Teriparatide
rhPTH(1-34), recombinant human parathyroid hormone (1-34), PTH(1-34), human parathyroid hormone (1-34), LY333334
Teriparatide is the first 34 amino acids of human parathyroid hormone, made by recombinant DNA technology. Given as a once-daily injection it is one of the few genuinely bone-building (anabolic) osteoporosis medicines, rather than one that merely slows bone loss. It has been licensed since 2002 and its fracture-reduction evidence is among the strongest in the osteoporosis field.
Mechanism
Teriparatide contains the entire receptor-binding region of parathyroid hormone. It is a full agonist at the type 1 parathyroid hormone receptor (PTH1R), a class B G-protein-coupled receptor expressed on osteoblasts, osteocytes and renal tubular cells. Binding couples predominantly to Gs, raising intracellular cyclic AMP and activating protein kinase A, with secondary coupling to Gq/phospholipase C and protein kinase C. In bone this drives transcription of RUNX2 targets, prolongs osteoblast lifespan by suppressing apoptosis, and recruits bone-lining cells into an active osteoblastic phenotype. It also suppresses osteocyte production of sclerostin, de-repressing canonical Wnt/beta-catenin signalling, which is a major part of the anabolic effect.
What matters clinically is the pattern of exposure rather than the molecule itself. Continuous PTH1R stimulation, as in primary hyperparathyroidism, upregulates RANKL and suppresses osteoprotegerin in osteoblast-lineage cells, driving osteoclastogenesis and net bone loss. Brief, once-daily spikes produce a period during which bone formation is stimulated before resorption catches up, the so-called anabolic window. Teriparatide's very short half-life is therefore therapeutic design, not a limitation. At the kidney, PTH1R activation increases distal tubular calcium reabsorption, inhibits proximal phosphate reabsorption and stimulates 1-alpha-hydroxylase, raising 1,25-dihydroxyvitamin D and intestinal calcium absorption, which explains both the transient post-dose hypercalcaemia and the hypercalciuria seen on treatment.
What the research shows
The pivotal Fracture Prevention Trial randomised 1,637 postmenopausal women with prevalent vertebral fracture to teriparatide 20 or 40 micrograms daily or placebo. Over a median 21 months, new vertebral fractures fell from 14 per cent on placebo to 5 per cent on the 20 microgram dose (relative risk reduction 65 per cent) and non-vertebral fragility fractures fell by 53 per cent. The trial was stopped early when osteosarcoma appeared in a lifetime rat carcinogenicity study, so the planned follow-up was truncated. The head-to-head VERO trial later randomised 1,360 postmenopausal women with severe osteoporosis to teriparatide or risedronate for 24 months and found new vertebral fractures in 5.4 per cent versus 12.0 per cent, and clinical fractures in 4.8 per cent versus 9.8 per cent, the first fracture-endpoint superiority of an anabolic over an oral bisphosphonate. In glucocorticoid-induced osteoporosis, an 18-month randomised comparison against alendronate in 428 patients showed greater lumbar spine gains and fewer new vertebral fractures with teriparatide.
The evidence is not uniformly positive and several important limitations deserve stating. Hip fracture was never an adequately powered endpoint in any teriparatide trial; the anti-fracture data at the hip rest on pooled and non-vertebral analyses rather than a dedicated trial. Bone mineral density at the distal radius falls slightly during treatment, reflecting increased cortical porosity as remodelling space expands, and the clinical meaning of this is still debated. Combination with alendronate blunted rather than enhanced the anabolic response in the PaTH study, and sequence matters. Giving a bisphosphonate first attenuates the subsequent teriparatide response. Gains are also not durable: bone density declines once treatment stops unless an antiresorptive follows. On the safety side, the rodent osteosarcoma signal that shaped the original labelling has not been reproduced in humans. Long-term pharmacovigilance linking prescription records to state cancer registries found no excess of osteosarcoma in treated patients relative to unexposed comparators or to background incidence, which led the FDA to remove the boxed warning and the two-year lifetime limit in November 2020.
Evidence assessment
High-quality evidence
Multiple large, replicated, placebo- and active-controlled randomised trials with radiographic and clinical fracture endpoints, plus more than two decades of regulator-approved labelling in the US, EU and UK and long-term registry-based safety surveillance. All five citations were confirmed against PubMed with matching titles, journals and years.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis Preclinical only
Teriparatide 20 micrograms daily reduced new vertebral fractures from 14 per cent to 5 per cent (relative risk reduction 65 per cent) and non-vertebral fragility fractures by 53 per cent, with lumbar spine bone mineral density rising about 9 per cent. The trial was terminated early after a rodent osteosarcoma signal emerged.
Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial Preclinical only
New vertebral fractures occurred in 5.4 per cent on teriparatide versus 12.0 per cent on risedronate (risk ratio 0.44), and clinical fractures in 4.8 per cent versus 9.8 per cent. First demonstration of fracture-endpoint superiority of an anabolic agent over an oral bisphosphonate.
Teriparatide or alendronate in glucocorticoid-induced osteoporosis Preclinical only
Lumbar spine bone mineral density increased 7.2 per cent with teriparatide versus 3.4 per cent with alendronate, and new vertebral fractures were fewer with teriparatide (0.6 per cent versus 6.1 per cent).
Teriparatide and osteosarcoma risk: history, science, elimination of boxed warning, and other label updates Preclinical only
No increase in osteosarcoma was found among teriparatide-treated patients compared with unexposed groups or with expected population background incidence. These data supported FDA removal of the boxed warning and of the 24-month lifetime treatment limit in November 2020.
Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial Preclinical only
In the open-label teriparatide arm, new vertebral fractures were significantly reduced versus placebo (under 1 per cent versus 4.2 per cent). Hypercalcaemia was more frequent on teriparatide (6.4 per cent) than on abaloparatide (3.4 per cent). Because the teriparatide arm was open-label, this does not constitute a blinded head-to-head fracture comparison between the two anabolic agents.
Safety
The commonest adverse effects are nausea, headache, dizziness, leg cramps, arthralgia and injection-site reactions. Transient hypercalcaemia occurs in a minority and typically peaks 4 to 6 hours after a dose; persistent hypercalcaemia or hypercalciuria warrants investigation. Orthostatic hypotension can occur, usually within the first few doses and self-limiting. Uric acid rises modestly. Anti-teriparatide antibodies develop in a small proportion but have not been shown to affect efficacy. The approved labelling lists pre-existing hypercalcaemia, severe renal impairment, metabolic bone disease other than osteoporosis (including Paget's disease of bone), unexplained elevation of alkaline phosphatase, prior external-beam or implant radiation therapy to the skeleton, skeletal malignancy or bone metastases, and open epiphyses as contraindications or as risk factors requiring caution; the precise categorisation changed with the 2020 labelling revision, so current labelling should be consulted. The rodent osteosarcoma finding that originally drove the boxed warning was dose- and duration-dependent in a species with lifelong bone growth and has not translated to humans, but caution in people with baseline osteosarcoma risk factors remains in the labelling. Bone density gains are lost after discontinuation unless an antiresorptive agent follows, so treatment sequencing is a clinical decision, not an optional extra. This entry is educational and does not describe how to use or obtain the medicine.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Authorised by the MHRA, originally via the EU centralised procedure in June 2003, for the same broad indications. Several follow-on teriparatide products are licensed in Great Britain and Northern Ireland. NHS use of anabolic agents is steered by NICE technology appraisals, which position teriparatide, abaloparatide and romosozumab for people at very high fracture risk and direct prescribers to the least expensive suitable option. Current NICE guidance should be checked directly, as appraisals in this area have been revised repeatedly. |
| United States | FDA-approved since November 2002 for postmenopausal women with osteoporosis at high fracture risk, men with primary or hypogonadal osteoporosis at high fracture risk, and men and women with glucocorticoid-induced osteoporosis at high fracture risk. The boxed warning for osteosarcoma and the 24-month lifetime treatment limit were removed in November 2020; osteosarcoma risk is now addressed under Warnings and Precautions. Multiple follow-on teriparatide products are marketed. |
| WADA (sport) | Not named on the WADA Prohibited List. The S2.2 growth factor catch-all is written around agents affecting muscle, tendon or ligament, which teriparatide is not. Athletes should nonetheless confirm against the current list, as a legitimate prescription for osteoporosis would in any case be documentable. |
Questions
Not quite. Native human parathyroid hormone is 84 amino acids long. Teriparatide is the first 34 of those, the fragment that contains essentially all the receptor-binding and biological activity. The remaining 50 residues are not required for PTH1 receptor activation, though they influence clearance and may have separate actions.
The difference is the exposure pattern, not the molecule. Continuously raised parathyroid hormone, as in hyperparathyroidism, sustains RANKL-driven osteoclast activity and produces net bone loss. A brief once-daily pulse stimulates osteoblast recruitment and survival and suppresses sclerostin before resorption fully catches up, creating a temporary window of net bone formation.
The concern originated in a lifetime rat study in which osteosarcoma developed at high doses over most of the animals' lifespan, in a species whose growth plates never close. Human surveillance linking prescription records to cancer registries found no excess risk. The FDA removed the boxed warning in November 2020 and lifted the 24-month lifetime limit at the same time.
Bisphosphonates are antiresorptive: they slow bone breakdown. Teriparatide is anabolic: it stimulates new bone formation. In the VERO trial teriparatide reduced new vertebral and clinical fractures more than risedronate in women with severe osteoporosis. They are not interchangeable, and the order in which they are used affects the result.
Bone mineral density declines relatively quickly after teriparatide is withdrawn. Trial and registry data consistently show that gains are best preserved when an antiresorptive agent follows, which is why anabolic therapy is generally described as a time-limited phase within a longer treatment plan rather than a standalone course.