ENP112: Osteoporosis and the SABRE Project

Summary

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ENP112: Osteoporosis and the SABRE Project

Endocrine News Podcast – May 18, 2026

Host: Aaron Lohr, Endocrine Society
Guests:

• Dr. Dennis M. Black (Professor of Epidemiology & Biostatistics, UCSF)
• Dr. Richard Eastell (Professor of Bone Metabolism, University of Sheffield)
• Dr. Marielle Buckstein (Professor of Orthopedic Surgery, Harvard Medical School)

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Episode Overview

This episode explores the landmark FDA decision to qualify total hip bone mineral density (BMD) as a surrogate endpoint for osteoporosis drug trials—a shift inspired by findings from the SABRE (Study to Advance Bone Mineral Density as a Regulatory Endpoint) Project. The panel of SABRE leaders discusses the scientific rationale, regulatory implications, and broader significance of this change for osteoporosis drug development and beyond.

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Key Discussion Points & Insights

Why SABRE Was Needed in Osteoporosis Drug Development

• Traditional clinical trials for osteoporosis required huge sample sizes (up to 15,000 people over five years) because fractures—the primary outcome—are relatively rare events.
• The scale and cost of these trials deterred drug development:

  "As a result, there are no phase 3 clinical trials proceeding at the moment."
  —Dr. Richard Eastell [01:34]

Challenges with Fracture Reduction as an Endpoint

• Low event rate of fractures necessitated very large, lengthy, and costly studies.
• Existing therapies force trials to use lower-risk populations or active comparators, further inflating required sample sizes.

  "Trials must enroll patients...who have lower risk and/or be done comparing to an active therapy, therefore, further increasing the sample size."
  —Dr. Dennis Black [02:49]

Establishing Hip Bone Mineral Density as a Surrogate

• BMD is already known to correlate with bone strength and fracture risk, but SABRE needed to prove change in BMD predicts fracture reduction at the trial level—not just individual correlation.
• SABRE used meta-regression to show high correlation (R² ≥ 0.65) between trial-level BMD change and fracture risk reduction, considered sufficient to serve as a surrogate endpoint.

  "We saw correlations as high as that and higher. So that was convincing...to the FDA."
  —Dr. Marielle Buckstein [04:19]

• Hip BMD outperformed lumbar spine and biochemical markers due to less confounding by age-related changes or mechanistic variability.

SABRE’s Dataset and Its Impact

• Database included 160,000+ patient records, 16 drugs, 7 mechanisms of action—bolstering generalizability.

  "That really adds to the generalizability of the results...regardless of the mechanism of action."
  —Dr. Dennis Black [06:13]

Transforming Clinical Trial Design

• New paradigm reduces trials from 8-10,000 subjects (3-4 years) to as few as 500 subjects (1.5-2 years).

  "It's an order of magnitude reduction in the resources required to carry out these trials."
  —Dr. Marielle Buckstein [07:06]

Enabling Innovation in Osteoporosis

• Supports not only antiresorptive but also anabolic therapies, broadening the scope for innovative drugs:

  "We expect in the future we're going to see more and more anabolic treatments, and...the SABRE approach [will] be valid."
  —Dr. Richard Eastell [08:07]

Why the FDA Change Took So Long

• Massive effort to collect and harmonize data from legacy trials; required new types of regulatory collaboration and navigation of multiple FDA divisions.

  “It took almost five years to assemble the database... So that out of the gate was a challenge.”
  —Dr. Dennis Black [08:55]

Immediate Industry Impact

• Lower barriers spur new interest: 7-8 groups have already initiated development efforts since FDA’s qualification, up from zero drugs in late-stage development before SABRE.

  "It's already shown an incredible increase in the amount of interest..."
  —Dr. Marielle Buckstein [10:58]

Prospects for New Drug Classes

• Expecting both acceleration of existing drug classes and emergence of novel mechanisms in coming years:

  "We can see there's already a lot of excitement...I'm sure we're going to hear about new classes over the next year or two."
  —Dr. Richard Eastell [12:00]

Safety Assessment with Smaller Trials

• Safety signals for serious adverse events in osteoporosis drugs have typically emerged through post-marketing surveillance, not pre-approval trials.

  "Almost all...have been picked up in post marketing surveillance...that's going to have to continue."
  —Dr. Richard Eastell [12:59]

• Preclinical assessment of bone quality and human biopsies remain required.

  "Our application recommended...the current requirement...provide an additional layer that the bone formed under these new treatments will be of good quality."
  —Dr. Dennis Black [14:01]

Post-Marketing Surveillance

• No major anticipated changes; established post-marketing monitoring remains critical.

SABRE as a Regulatory Science Model

• Potential for the approach to be adopted in other diseases (e.g., oncology, Alzheimer’s) needing validated surrogate endpoints.

  "We've defined kind of the level of evidence...the FDA can feel comfortable approving other endpoints as surrogates."
  —Dr. Marielle Buckstein [15:18]

Lessons in Team Science & Partnerships

• Success relied on partnership among NIH, Foundation for NIH (FNIH), FDA, industry, and academic societies.

  "It really got us connected, I think, in ways that we, as academic investigators on our own could not have gotten these same connections."
  —Dr. Marielle Buckstein [16:22]

• Academic investigators had to learn regulatory science quickly, with strong support from professional societies like ASBMR and Endocrine Society.

International Perspective

• FDA is the first regulator to accept hip BMD as a surrogate in osteoporosis, but others (EMA, MHRA) are interested and may accept the same data package.

  "Once a drug is approved by the FDA, the MHRA will give it accelerated approval in the UK...We're looking around the world to try and make sure that the acceptance of this approach is worldwide."
  —Dr. Richard Eastell [21:30] "The European Medicines Agency has indicated...the data package...will probably be acceptable."
  —Dr. Dennis Black [22:34]

Future Outlook for Osteoporosis Drug Development

• The shift has already happened, argues Dr. Black:

  "Osteoporosis drug development changed in December 2025...bone density can be used as a primary outcome in future trials will clearly streamline drug development."
  —Dr. Dennis Black [19:04, summarized]

• Hopes for more patient options and addressing the treatment gap:

  "I think this decision is really going to help us address the treatment gap in the management of osteoporosis."
  —Dr. Dennis Black [20:41]

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Notable Quotes & Memorable Moments

• On trial feasibility:

  "Some trials were as large as 15,000 people studied over five years. And this was just too daunting to consider."
  —Dr. Richard Eastell [01:34]

• On BMD as a surrogate:

  "We saw correlations as high as that and higher. So that was convincing...to the FDA."
  —Dr. Marielle Buckstein [04:19]

• On why BMD ‘won’ as a surrogate:

  "We did look at other bone density sites...surprisingly [lumbar spine] wasn't [the most useful test]."
  —Dr. Richard Eastell [05:09]

• On database power:

  "We had over 160,000 individual patient observations...that really adds to the generalizability of the results."
  —Dr. Dennis Black [06:13]

• On post-marketing surveillance:

  "Almost all...have been picked up in post marketing surveillance...that's going to have to continue."
  —Dr. Richard Eastell [12:59]

• On global impact:

  "This approval from the FDA will have hopefully quite a few knock on effects around the world."
  —Dr. Richard Eastell [21:30]

• On SABRE’s legacy:

  "This decision is really going to help us address the treatment gap in the management of osteoporosis."
  —Dr. Dennis Black [20:41]

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Important Timestamps

• 00:00–01:16 — Introduction & panel introductions
• 01:34–02:49 — Problems with traditional trial design in osteoporosis
• 03:15–06:56 — Scientific rationale and statistical validation for BMD as a surrogate
• 07:06–08:02 — Impact on trial size and duration
• 08:07–08:45 — Applicability to new, mechanistically distinct therapies
• 08:55–10:50 — Challenges in assembling the SABRE database and regulatory navigation
• 10:58–12:39 — How SABRE is already reshaping the development pipeline
• 12:59–14:46 — Safety assessment, quality measures, and ongoing requirements
• 15:18–16:13 — Broader significance for regulatory science
• 16:22–18:26 — Lessons on collaboration and overcoming barriers
• 19:04–20:41 — Looking ahead: impact on patients, providers, and the treatment landscape
• 21:29–22:34 — International regulatory considerations

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Conclusion

The FDA’s decision, underpinned by the SABRE Project’s comprehensive analysis, offers a pivotal shift in osteoporosis drug development—dramatically reducing trial size, cost, and duration, and opening the door to therapeutic innovation. The process demonstrates the value of large-scale data, public-private partnership, and regulatory flexibility, setting a precedent for other fields. The panel expresses optimism that this change will lead to a new era of therapeutic options and improved care for osteoporosis patients worldwide.

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Transcript

[A]

Hello, I'm aaron lohr, and this is the endocrine news podcast. Recently, the US Food and Drug Administration qualified total hip bone mineral density as a surrogate endpoint to support clinical trials for osteoporosis drugs. This decision will significantly impact clinical trials moving forward, as the traditional endpoint of fracture outcomes comes with many challenges regarding sample size, duration, and cost. The change came about because of findings from the study to advance bone mineral density as a regulatory endpoint project, also known as the Sabre Project. What is the Sabre project, and how did it arrive at these findings? How will this decision affect the design of clinical trials and time to approval of new osteoporosis therapies? To help us answer these questions and many more, we have three leaders of the Sabre Project joining us today. Dr. Dennis M. Black, professor of Epidemiology and Biostatistics at the University of California, San Francisco, Dr. Richard Eastle, professor of Bone Metabolism at the University of Sheffield, and Dr. Marielle Bucksine, professor of Orthopedic Surgery at Harvard Medical School. Thank you all for being here today.

[B]

Nice to be here.

[C]

Nice to be here. Thank you for the opportunity to talk to the Endocrine Society. Yep.

[D]

Thank you.

[A]

Wonderful. So, for listeners who may not be familiar, what problem was Sabre trying to solve in osteoporosis drug development?

[D]

So the big problem that we have in the area of osteoporosis is that we have no new drugs being developed, and yet there's a big need for them. And the obstacle that we faced was that the clinical trials that we're doing have become so large. So some trials were as large as 15,000 people studied over five years. And this was just too daunting to consider. And as a result, there are no phase 3 clinical trials proceeding at the moment.

[A]

And why has fracture reduction been such a difficult endpoint to work with historically?

[D]

So fracture events are very uncommon, even in people with osteoporosis. And so that means that when we're designing our studies, we need to be studying many thousands of people for many years in order to be able to capture enough events to have the power to be able to identify a response to treatment. And so this is what motivated us to think of a different way of designing our trials that could be done in a smaller number of people, and that would allow us to get the answer we could still be confident in.

[B]

If I could jump in on that just for one other bit of information. Because we have effective therapies available, trials must enroll patients or subjects who have lower risk and or be done comparing to an active therapy, therefore, further increasing the sample size of the trial required to show a reduction in fractures as an endpoint.

[A]

What convinced you that hip bone mineral density could function as a true surrogate rather than just a correlate?

[B]

Oh, that's such a terrific question, Erin. One of the fundamental things that we know is that bone mineral density is very strongly associated with bone strength in the laboratory. This is the kind of work that my laboratory does. We show very strong correlations between BMD as measured clinically. And when I take a bone specimen and break it in the lab to simulate, for example, a hip fracture. The other thing that we know for many years now is that low bone mineral density is strongly predictive of an increased risk of fracture. We can see in observational studies the relationship between low B and B and fracture. What we needed to do in this study was to show that the change in bone density could predict the outcome.

[A]

And in the sabre analysis, what convinced you that this was a good surrogate endpoint for fracture?

[C]

Well, the. Our primary analysis tool was correlating the changes that you see within each trial with the fracture reduction in that trial. And so we did called a meta regression to do that. And you can measure the strength of the association by the R squared, the correlation between the changes in BMD and the changes in fracture reduction across the trials. And then that correlation. It's been suggested in the past that for the types of techniques we used, a correlation of about 0.65 on a scale of 0 to 1 was sufficient. And we saw correlations as high as that and higher. So that was convincing to not only to us, but also to the fda.

[D]

Could I jump in as well to say that as well as looking at the total hip, we did look at other bone density sites, such as the lumbar spine, because many people were expecting lumbar spine to be the most useful test, and surprisingly it wasn't. And we think the main reason for this is that as people get older, they tend to get degenerative change in the spine, which makes it a less useful measurement. And then we also thought it might be helpful to have biochemical markers of bone turnover, because these are the ways through which the drugs are working. And we did have quite a large number of results of the bone turnover markers, but they didn't prove to be as useful as the bone density. And that's partly because some of our treatments work by stimulating bone formation and some work by inhibiting bone resorption. And so the markers going different directions. So we Couldn't have one rule for everything. And this is why bone density proved to be such a useful test, because increasing bone density went along with reduction in fracture risk.

[B]

And also, Erin, if I could add, I think if we take a step back, one of the things that gave us confidence in the results that Dr. Black just mentioned was the large database that we had with over 160,000 individual patient observations in our database that includes data from 16 different drugs that had seven different mechanisms of action. That really adds to the generalizability of the results that we found and allows us to think that regardless of the mechanism of action of a new therapy that might come along, that it would likely fit into this paradigm, showing that higher changes in BMD would predict greater reductions in fracture.

[A]

So we talked about how significant the Sabre project is. How does its findings potentially fundamentally change the design of a phase three osteoporosis trial?

[C]

Well, as we've heard before already in this podcast, that the typical osteoporosis trials in the past were large and long duration, up to eight to 10,000 patients, typically three to four years duration. So the Sabre guidelines fundamentally change the way future trials would be done. In terms of sample size, we've calculated that the sample size could be as small as 500 patients, 250, say, per treatment group, again compared to 10,000, which is a substantial change. And in terms of duration, which is very important, particularly for drug developers. But the duration of the trials, they could be two years, possibly only a year and a half, instead of eight to 10 years. So this is. It's an order of magnitude reduction in the resources required to carry out these trials.

[A]

And does this open the door to testing more mechanistically novel therapies?

[D]

Yes, we believe it does. We were able to have access to several clinical trials of anabolic treatments. And the relationship between the bone mineral density at two years or one year and the fracture risk reduction was just on the same line as for the antiresorptive drugs. So it does look as though this is actually appropriate for anabolic treatments. And this is really important because we expect in the future we're going to see more and more anabolic treatments, and this is going to be allow this approach, the Sabre approach, to be valid.

[A]

So this is the first FDA qualified surrogate endpoint in this space. So why did it take so long?

[B]

Okay, that is such a good question and a little bit embarrassing to answer. Erin, thank you so much. I would say, you know, out of the gate, one of the things that took the longest was actually the collection of the database. And so we were collecting data with the help of the foundation for NIH from industry sponsors where the drug was now generic and the people who initially conducted the trial did not have the data or have the ability to sign the data sharing agreement. So there was a lot of sleuthing at the very beginning and it took almost five years to assemble the database. So that out of the gate was a challenge and really took some digging to collect the data. Secondly, and I think more looking inwardly, we are a team of academic investigators that don't have a tremendous amount of experience in regulatory science. So I think we had some learning to do to how to put this package together. And we had a lot of guidance from the fda. But also I think this was a new, relatively new pathway for them. And so figuring out and working together took a little bit of time. And of course the FDA takes time to review things very carefully. So we would submit something and have a decent amount of time waiting for their review to come back. I would say one of the other sort of challenges on the FDA on the regulatory side is that our application included components of having a device, the DEXA machine drug development as well as the biomarkers group. So there were three divisions within the FDA that had to come together to work on this qualification project. So I'm sure that that contributed to some of the challenges on their side in the review process.

[A]

And now that we have these findings, how should industry think differently about osteoporosis pipelines?

[C]

I think it very importantly lowers the bar for what it takes to get into this because the resources requ acquired are much less. And so I think it's less intimidating for companies and people, individual new startups. And so because of that there have been, there's a huge amount of interest in Only this is less than six months since the qualification was given by the fda, but there are a number, I mean, who knows, we don't know exactly how many, at least seven or eight different groups that have now jumped into it. Whereas before this time there were no drugs in late stage development at all in osteoporosis for a number of years. So it's, it's already shown an incredible increase in the amount of interest in developing newer therapies.

[A]

So based on that response, I can predict the answer to this next question, but I'm going to ask it anyway. Do you expect a wave of new drug classes or primarily faster development of existing ones?

[D]

Thank you, Aaron. I think we're going to see classes here when we attend the Bone meetings. We hear about all of the new exciting pathways for the regulation of bone turnover. And we also hear about the clinical, the preclinical models of new drugs. So we can see there's already a lot of excitement. And then myself, I've had quite a few companies approach me asking me about new drugs and how we could apply sabre to their development. So I'm sure we're going to hear about new classes over the next year or two.

[A]

So I'm going to take a quick pause real quick. So I thought. Mary, I saw you wanted to say something and.

[C]

No.

[A]

Okay. Just wanted to make sure. So we talked earlier about the new clinical trials may now have smaller sample sizes. So how will the safety of those trials be assessed when we have those smaller sample sizes?

[D]

Yeah, we've encountered this as being one of the most common questions that we have about Sabre is the whole issue about safety. Because of course the sample size will be smaller, as you say, and so that's less ability to pick up side effects in the short term. But when we think about the drugs that have been developed for osteoporosis over the last 20 or 30 years and we think about the side effects that have been encountered, almost all of these, not all, but almost all of them, have been picked up in post marketing surveillance or the description by seasoned investigators of case series of adverse events. And I'm thinking here about conditions such as atypical femur fracture, osteonecrosis of the jaw or even esophagitis with the oral bisphosphonates. So that's going to have to continue to be the same way, I believe, and that we don't lose a lot in terms of safety by having smaller trials.

[B]

And I think one thing also, if I can step in here, is that our application recommended that the current requirement for preclinical studies to show good bone quality by maintaining a relationship between bone mass and bone strength, as well as maintaining the current requirement of biopsies in humans during some phase of the clinical trial development, provide an additional layer that the bone formed under these new treatments will be of good quality. So in addition to what Dr. Eastall said, I think we have the other requirements that will remain in place and won't change based on this ruling.

[A]

How should post marketing surveillance adjustments adapt in this new paradigm?

[C]

I'm not sure it really needs to adapt. A post marketing surveillance has been a feature of approval of all recent osteoporosis drugs and I think it would just be a similar type of post marketing experience.

[A]

And do you see this as a template for other diseases, validating surrogate endpoints using pulled trial data?

[C]

I think that yes. And I think other fields do see this as an innovative pathway. We've defined kind of the level of evidence and the type of evidence that needs to be collected so that the FDA can feel comfortable approving other endpoints as surrogates. I think there are a number of fields that have been really hungry for this kind of thing. And cancer, for example, tumor size as a tumor change with treatment as a predictor of long term cancer free survival is one area. Another area is an Alzheimer's disease where we know the treatments that are based on attacking amyloid or tau tangles. And now there are enough trials in that field to also be. Those could be used as potential surrogates as well. Just a couple of examples. There are a lot of examples in other therapeutic areas.

[A]

There is so much to learn from this project. What does Sabre teach us about team science and public private partnerships?

[C]

Well, we, we worked very closely in the beginning, starting with the NIH, but then very quickly bringing in, as Dr. Buckstein mentioned, the foundation for NIH. And what the foundation was able to do for us is to create this partnership with industry, very importantly to help us be able to get the individual patient data we needed, and then secondly also to get us funding to go through this. And as well as a connection with the fda, the foundation for NIH has a close connection with biomarkers, in particular in the FDA that also helped us. So it really got us connected, I think, in ways that we, as academic investigators on our own could not have gotten these same connections. So I think that that's really important. So I think I would strongly recommend this particular pathway. I think FNIH was very, very helpful to us.

[A]

Obviously, a lot of work went into this and there's a lot of moving parts. Did you encounter any scientific or political barriers that you needed to overcome?

[B]

I think it such a good question. You know, I think the only, you know, the barriers that we had were related to gathering the data in the first place, as I mentioned, and also just learning how to work with the fda. I think we felt that we had a very supportive and engaged relationship with the folks that we talked to at the fda. But again, framing this kind of work into regulatory science was different experience than most of us had done before. So I think not necessarily a barrier, but more just a lot of learning had to go on in order to think about how to do the analyses, how to present the analyses, what issues had to be considered from the regulatory viewpoint that we, you know, probably didn't have as much experience doing. So that was probably the biggest thing. I don't know if my colleagues want to mention anything.

[C]

No, I guess in terms of support, though, to go back to that. And I think it would also mention that something. One thing that was very helpful is to have cooperation from some key societies. For example, the American Society in Bone and Mineral Research made this as one of their strategic objectives. And I think the Endocrine Society has also been very supportive of this and I think that has eliminated a barrier, barriers. So I think that's. That's been very helpful.

[A]

I always like to close out a podcast a future looking question. So what does osteoporosis drug development look like 10 years from now because of Sabre?

[B]

All right, I'll take. I'll take a stab. I think it's not actually 10 years from now, Erin. I think that osteoporosis drug development changed in December 2025 and that the ruling is going to be applied. There are two therapies that have either completed phase two or are currently in phase two. So they will be able to apply this in their phase three trial very soon, in the next year or two, probably. So I think that the FDA's decision to approve SABR and that bone density can be used as a primary outcome in future trials will clearly streamline drug development. I believe this landmark decision is going to spur interest, innovation and investment in the osteoporosis field that is broadly needed because this is a very common disease that impacts one in two women over the age of 50 and about one in five men who will suffer a fracture in their remaining time, in their remaining lifetime. So hopefully having new options for patients and providers will address some of the unmet treatment gap that we see in osteoporosis. Can I say that again?

[A]

Sure.

[B]

I don't like unmet treatment gap.

[C]

It was very good, Mary.

[B]

I don't know. Just the last part

[A]

we can keep most of. If there's one particular sentence you want

[B]

to reword the very end.

[D]

All right.

[A]

Yeah.

[B]

Yeah. So I. I think this decision is really going to help us address the treatment gap in the management of osteoporosis.

[A]

Well, that is about all the time we have for today. I really appreciate the three of you taking time out of your busy days to talk to us about the SABR project. Thank you so much.

[B]

Thank you for having us.

[C]

Thank you. Yeah.

[A]

So we'll call that a wrap. You know, as we were talking I had one question that we never discussed and maybe it's not worth talking about, but we do have a lot of listeners from outside of the United States and I'm not sure what the regulatory field looks like outside or have, have other countries already adopted this kind of regulation when it comes to clinical trials and osteoporosis, Is this the first to, to use, you know, hip bone marrow density? Is this the first?

[C]

Yes.

[D]

Can I answer that first? So yes, the FDA is the first. The beauty about the FDA is they had in the US had in place these rules based on the 21st Century Cures act, which we had to follow. And so that was all in place and so we followed that. But for sure other regulatory agencies are interested in this whole topic of surrogacy and we've already had discussions with the European Medicines Agency and I've inquired with in the uk we have the mhra and they will, once a drug is approved by the fda, the MHRA will give it accelerated approval in the uk. So this approval from the FDA will have hopefully quite a few knock on effects around the world. And we're also inquiring with the Japanese agency and Australia and so forth. We're looking around the world to try and make sure that the acceptance of this approach is worldwide wonderful.

[B]

Also, the European Medicine Agency has indicated that the data package that was put together for the FDA submission will probably be acceptable, that we won't need to gather new data specifically for different regulatory agencies that will be able to use largely the same analyses that were put together.

[A]

And that's all for this episode. I hope you enjoyed hearing about the Sabre Project. The idea for today's episode was brought to my attention from the Endocrine Society's Bone and Mineral Special Interest Group. The Society's Special Interest Interest groups are members only communities created to foster connections and share knowledge online and in person. At Endocrine Society meetings, there's groups covering topics such as adrenal and pituitary obesity, neuroendocrinology, early career and so many more. There's a group for everyone. If you've not yet joined, consider this your invitation. Come on out and be part of the community. We'll provide a link to the special interview US groups in today's episode. Description until next time, thanks for listening.