone depending on the pattern of exposure. Continuous elevation (as in hyperparathyroidism) increases RANKL expression by osteoblasts, promoting osteoclastogenesis and net bone resorption, raising serum calcium. In contrast, intermittent, pulsatile administration (once-daily dosing) preferentially stimulates osteoblast number and activity over osteoclasts—increasing osteoblast lifespan by reducing apoptosis and increasing IGF-1 signaling—leading to a net anabolic effect: increased bone formation, improved trabecular microarchitecture, and increased bone mineral density (BMD), particularly at the spine.

Use duration is limited to 2 years due to concern for osteosarcoma seen in rat studies at high doses (boxed warning), so it is contraindicated in patients with Paget disease, unexplained elevated alkaline phosphatase, open epiphyses, prior skeletal radiation, or bone metastases.

Clinical significance/Step relevance: Teriparatide is a classic example of a drug where dosing schedule determines opposite physiological effects (anabolic vs. catabolic)—a favorite USMLE testing point contrasting continuous vs. intermittent PTH exposure. It's often compared with antiresorptive agents (bisphosphonates, denosumab, raloxifene) which decrease bone turnover rather than stimulate new bone formation. After discontinuation, patients are typically transitioned to an antiresorptive agent to maintain BMD gains.

Adverse effects: transient hypercalcemia, orthostatic hypotension, leg cramps, nausea, and the black box warning of osteosarcoma risk (based on animal studies).