Researchers Say Age, Not Decrease in Estrogen, at Root of Osteoporosis

Newswise — Marking a shift in decades of thought on the cause of osteoporosis, researchers at the University of Arkansas for Medical Sciences (UAMS) have identified an age-related mechanism – not a decrease of the hormone estrogen – as the primary culprit.

Aging and the body’s increased inability to defend against bone-damaging molecules produced through a process known as oxidative stress are most directly responsible for the bone-weakening disease – and perhaps other age-related diseases, reported researchers led by Stavros Manolagas, M.D., Ph.D., in the UAMS Center for Osteoporosis and Metabolic Bone Diseases. The research was detailed in an article in the Feb. 3 issue of the journal Cell Metabolism and a review by Manolagas, an internationally known osteoporosis expert, published online by the journal Endocrine Reviews in January.

Researchers found that age weakens the defenses against oxidative stress. In particular, an age-related loss of certain proteins that defend against oxidative stress increase the risk of osteoporosis. Manolagas said conditions such as a loss of estrogen can further decrease the molecular defenses against oxidative stress.

“We feel like we have turned a page in our understanding of osteoporosis,” said Manolagas, director of the Division of Endocrinology and Metabolism in the UAMS College of Medicine. “This emerging evidence provides a paradigm shift from the ‘estrogen-centric’ view of what causes osteoporosis to one in which these age-related mechanisms are the main protagonists and other changes – including the reduction of estrogen – accentuate them.”

Manolagas said that belief in the cause and treatment of osteoporosis for about 60 years had been driven by two observations: the decline of ovarian function at menopause in women leads to a loss in bone mass; and estrogen replacement prevents such loss.

Manolagas pointed to studies that showed bone loss in both women and men – who also can develop osteoporosis – begins as early as the early part of the third decade, which is long before any change in sex hormone production. He said other research showed age as a main factor in compromised bone strength and increased risk of bone fractures.

In the most recent UAMS research, scientists identified a specific family of proteins that served as a defense mechanism against oxidative stress. When the proteins, called forkhead box transcription factors, were removed in young mice, oxidative stress increased and bone weakness developed. When the protein was increased, oxidative stress decreased and the number of bone-forming cells increased and bone mass improved.

“These proteins that defend against oxidative stress are indispensable for maintaining bone mass,” Manolagas said.

The proteins constantly defend against oxidative stress to ensure a normal healthy life span, he said. With age the oxidative stress begins to overwhelm the defense mechanisms.

“Now we will look for what specifically causes the defense mechanisms against oxidative stress to fail over time,” he said.

Manolagas noted that oxidative stress has been implicated as a factor in a range of diseases, including diabetes and age-related conditions such as hardening of the arteries, stroke and Parkinson’s disease. This raises the potential that successful treatments against oxidative stress could impact multiple diseases, he said.

The article “FoxO-Mediated Defense Against Oxidative Stress in Osteoblasts Is Indespensable for Skeletal Homeostasis in Mice” is available online at www.cell.com/cell-metabolism. The lead author of the author was Elena Ambrogini, M.D., an endocrinologist in the UAMS Center for Osteoporosis and Metabolic Bone Diseases. Additional UAMS authors included Manolagas, Maria Almeida, Ph.D., Marta Martin-Millan, M.D., Li Han, M.D., Joseph Goellner, B.S., Robert S. Weinstein, M.D., Robert L. Jilka, Ph.D., and Charles O’Brien, Ph.D.

Manolagas authored the article “From Estrogen-Centric to Aging and Oxidative Stress: A Revised Perspective of the Pathogenesis of Osteoporosis,” which is available online at http://edrv.endojournals.org/.

UAMS is the state’s only comprehensive academic health center, with colleges of Medicine, Nursing, Pharmacy, Health Related Professions and Public Health; a graduate school; a 540,000-square-foot hospital; six centers of excellence and a statewide network of regional centers. UAMS has 2,775 students and 748 medical residents. Its centers of excellence include the Winthrop P. Rockefeller Cancer Institute, the Jackson T. Stephens Spine & Neurosciences Institute, the Myeloma Institute for Research and Therapy, the Harvey & Bernice Jones Eye Institute, the Psychiatric Research Institute and the Donald W. Reynolds Institute on Aging. It is the state’s largest public employer with more than 10,000 employees, including nearly 1,150 physicians who provide medical care to patients at UAMS, Arkansas Children’s Hospital, the VA Medical Center and UAMS’ Area Health Education Centers throughout the state. Visit www.uams.edu or www.uamshealth.com.