Sundeep Khosla, M.D., featuring Christine Lary, Ph.D.

In this special episode celebrating the 40th anniversary of the Journal of Bone and Mineral Research (JBMR), host Dr. Christine Lary sits down with Dr. Sundeep Khosla, a renowned endocrinologist at the Mayo Clinic and one of the leading voices in osteoporosis and aging research.

With more than 35 years of experience, Dr. Khosla reflects on his remarkable career—from his early training at Mass General under influential mentors like Hank Cronenberg and Larry Riggs, to his groundbreaking discoveries that reshaped our understanding of bone biology. He discusses his pivotal work demonstrating the critical role of estrogen in male bone health, innovations in imaging bone microarchitecture, and his more recent research uncovering how cellular senescence contributes to age-related bone loss.

The conversation also explores the evolution of the field, including major technological advances, emerging therapies, and the expanding intersection between bone biology and aging science. Dr. Khosla shares insights from his long-standing relationship with JBMR and the American Society for Bone and Mineral Research, as well as lessons learned from decades of publishing, leadership, and collaboration.

Finally, he offers thoughtful advice for early-career researchers and clinicians—highlighting the importance of mentorship, intellectual curiosity, adaptability, and maintaining a “big picture” perspective in science.

This episode is both a retrospective on a distinguished career and an inspiring look ahead at the future of bone and mineral research.

Transcript

SPEAKER_00 0:03

Hello, my name is Kristen Larry, and I am the current chair of the American Society of Bone Mineral Research Publications Committee. This year we are celebrating the 40th anniversary of the Journal of Bone Mineral Research, and as part of that anniversary, we're hosting a series of interviews with the primary researchers who have made important contributions to this field. It's my honor today to interview Dr. Clinton Kosla. Dr. Kosla has over 35 years of experience in bone health research with our pregnancy endocrinologist at the MAO Clinic and is the Dr. Francis Tucker and Nathan Landau Research Professor of Medicine and Physiology. Dr. Kosl's in an old work in many areas, including understanding the role of estrogen and predicting factor risk and bone density of moon, understanding the effect of aging on bone microstructure, and the use of high-resolution peripheral quantitative computing tomography, which are PTP or A-Beline of Bone Defensive, and more recently studying the effect of telemetry methods on each-burly bone loss. He's also explored the prevention of post-modulasal bone loss with the debate of a cartonal law, which is a study I've had the pleasure of contributing to within terms of leadership. He has served as a 10-year term as editor-in-chief with the Journal Bone and has served as class president of the American Society of Bone Mineral Research. He has published 645 publications with over 73,000 citations, establishing him as one of the world's leading experts in osteoporosis research. So, Dr. Kozla, thank you so much for being with us today. I really appreciate it.

SPEAKER_01 1:31

Thank you for having me.

SPEAKER_00 1:33

So let's maybe start with your early career development and training. Can you tell us a little bit about your early training, who were your influential mentors, and how you became interested in bone mineral research?

SPEAKER_01 1:44

Sure. So after I finished my uh clinical uh endocrine training at uh Mass General Hospital, um, I uh uh had the opportunity to kind of look around for research mentors, which was part of the fellowship. And the person I uh connected with most, both kind of on a personal level and scientifically, was Hank Cronenberg. So I ended up uh spending a couple of years in in Hank's lab working on a very basic molecular biology project, uh namely uh cloning of chicken parathyroid hormone. And of course, this was back in the late 80s when you know cloning wasn't just pulling a sequence off of electronic databases, you actually had to make phage libraries and do the cloning and look at a sequence and all of that. So when I finished my uh time in the lab there, I uh decided to take a position at Mayo Clinic on the clinical faculty and really wasn't sure if I was going to pursue uh a research career. And that was when uh Larry Riggs, who was running a large osteoporosis program at the time, uh really was very influential in uh getting me more excited about uh, in you know, in this case, more translational and clinical research. I kind of had the best of both worlds. I had an outstanding basic science mentor in Hank, and then, you know, uh kind of a parallel outstanding uh uh clinical research mentor in Larry Riggs. So it was sort of inadvertent, but I couldn't have planned it any better.

SPEAKER_00 3:21

And I I love I see both of those, you know, factors in your work. So I love that you had both of those mentors in your early career. Um and Hank is one of also one of the people we're interviewing for this podcast series, so that's really appropriate. Um so I think you kind of addressed this, but what or who was the strongest influence upon your career?

SPEAKER_01 3:41

I'd have to say both of those individuals, you know, um, and I've tried to incorporate uh kind of what I learned from each of them, uh, both about the science in terms of basic versus clinical science, but also the approach to science. And you know, it was pretty remarkable to me that even though Hank and Larry worked in different areas of bone research or osteoborosis research and bone research, um, outstanding scientists, whether they do basic or clinical research, have certain things in common. And you know, one of the main ones that that I saw in both of them was the ability to not just get lost in the weeds and step back and look at the big picture. And that I think is really critical, particularly for younger people coming on, is that you often get so embedded in what you're doing that you don't step back and look at, you know, why is it important and why am I pursuing this line of research? So that was something critical I learned from both of them that they actually had in common. And the other thing I think were, you know, and this is really unique to both of those individuals, they're two gentlemen. You'll never see where, you know, when Larry was active in ASBMR, um, you know, always courteous, always polite, uh, ask hard, tough questions, but not in a way that would in any way embarrass a speaker at the podium and so forth. And I think that's critical to maintaining collegiality in science.

SPEAKER_00 5:08

Right, but so important. Um, so yeah, really interesting. Maybe we can move on to your research. Um, so what key research finding in your career do you believe had the biggest impact on the bone mineral research field, either in terms of research or in terms of uh clinical practice?

SPEAKER_01 5:24

Yeah, so you know, I've kind of had an opportunistic research career, and I kind of emphasized that to my employees. So I'd really have to point to two different things. So one was when I moved to Mayo and started to work with Larry, uh, it was around that time that the New England Journal published a case report of a male with uh homozygous mutations and activating mutations in the estrogen receptor gene. And at that time, you know, ER beta hadn't been cloned, so it was just ER-alpha. Uh and surprisingly, you know, contrary to conventional wisdom, where it was thought that testosterone was the major hormone regulating bone in men, this individual turned out to have osteopenia and open epiphyses. So that really led me to think about the role of estrogen in men. And, you know, Larry and I ended up uh designing a number of epidemiological studies looking at the correlations of sex steroids with bone density and microarchitecture in men. And then really a definitive interventional study that was published around 2000, where we uh made men hypogonal and then gave them either estrogen or testosterone on both, and really directly uh demonstrated that even in men, estrogen was the dominant sex steroid regulating bone metabolism in men. So at that phase of my career, you know, that was kind of a major finding that helped, you know, uh uh kind of uh uh uh propel my work. And I spent many years after that looking at estrogen action on bone in human studies and in mouse models and so forth. And then around the time uh after the Women's Health Initiative came out, there was declining interest in studying estrogen, period. Now, you know, fortunately that pendulum is swinging back now. But it was around that time that we formed the Center on Aging. And again, being opportunistic, uh, I actually decided to kind of retool and take a completely different direction, which is more aging biology. So that was kind of my second career and second, you know, uh second wind, if you will. And I had to learn a whole nother field in terms of uh aging and senescence. And so I guess the second kind of major uh finding from my career was demonstrating the role of cellular senescence in mediating age-related bone loss initially in mouse models, and then eventually translating that to the first randomized control trial of a senolytic intervention in humans in any tissue, and demonstrating that women who had, by our measures, a high senescent cell burden did in fact have a positive response to the senolytic intervention. And that I think has helped is helping to set up future studies looking at uh senolytics, not just in bone, but across other tissues, including, you know, brain and uh uh frailty and so forth. So I kind of think of my career as two different phases, um, you know, sometimes driven by external forces in terms of how the fields were changing. But I think that's the key to science is being willing to adapt and learn new directions if you have to.

SPEAKER_00 8:41

Yeah, absolutely. Um so thinking back through all that work, and it because we're celebrating the anniversary of JBMR, the 40th anniversary, can you think about what your first uh paper was in JBMR?

SPEAKER_01 8:54

I distinctly remember that. Uh it was uh published in uh in uh 1988, uh volume three, and the title Wow, early. Uh and the title was uh Nucleotide Sequence of Clone C DNAs encoding chicken pre-proparathyroid hormone. And the authors were myself, Marie Demay, who really helped me with that project, uh, Mark Pines and Schmuel Horwitz, who were collaborators, uh external collaborators, and John Potts and Hank Runenberg. So it was uh you know my first JBMR paper, uh, my first first author paper, actually. And uh I was really proud of that because it represented several years of work and the cloning of the first uh non-mammalian PTH, uh, which was somewhat different uh, you know, from mammalian PTHs, particularly after about amino acid 34. And it provided, I think, some useful structure function insights into PTH action. Um so uh that was uh I'll never forget that paper.

SPEAKER_00 9:59

Very, very important, important paper. Um so and what what impact in thinking about other papers that you've done in JBMR, you know, what impact have those publications had on your career or or on research in your field in general?

SPEAKER_01 10:13

Yeah, uh I think you know, in terms of JBMR and ASBMR, I mean, uh you know, ASBMR has been my scientific home, you know. Now, even as I've moved into kind of the aging biology field, I still never miss uh I had to miss uh uh last year's ASBMR for the first time, I think, in you know, 35 years, uh just because of some personal issues. Um, but you know, I plan to go to ASBMR again this year, and I never missed the annual meeting, both for the science and the camaraderie. And I think parallel to that, I consider, you know, even in this age, day and age of proliferation of scientific journals, I consider JBMR, you know, as uh uh one of my main scientific homes. And uh whenever possible, I do try to submit there. And I've, you know, uh, I think over the decades published many papers in in JBMR, including kind of some of the early papers uh establishing in epidemiologic studies the stronger correlations of of bone density and uh uh with estrogen rather than testosterone, uh, and then uh almost all of our work that we did with HRPQCT, uh, we published in uh JBMR. Um with the aging biology, I've split some of that between JBMR and some of the aging uh journals like Aging Cell and other journals, but JBMR has remained one of my primary uh journals that I'm proud to publish in.

SPEAKER_00 11:44

Awesome, fantastic. So maybe let's think about um uh advice and thinking about what you would say to early career researchers. Um, so what message would you like to share with the next generation of bow mineral, either researchers or clinicians?

SPEAKER_01 12:00

Yeah, I think, you know, for both, I think this is an extraordinarily exciting time in science, you know, with all the tools that are becoming available. I mean, at the more basic level, kind of the single-cell transcriptomics, proteomics, all the bioinformatics, systems biology, the AI tools. I mean, it's just an explosion of technologies that I'm having actually trouble keeping up with. But, you know, they really provide you with exquisite tools to delve deep into underlying mechanisms, both in animal and more and more in human studies. And I think for the physician and clinician scientists, I think it's really an exciting time for translation in all areas of research, including osteoporosis and rare bone diseases. I mean, you could argue that, well, you know, we have good treatments for osteoporosis, what's left to do? There's a lot left to do. I think, you know, uh, for example, this, you know, the new uh approval by the FDA to uh consider drugs for approval for osteoporosis based on BMD changes that came out of the Sebra project, uh, that's really, you know, uh, I think uh uh the impact of that is going to be really huge because uh it allows a pipeline of new drugs to come in, which would not have been possible had, you know, we all still been required to do large-scale fracture trials. And with a strong, you know, concordance between BMD changes and fracture risk that Dennis Black and colleagues were able to show, I think that decision is really uh appropriate and will also uh open up new possibilities for uh clinical clinical scientists to explore uh novel therapeutics uh for osteoporosis and also for rare bone diseases, where there's a lot of interest in with the advances in genomics. So, I mean, compared to when I started in the bone field, you know, back in the late 80s to where we are now, uh, it's just you know so many more tools and resources that are available to advance both the fundamental and the clinical science. I know, you know, clinically and research uh funding, uh, these are you know challenging times, but I've been in the field long enough to know that these pendulums come and go, and you just have to write it out and you know stick with it. And I think people, young, younger faculty who do that, uh I think will be well rewarded with all of the opportunities that are you know continuing to be available. So I'm actually quite excited and optimistic, even at this late stage of my career. And in fact, you know, part of the reason I have no plans to retire in the foreseeable future is just because I'm so excited about what I do. I don't know what I would do with myself if I actually work and do all the things that I do every day.

SPEAKER_00 14:52

Uh-huh. Absolutely fantastic. Well, let me ask you, let me ask you one more question about um mentorship, and just because you're talking about the next generation of um researchers and clinicians. So, what what is your approach to mentorship and um what are good qualities both of a successful mentor and of a successful mentee? And how do you kind of nurture those relationships?

SPEAKER_01 15:14

Yeah, I think, you know, uh in terms of mentorship, I think the first thing, you know, and this is pretty obvious, you really have to care deeply about the person that you're mentoring and you know what their kind of goals and uh metrics for success are. So I think, you know, regular meetings with the mentee, being completely open with them, and you know, and and I mean that in a positive and a negative way, in that if our, you know, rather than beating around the bush, I've always been completely transparent with people that I'm mentoring. When they're meeting or exceeding expectations, I give them that feedback. Where I see opportunities for improvement, I actually don't wait too long before conveying that message to them, you know, that these are the areas that for you to be successful, uh, you really need to work on. Um and they appreciate that because they know I do that with everybody. And you know, I make it a point to tell them to give me the same feedback. Where if there are things that I can improve as a mentor, I'm open to that, you know, or um maybe sometimes they feel that, you know, I didn't pay close enough attention to some you know issue that they had raised. So well, tell me about it so we can we can revisit it. I think setting realistic expectations is important. Um, you know, pretty quickly a mentor can kind of gauge uh kind of what the range of capabilities of the mentee is. Now you're always trying to expand those, but I think giving them tasks that you know they're gonna fail at before they're ready to do it is just you know asking for uh uh kind of a uh a bad path for the mentee. Um I think conveying that I really do care about their career uh and uh regular meetings and so forth, I think all of those things are really critical. Uh and I'm actually really proud because uh just most recently uh I had some of the best trainees and mentees that I've had. And uh Josh Farr, who worked with me for a long time, has now actually has an endowed uh professorship at the University of Arizona, uh Madison School, um, you know, has been on the faculty now at the University of Connecticut. Uh Dominic Saul, who is from Germany, just went back to a nice position in Germany. So seeing people that I've worked with, you know, move on to successful positions elsewhere and develop their own careers, I think has been uh really gratifying for me.

SPEAKER_00 17:44

Yeah, that's fantastic.

SPEAKER_01 17:45

That's obviously I think that's the best part of my job when I see my mentees, you know, and I think for the mentees, I think the message that I would give is you got to take ego out of it. That's for the mentee and a mentor, but you know, being open to constructive feedback in both directions, you know, science is too important to have egos get involved, really. It's fun and it's too important to, you know, have uh a thin skin and get you know worried about being criticized and so forth. Uh the other thing for mentees, I would say, is that you know creativity is really important, but what I've learned over the years as create the creative process really happens when you continue to read extensively. So even you know, within your area, but even outside your area as much as possible. When your head is full of all the stuff that's happening in science, that's when you can be the most creative. So it's very hard to be creative in a vacuum, at least in my opinion. Uh being embedded and keeping up with the literature, which you know, now in the past I used to get paper journals and would rip out articles. Now it's so easy to keep up with the literature, you know, with all the electronic table of contents and PubMed, and then uh I use uh you know various literature searches. So I actually set aside uh generally uh you know it's pretty much been, you know, throughout my career. Um Sundays I tend to read. So, you know, now the the corollary to that is I don't read much fiction or other books, I read science. So Sundays is when I'll I'll I'll kind of file all my electronic table of contents and stuff during the week. And Sundays I kind of catch up on that, download papers I'm interested in, and sometimes I'll do that when I'm watching the football games or whatever. So Mondays I often come up with, you know, come to the lab with new ideas that I've thought about over the weekend. And I think that process is really critical.

SPEAKER_00 19:47

That's that's awesome. I love that. Um, so any last words for you know for ASBMR, for for JBMR, for young bone mineral density researchers um that you know you want to reflect on uh over the course of your year?

SPEAKER_01 20:01

Yeah, I just feel that the you know ASBMR and the bone research community is really unique. I mean, I've you know participated in other meetings and you know, I'm spending some time in the aging community at this point. I think the you know, the level of kind of collegiality and interconnectedness that we have in the in ASBMR, the outstanding journal that we have, and I think the exciting science that we have. I mean, I think there's you know, expanding horizons about bone and calcium metabolism in terms of the integrated physiology of bone, how bone interacts with other tissues and crosstalks with other tissues, how it ages along with other tissues, how it grows, you know, the rare bone diseases. There's so much science that's you know still to be done. And it's it's such a wonderful community overall that despite the challenges that we face, you know, which are substantial in terms of NIH funding, potentially declining pharma interests, all of those things. I don't think we should let those things discourage us, but we should keep pressing the science forward, and I think the other things will continue to fall into place over time. So I'm I remain optimistic, and that's why, as I say, I choose not to retire and come to work every day because this is what's fun for me.

SPEAKER_00 21:21

Awesome. Well, thank you so much, Dr. Sundeep Klosla. I really appreciate it. It's truly an honor, and thank you so much for doing this today.

SPEAKER_01 21:29

Thanks, Christine.