Osteoporosis affects 10 million Americans, causes 2 million fragility fractures a year, and carries $20 million in associated health costs.  More than 40 million Americans have low bone mass and are at risk of developing osteoporosis.  Yet there’s surprisingly little known about precisely how and why bones age.  Roman Eliseev, MD, PhD, Associate Professor of Orthopaedics in the Center for Musculoskeletal Research, has earned a five-year, $2 million grant from the National Institute of Aging to better understand whether changes in bone cell energy metabolism are responsible for bone aging. In the process, he and his team hope to answer questions first raised by renowned University of Rochester researcher William Neuman, who first studied metabolism in bone cells and tissues here in the 1970s.

Limitations of Current Treatments
New answers can’t come too soon. Current osteoporosis treatments include hormone replacement, vitamin D, calcium, anti-resorptive bisphosphonates to slow bone loss such as Reclast, and anabolic compounds to stimulate bone activity such as teriparatide and anti-sclerostin antibody. But all of these approaches have serious limitations or are extremely costly.  

Skeletal health is a complex, lifelong system of metabolic processes. In bone remodeling, old bone continually breaks down and the body creates new bone to replace it; the human skeleton completely remakes itself every decade.

Eliseev osteoporosis stages
Osteoporosis happens when too little new bone forms as existing bone is lost. Common wisdom says bone loss is hormone-related, and there is indeed a link between hormonal changes and post-menopausal osteoporosis in women. But bone mass peaks in a person’s 30s and begins to drop in both men and women, long before age-related hormone changes occur. So, what is really going on when bones weaken?

To answer that, the research team will look at the complex interplay between cellular pathways that communicate with each other. Those connections provide energy and vital metabolites required for function of bone-forming cells on bone surfaces called osteoblasts.  

In young, healthy people, osteoblasts produce collagen and then deposit mineral into it to form new bone tissue. But in older people, the normal pathway of bone formation takes a wrong turn. Osteoblasts become less active and make less new bone. Eliseev believes this happens because the way osteoblasts use nutrients to extract energy dramatically changes in aging.

The search for new therapies for osteoporosis is of utmost importance, Eliseev said. “The literature indicates that the imbalance in bone remodeling in aging may, in large part, be due to decreased bone formation by bone osteoblasts. Improving osteoblast function is a promising therapeutic avenue for treating osteoporosis. The cause of osteoblast dysfunction in aging remains incompletely understood, which presents a critical barrier to developing new therapies.”

The basic question centers on which metabolic pathway, at the cellular level, is most important for new bone formation by osteoblasts.

Cells usually have three sources of nutrients from the food we eat: glucose, fatty acids, and glutamine, the major amino acid found in the bloodstream, Eliseev said.

The Controversy: Aerobic Glycolysis vs. Oxidative Phosphorylation
There are two schools of thought about bone metabolism and the way bone cells generate adenosine triphosphate (ATP), a major source of energy for all cellular reactions: aerobic glycolysis, a metabolic process that involves the conversion of glucose into lactate; or oxidative phosphorylation, a process that uses various fuels within mitochondria in the presence of oxygen.

Neuman supported the theory of aerobic glycolysis. His and other researchers’ observation that osteoblasts derive their energy from glucose “became dogma in the field,” Eliseev said.

Fifty years on, Eliseev and his team used modern methods unavailable in Neuman’s time and made discoveries that led to another conclusion. Their work showed that oxygen-fed cellular activity is as important for skeletal cells as glucose-fueled metabolism.

The field established that in addition to glucose, amino acid glutamine and fatty acids are equally important fuels for osteoblasts, and these fuels are broken down in cellular organelles called mitochondria, Eliseev said. “We do see that osteoblasts take up a lot of glucose and break it down to extract energy. But we also observed that osteoblasts take up and break down glutamine. To our surprise, we found that most of the glucose consumed in osteoblasts goes into the so-called Pentose Phosphate Pathway (PPP).  PPP is crucial for the balance of reduction-oxidation in cells and for biosynthesis of cellular building blocks. That is why very little of glucose is converted to lactate in osteoblasts. In aging, however, this metabolic setup changes and glucose supply of the PPP is decreased. This is a novel finding suggesting that changes in metabolic pathways in osteoblasts are a reason for bone tissue aging.”

A Deeper Understanding of Bone Aging
Just like heart cells and muscle cells, bone cells need oxygen and an oxidative pathway of energy production to function properly and to develop into mature cells, Eliseev added. “This has been a source of confusion in the field – some researchers stick to the glycolytic metabolism theory; others claim it’s all oxidative metabolism.” Eliseev hopes the NIH grant project can settle the controversy; his research to date suggests both processes are crucial.

Energy metabolism and changes in how it functions contribute to all the different hallmarks of aging. This whole field started at URMC with Neuman’s research, among other places; maybe now we can expand on his discoveries and deepen our understanding of bone metabolism.

Eliseev and his team already can alter the energy metabolism affecting bones in mice, enabling aging bones to recover.

Drugs exist that act on the metabolic mechanisms we study, he said. The NIH research will focus on basic science that can lead to translational therapies to defend against excessive bone loss and support the body’s production of new bone.

What we learn from this project can open up new avenues to study the mechanisms of bone aging in detail and how osteoporosis develops. Eventually, we may be able to suggest certain treatments focused on fixing the energy metabolism process in humans, in addition to current therapies like hormone replacement and antiresorptive drugs.

Source: https://www.urmc.rochester.edu/news/story/ur-scientists-working-to-crack-enduring-mystery-of-bone-loss-regeneration