What was the Teriparatide Fracture Prevention Trial (FPT)?
Also known as the Fracture Prevention Trial (FPT), the teriparatide study was a groundbreaking, randomized, double-blind, placebo-controlled Phase 3 clinical trial conducted in the early 2000s. It was designed to evaluate the safety and efficacy of teriparatide (Forteo®), a synthetic form of the parathyroid hormone (PTH), in preventing fractures in postmenopausal women with established osteoporosis. Published in The New England Journal of Medicine in 2001, the trial's results led to the FDA approval of teriparatide as the first anabolic (bone-building) agent for osteoporosis treatment.
Before this trial, most osteoporosis treatments were anti-resorptive, meaning they worked by slowing down the breakdown of bone. Teriparatide offered a new, anabolic approach by stimulating the cells responsible for building new bone. This unique mechanism made the FPT a critical study for advancing treatment options for patients at high risk of fracture, a population for whom other therapies had proven insufficient.
Study Design and Methodology
Patient Population
The FPT enrolled 1,637 postmenopausal women with existing osteoporosis and at least one prior vertebral fracture. The median age of participants was approximately 70 years. In addition to their assigned treatment, all participants received daily supplements of calcium and vitamin D to support bone health. The inclusion criteria focused on a high-risk population to clearly demonstrate the drug's effect on fracture prevention.
Treatment Arms
Participants were randomly assigned to one of three groups:
- Placebo: Daily subcutaneous injections of a placebo.
- Teriparatide 20 µg: Daily subcutaneous injections of teriparatide at the dose later approved for market.
- Teriparatide 40 µg: Daily subcutaneous injections of teriparatide at a higher dose to assess dose-dependency.
Duration and Assessments
The original trial was designed to last 36 months, but it was terminated early due to concerns from concurrent animal studies. The median duration of treatment was approximately 19 months. The primary outcomes were new vertebral and nonvertebral fractures, which were assessed through radiographs taken at baseline and regular intervals. Bone mineral density (BMD) was also measured using Dual-energy X-ray Absorptiometry (DXA) at the spine and hip.
Key Findings and Results
Vertebral Fractures
The most dramatic finding of the FPT was the significant reduction in new vertebral fractures. Compared to the placebo group, the daily 20 µg dose of teriparatide reduced the risk of a new vertebral fracture by 65%. For patients with severe baseline vertebral fractures, the risk reduction was even higher. A follow-up study also showed that this reduction in fracture risk persisted for at least 18 months after stopping therapy, although the benefit is known to wane over time without subsequent anti-resorptive treatment.
Nonvertebral Fractures
The trial also demonstrated a statistically significant reduction in nonvertebral fractures (fractures in bones other than the spine) in the 20 µg teriparatide group compared to placebo, with a relative risk reduction of 53%. However, the trial was not powered to show significant differences for individual fracture sites, such as the hip. Subsequent real-world data and meta-analyses have since confirmed a reduction in hip fracture risk associated with teriparatide treatment.
The Impact on Bone Strength Beyond BMD
A notable finding from a post-hoc analysis of the FPT was that teriparatide's fracture reduction effect was greater than what would be predicted from the change in bone mineral density alone. This highlighted that teriparatide improves bone strength not just by increasing mass, but also by enhancing bone quality and microarchitecture. The improvements in bone structure are a key differentiator from anti-resorptive drugs.
The Importance and Legacy of the FPT
The teriparatide Fracture Prevention Trial was a landmark study that revolutionized the approach to severe osteoporosis. Its success led to teriparatide's FDA and EMA approval, giving clinicians a powerful anabolic tool to use in patients with a very high fracture risk. The trial demonstrated that it was possible not just to stop bone loss, but to actively build new bone, offering renewed hope for those suffering from the most severe cases of osteoporosis.
However, the trial's termination due to animal study findings and the potential for a rebound in bone loss after treatment cessation underscored critical considerations for long-term management. As a result, standard protocol today dictates that teriparatide treatment, typically for a maximum of 2 years, must be followed by an anti-resorptive agent like a bisphosphonate to preserve the hard-won bone gains. The FPT permanently changed how severe osteoporosis is treated.
Comparing Teriparatide to Other Osteoporosis Treatments
| Feature | Teriparatide (Anabolic Agent) | Bisphosphonates (Anti-Resorptive) |
|---|---|---|
| Mechanism of Action | Stimulates new bone formation by activating osteoblasts. | Inhibits osteoclast activity, which slows bone breakdown. |
| Route of Administration | Daily self-administered subcutaneous injection. | Oral tablets (daily or weekly) or intravenous infusion. |
| Treatment Duration | Maximum of 24 months per course. | Often years, depending on the specific drug and patient. |
| Effect on Fracture Risk | Strong reduction in vertebral fractures; also reduces non-vertebral fractures. | Reduces vertebral and non-vertebral fracture risk. |
| Target Population | High-risk patients, especially with prior vertebral fractures. | Broad range of osteoporotic patients. |
| Effect on Bone Quality | Improves bone microarchitecture beyond density increase. | Primarily affects bone quantity by preserving existing bone. |
Potential Risks and Limitations of the Trial
The most significant limitation of the FPT was its early termination. This was prompted by preclinical animal studies in rats that showed a dose-dependent increase in osteosarcoma, a type of bone cancer, with high-dose, long-term teriparatide exposure. While this risk has not been replicated in human studies at therapeutic doses, it led to a "black box" warning on the drug's label and its limited treatment duration.
The trial also revealed a few common, though generally mild, side effects that were more prevalent than in the placebo group:
- Dizziness or lightheadedness, particularly after initial injections.
- Nausea.
- Leg cramps.
Additionally, the study was not initially powered to specifically analyze the risk reduction for all individual fracture types, though supplementary analyses and real-world data have provided further context.
Conclusion
The teriparatide fracture prevention trial was a landmark achievement in osteoporosis research, fundamentally altering the therapeutic landscape for patients with severe disease. The trial convincingly demonstrated teriparatide's ability to not only halt but reverse the progression of bone loss by actively stimulating new bone formation, leading to a significant reduction in vertebral and non-vertebral fractures. While the trial's legacy includes a short treatment window and safety considerations stemming from animal studies, its contribution of a new anabolic class of medication remains profoundly important. The FPT solidified teriparatide's place as a potent and effective tool for those most vulnerable to the devastating consequences of osteoporotic fractures, particularly when used in sequence with subsequent anti-resorptive therapy to sustain the gains.
Bone Health & Osteoporosis Foundation: Teriparatide Overview
