More than 35% of adults in the U.S. experience chronic sleep restriction, which can be attributed to either health-related conditions or night shift work. This sleep restriction is associated with adverse health conditions and, increasingly, negative bone health such as bone loss, bone fractures and osteoporosis.
Dr. Jeffery Toth, professor of biomaterials in the Department of General Dentistry and associate dean for research at the School of Dentistry, is co-investigator on a project, funded by an R01 award from the National Institutes of Health’s National Institute on Aging. It aims to determine the mechanisms by which chronic sleep restriction impairs bone remodeling, a lifelong process of bone renewal, and how this impairment may change the trajectory of normal bone health toward osteoporosis and fragility later in life. The award has an expected value of $2.38 million over four years, with Marquette to receive just over $304,000.
Toth is a multiple principal investigator on the project with Dr. Carol Everson, professor of medicine in the Division of Endocrinology and Molecular Medicine at the Medical College of Wisconsin. The award came after Everson and Toth completed a pilot study in 2023 that obtained preliminary biomechanical and histologic data on how chronic sleep restriction impacts age-related bone disease in rats.
“Dr. Everson reached out to me to seek my expertise to review bone histology slides of animals that were sleep restricted versus bone histology slides of animals from a control group,” Toth says. “Open to collaboration, I said ‘yes,’ and when I initially viewed the sleep restricted bone histology slides, the differences were striking!”
Those initial findings and the complementary expertise of the two researchers suggested the potential for a major research project. Everson’s research interests revolve around the necessity of and restorative properties of sleep. Her lab often addresses the question: “What does sleep do at a cellular and systems level?” With his expertise in cellular-level bone structure and evaluation, Toth will oversee protocol development and quantification of bone modeling and remodeling for the investigative team for integration in the findings in each of the objectives.
“Open to collaboration, I said ‘yes,’ to reviewing bone histology and when I initially viewed the sleep restricted bone histology slides, the differences were striking!”
Chronic lack of sleep places people at risk for bone loss and bone fragility that characterize osteoporosis, an age-related, debilitating disease affecting millions of U.S. men and women. This can lead to lost independence and early death. Toth and Everson’s research will define the biology of chronic sleep deficiency — how it changes bone structure and remodeling activities that underlie bone fragility and fracture risk, using a validated animal model that effectively simulates the human condition it is intended to model. The knowledge gained will be a foundation for translational research aimed at reducing age-related morbidity imposed by chronic sleep deficiency.
Dr. Jeffery Toth answered some questions on his research interests and approach, how he got involved with the School of Dentistry, and the public awareness element to this R01.
You don’t have a dental background, but you serve as the School of Dentistry’s associate dean of research. How has your biomaterials background and research helped you create this bridge between biomedical engineering and dental research?
I direct the OREC Biomaterials and Histology laboratory located on the first floor of the William Wehr Physics Building at Marquette. For over 30 years, my research themes have included biomaterials for bone graft substitutes, bone tissue engineering, explant analysis of spine devices, and testing of spine, orthopaedic and dental biomaterials. Biomaterials are materials used in the body, and I teach biomaterials courses at Marquette in biomedical engineering as well as at the School of Dentistry and Medical School campuses.
As an active researcher, you are aware of what it takes to foster research collaboration. What have you learned in that role that you are able to carry over into your associate dean position?
I think that in order to be successful as a researcher and research dean, the person must be an effective “team player” — exhibiting a willingness and ability to work with many people as part of a team. From both my extramural funding record and publication history, one can see that I have collaborated with and published with dentists, orthopaedic and spine surgeons, basic science researchers and numerous other investigators around the world to carry out collaborative research. There are many repeat collaborators on the publications and grants which implies successful continued collaboration.
What is the focus of your research career? What is your specialty?
I have research expertise in evaluating bone healing and efficacy of spine, orthopaedic and dental biomaterials using bone histology, biomechanics and radiography. In fact, the most frequent surgical procedure performed upon humans is the dental extraction. Bone healing is also necessary and required in bone fracture repair and many orthopedic and dental surgical procedures, especially in older adults (e.g., hip and knee arthroplasty, spinal fusion, tooth extraction and dental implants).
You mentioned that Dr. Everson’s pilot grant with rats yielded some interesting results. How did that support this current R01?
The sleep-restricted animals had almost no active sites of intramembranous ossification, which we would expect to see in a growing rat bone. In addition, hematopoietic marrow (which makes our red and white blood cells and platelets) was nearly exclusively found in intertrabecular spaces (spaces within the boney tissue network) with little to no fatty marrow in sleep-restricted rats. Each abnormal feature found is expected to be consequential. We did more collaborative research work resulting in a paper and worked to develop a competitive R01 research grant application to the NIH’s National Institute on Aging, since understanding osteoporosis in aging is a major health initiative.
What are the underlying goals of these projects?
It’s incorrect to assume that all patients’ bones will heal the same way, as we know of some preexisting conditions that can affect bone healing. Inadequate blood supply, diabetes, smoking and implant instability are all known conditions that impair bone healing, but chronic sleep restriction, the subject of our new grant award, is a largely unrecognized cause of impaired bone remodeling that is poorly characterized. Understanding mechanisms that impair bone healing has significance in dentistry, orthopaedics, spine surgery and many other areas of medicine, especially in relation to healing after dental and orthopaedic procedures with implanted biomaterials.
The new grant is mechanistic — we are focusing on understanding the biology underlying this unrecognized, major risk factor for bone loss, fractures and osteoporosis — chronic sleep deficiency and its consequences for healthy aging.
Is there a public awareness goal to this research on the benefits of proper, consistent sleep habits?
More than 35% of adults in the U.S. undergo chronic sleep restriction, which is associated with multiple, incompletely understood adverse health outcomes. Chronic sleep restriction is increasingly recognized as a risk factor for bone loss, bone fractures and osteoporosis. The U.S. Department of Health and Human Services has named reducing osteoporosis a major objective of “Healthy People 2030.” Our research on chronic sleep restriction as a cause of osteoporosis is expected to be instrumental in advancing both public awareness and medical practice by providing the biological basis of this modifiable risk factor.
Night shift work and chronic sleep restriction in middle-age to older adults imparts a similar risk of fracture as corticosteroid therapy, the most common cause of secondary osteoporosis. The effects of sleep restriction on bone health during adulthood are unknown and the implications for diseases of aging may be different than for immature bone. Osteoporosis, which increases dramatically with aging, is a leading cause of disability, lost independence and premature death. About half of women and 1 in 5 men over the age of 50 experience osteoporotic fractures.
The R01 study began at the beginning of April 2024 and will run through March 2028.
