Osteoporosis weakens bones and makes them more likely to break. The disease affects about 10 million Americans over age 50, including 1 in 5 women. And those numbers are expected to rise as the share of Americans 65 and older climbs from 18.9% to 23.4% by 2060.
Until now, clinical researchers have tested the effectiveness of drug treatments to strengthen patient bones by tracking whether they suffered fractions. The approach can take years, making new drug development slow and expensive.
But a landmark decision by the U.S. Food and Drug Administration (FDA) late last year changed that. The FDA will now allow researchers to use changes in hip bone density instead of fractures as the primary measure of success in certain late-stage clinical trials of new osteoporosis drugs. For now, the change applies to trials involving postmenopausal women with osteoporosis.
The change grew out of research co-led by UC San Francisco as part of the Study to Advance Bone Mineral Density as a Regulatory Endpoint (SABRE), a public-private collaboration involving academia, the National Institutes of Health (NIH), the FDA, industry, and nonprofits.
We spoke with Dennis Black , PhD, UCSF professor of Epidemiology and Biostatistics and co-lead of the SABRE Project, about what the change means for drug development and patients.
How long has it been since a new drug was developed for osteoporosis?
The most recent drug approval was for Romozumab in 2019. But since then, there were no new drugs in the pipeline because of the expense and time to develop them. Everything just stopped. We wanted to get things going again.
Why did the SABRE Project get started?
The goal was to facilitate the development of new therapies that would give patients more options.
We already have several effective osteoporosis drugs. Why develop new ones?
There are treatments that are effective for osteoporosis, but we need more because some people have rare side effects or find the dosing regimens inconvenient, so many people have life-changing fractures that could have been avoided.
What's the new trial process?
The original trial process required that the companies show that fractures were reduced. Clinical researchers had to study a group of people taking part in drug trials, mostly women because they're at higher risk, and follow them long enough to assess the effect on fracture risk.
A typical Phase 3 trial involved 6,000 to 15,000 patients for three to five years in order to see enough fractures to evaluate whether the drug worked. Under the new approach, trials can involve about 750 patients followed for a year and a half to two years.
Why bone density?
Bone marrow density (BMD) is an important clinical tool that has been used on millions of patients since its introduction in 1988. We looked back at dozens of osteoporosis studies and found a very strong relationship between larger increases in bone density and larger fracture reductions. Further, BMD scanners were first used in 1988 and the technology has been fairly stable so that our analyses could include all trials since that time. As a substitute for occurrence of fractures in trials, changes in bone density can be tracked over shorter periods and involve fewer people - allowing trials can be faster and less expensive.
What gives you confidence in this new approach?
Looking across all these trials, we found that if a drug increased bone density above a certain threshold, there was more than a 95% chance it reduced fractures.
And that held true across drugs that work in very different ways. Some slow the breakdown of bone, while others help build bone. So, while measuring bone density makes trials easier to conduct, the evidence gives us a high degree of confidence that a large enough increase in bone density predicts a reduction in fractures.
This change was more than a decade in the making. What made it so challenging?
There were two big challenges. The first was getting the data. We ultimately assembled data from more than 50 randomized trials involving about 170,000 patients, much of it belonging to private companies, including some companies that had changed ownership several times.
The second challenge was the FDA process. Nothing quite like this had been done before at the FDA, so there were a lot of unknowns and several levels of review. Change in BMD to replace fracture risk is the first surrogate endpoint to be formally qualified by FDA in any therapeutic area since the qualification formal biomarker process qualification process was initiated by FDA.
What could this decision ultimately mean for people living with osteoporosis - and those at risk of developing it?
When people get to the point where their doctor thinks they need treatment, there will be more choices for them. There will be more variety in how drugs are administered, how long they're taken, and their side effects. Some people may be more concerned about a particular side effect or be more at risk for one, and they could choose a different drug.
So that's really the idea - having more choices. And I think more competition could mean that new drugs will be less expensive and, hopefully, access will be better.
Importantly, the acceptance of BMD to replace fracture risk in trials can set a precedent for similarly accelerated development in other therapeutic areas such as cancer or Alzheimer's disease.
