Childhood and adolescence are a critical time of development for bone health. When children have everything they need to thrive, they can develop strong bones that last a lifetime and stave off problems of old age, like fragility fractures. When medical complications prevent strong bone from developing, examining the underlying causes and identifying changeable cofactors can allow these young people to develop better bone density and prevent fractures.
Madhusmita Misra, MBBS, MD, MPH, is a pediatric endocrinologist, chair of pediatrics at UVA, and the physician-in-chief for UVA Health Children's. She researches and conducts clinical trials focused on determining the most effective ways to improve bone health in the context of conditions like anorexia and autism.
What are you working on right now?
I am working on a couple of clinical trials, one of which is funded by the Department of Defense, and the other by the National Institutes of Health.
The first is a double-blind, randomized, placebo-controlled study of oxytocin in children 6-18 years old with autism spectrum disorder. Children with autism are at risk for low bone density and fractures, likely related to dietary deficiencies, insufficient bone loading, reduced muscle mass, and relatively high cortisol levels.
Oxytocin is known to increase bone formation, decrease bone resorption, increase muscle mass, and reduce cortisol levels. Participants will be randomized to receive oxytocin or placebo for 12 months, followed by a 6-month open label phase when all receive active oxytocin.
The second study is a double-blind, randomized, placebo-controlled study of romosozumab followed by zoledronic acid in young women 16-25 years old with functional hypothalamic amenorrhea. The study will enroll young women who are amenorrheic because of anorexia nervosa or excessive exercise. Participants will receive romosozumab (a bone anabolic drug) or placebo for 6 months, following which all will receive a single dose of zoledronic acid (a long-acting bisphosphonate that reduces bone resorption). All will receive calcium and vitamin D supplements and physiological estrogen replacement.
Adolescents and adults with anorexia nervosa or exercise induced amenorrhea are at high risk for low bone density and fractures. While transdermal estradiol with cyclic progesterone results in some improvement in bone outcomes, these measures often remain well below normal. The hope is that the proposed sequential administration of romosozumab and zoledronic acid will normalize bone measures.
What are the most intriguing potential clinical applications of your work?
My research is primarily clinical and the direct applications relate to the specific populations we study. Data from the ongoing clinical trial of oxytocin in children with autism will be directly applicable to this population, and if the results are positive, we should be able to consider oxytocin as a strategy to improve bone health in children with autism.
Similarly, results from the study of romosozumab and zoledronic acid in functional hypothalamic amenorrhea will be applicable to young women with anorexia nervosa and exercise induced amenorrhea who have low bone density despite optimizing calcium and vitamin D status and despite estrogen replacement.
What made you choose UVA Health as the place to do your research?
I joined UVA Health as the chair of pediatrics and as physician-in-chief of UVA Health Children’s last year, and one of the reasons I felt comfortable moving my research here was because UVA Health has a rich heritage of ground-breaking research and excellent resources for all kinds of research. The clinical trial unit provides support for the necessary components of performing a clinical trial, and a key component of my research is designing and running clinical trials.
I was also able to procure a very sophisticated bone imaging instrument, the high resolution peripheral quantitative computed tomography, for my lab that is now necessary for bone-related clinical research. Further, I was aware of the excellent support that is available here for grant submissions (both pre- and post-award). Finally, I still collaborate with my colleagues at Massachusetts General Hospital (where I worked until last year), and being at UVA Health has allowed us to expand our recruitment efforts with recruitment occurring at both sites.
What do you wish more people knew about your area of research?
The studies we conduct are designed to address critical gaps in knowledge and in the management of conditions in children, adolescents, and young adults that are understudied and important to address to avoid long-term effects, such as a lifetime of impaired bone density and heightened fracture risk.
It is thus essential to be able to recruit the necessary number of participants to these studies. I wish more people knew how important it is to enroll participants in a timely fashion (as funding for these studies is limited), and the numerous safeguards that are built into study protocols to minimize possible risks to study participants.
We rely on our primary care providers and specialists to inform possible participants and their families of the study in question, and to spread the word about ongoing studies. We also make the studies as straightforward as is possible for participants and the recruitment process as simple as possible for referring providers.
How did you become interested in your area of research?
My interest in bone health started way back during my fellowship in pediatric endocrinology at Massachusetts General Hospital, when I inherited a partially completed study examining bone accrual over time in adolescents with anorexia nervosa from a previous fellow in the program.
Over the years, one study has led to the next; the initial studies defined bone outcomes in anorexia nervosa, and led to subsequent studies that examined factors that contributed to these outcomes, and finally to clinical trials to improve bone health based on our knowledge of contributing factors. I have since studied bone health in hyperexercising young women, in youth with obesity (particularly following metabolic and bariatric surgery), in type 1 diabetes, and more recently in children with autism spectrum disorder.
My interest in autism developed when a colleague who directed the Lurie Center for Autism in Boston came to me after a talk I was doing on anorexia nervosa to ask whether I knew how autism impacted bone (given her clinical observation of fractures in children with this condition). She and I have since collaborated on studies examining bone outcomes in autism, factors that contribute to impaired bone health in these children, and more recently, treatment strategies to address low bone density.
