New Insights Into the Complex Biology of Osteoporosis

"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

The loss of bone volume and density resulting in osteoporosis affects all racial, ethnic, and gender groups. In the U.S., an estimated 10 million people age 50 and older have osteoporosis, and about 2 million are men.

As with many chronic degenerative conditions, the pathogenesis of this metabolic bone disease is complex and multifactorial, arising from the synergy of genetic, intrinsic, exogenous, and lifestyle factors. Osteoporosis is the result of accelerated bone loss and is characterized clinically by a reduction in skeletal mass and strength due to an imbalance between bone resorption and bone formation.

Osteoporosis is treatable, but not curable -- at least yet. It can lead to life-restricting immobility and severe fractures from minimal trauma – sometimes requiring hospitalization and surgery, which in some cases results in death.

For decades, osteoporosis was considered a phenotypical syndrome of back pain, low bone mass, and vertebral fractures, and identifying secondary causes of low bone mass was the principal objective of many clinicians. Now, however, osteoporosis is classified as a systemic primary disorder of the skeleton related to profound metabolic changes not only in bone but also in whole-body homeostasis.

"Over the past decade or so we've developed an increasingly sophisticated and nuanced understanding of the process of bone remodeling, of how old damaged bone is removed and new bone laid down, and how this relates to conditions such as osteoporosis," Sarah Keller, MD, of the Cleveland Clinic, told MedPage Today. "It's a process of cell signaling on a continuum. We used to think remodeling was two separate processes but now we know they are not sequential. Both processes take place simultaneously at different sites within the bone remodeling unit as a whole, which is known as the basic multicellular unit, or BMU."

In simple terms, bone maintenance involves this coupled dynamic process of breakdown and replacement. "But as we age, there's a mismatch, and the rate at which we break down old bone outpaces our ability to form new bone," explained Suzanne Jan de Beur, MD, of Johns Hopkins Medicine in Baltimore. "There's a particularly rapid loss of bone in women just after menopause when they lose estrogen, but this high rate tapers off to lower age-related rates of bone loss."

In addition, she said, with age, we start to have a greater number of fat-producing (adipocytes) than bone-producing (osteoblasts) cells in bone marrow: "Fat and bone are based on the same stem cells, and you get more cells driven to the fat lineage and away from bone cell formation."

According to Clifford J. Rosen, MD, of the Maine Medical Center Research Institute in Scarborough, although adipocytes may provide some energy and support for bone, an overabundance does the opposite. "We've made great progress in identifying the precursor cells that shift into becoming adipocytes, and the next step is to find out how to interfere with that shift," he said in an interview.

Biology of Bone Remodeling

As noted, bone metabolism and remodeling are controlled by a delicate partnership of checks and balances between multiple molecular players from growth factors to apoptosis regulators.

Osteocytes interconnect in the solid matrix of bone via an extensive canalicular network that senses both mechanical loading and focal bone damage. Osteocytes secrete molecules that regulate both the location of and the rate of bone remodeling. Osteocyte activity is, in turn, regulated by mechanical loading and circulating hormones including parathyroid hormone (PTH) and estrogen.

It was initially thought that the BMU responsible for bone remodeling consisted of osteoclasts and osteoblasts functioning through a hierarchical sequence of events organized into distinct stages. As Keller indicated, recent discoveries, however, suggest that all bone cells participate in BMU formation by interacting both simultaneously and at different stages of differentiation with their progenitors, other cells, and bone matrix constituents.

Bone remodeling, therefore, is considered a physiological outcome of continuous cellular operational processes optimized to maintain the structural integrity of the skeleton and support the mineral metabolism needs of the body.

Among the key operative agents working in the skeletal system is PTH, whose receptors are found on bone-producing osteoblasts. Stimulation by this hormone increases osteoblast production of the receptor activator of nuclear factor kappa-B ligand (RANKL), which in turn promotes osteoclast differentiation and action.

Hematopoietic cell precursors in marrow induced by macrophage colony–stimulating factor give rise to osteoclasts that express the RANK receptor. The RANKL interaction with RANK in turn stimulates differentiation of the osteoclasts so they can resorb old bone.

The RANKL gene product RANKL is an apoptosis and osteoclast regulator. RANKL action is modulated by its binding to osteoprotegerin. The decoy osteoprotegerin receptor binds RANKL, thereby preventing the RANKL/RANK interaction.

The net effect is osteoclastogenesis inhibition and a slowdown of bone turnover. For its part, the sex hormone estradiol increases production of osteoprotegerin to diminish bone resorption.

Another player in the intricate check-balance system is sclerostin. Produced by osteocytes, sclerostin acts on osteoblasts to inhibit bone formation. Therefore the remodeling of bone is highly regulated by factors that promote the process as well as factors that limit the process to achieve balance.

Predisposing Genes

Jan de Beur agreed that thinking about bone development has changed in the last 10 years or so. "We now know that our bone mass is about 70% genetically determined, although many other factors have an effect," she told MedPage Today.

Several osteoporosis-associated genes have been identified by whole-genome studies, including RANK and RANKL. While others have been discovered by investigating rare bone diseases, other associated genes regulate vitamin D and estrogen receptors, collagen 1A1, interleukin-1, and insulin-like growth factor 1.

An interesting candidate on the playing field is the WnT (wingless-related integrated site) gene, which regulates a protein involved in bone mass. Interestingly, mutations in this gene were found in a North American family with exceptionally high bone density. "Their skull bone was so thick it squeezed off the cranial nerves," Jan de Beur said. "In one kindred, affected family members couldn't float in a pool because their bones were so heavy."

Finding such mutations has helped advance the understanding of how the WnT signaling pathway is important for bone mass. Another candidate gene with strong heritability and predictive value for osteoporosis in the same signaling pathway as WnT is LRP5, which produces a low density lipoprotein receptor–related protein also found to be mutated in families with high bone mass.

But unlike the BRCA1/2 genes in breast cancer, so far there are no preeminent genes governing osteoporosis risk, said Rosen. "There are likely several mutations involved in severe osteoporosis, including some at the stem cell level," he said.

Defining the role of genetic factors and their interaction with established environmental and hormonal determinants will be the most difficult challenge facing basic and clinical researchers, Rosen noted in a review of the epidemiology and pathogenesis of osteoporosis.

Depending on the cohort, the phenotype, and the number of individuals studied, hundreds of genes may contribute to individual variations in bone mass, Rosen said. "Twin studies examining discordant or concordant phenotypes are also helpful, as are sib-pair studies, although the results have been less generalizable."

The Immune System

The last 2 decades have also seen a greater understanding of the interaction between bone and immune cells. According to a report by Iseme and colleagues, the chronic inflammation and immune system dysfunction seen during the aging process and in other pathologies is also associated with osteoporosis. This has led some researchers to think that immune perturbation is an important determinant of bone disease, a view supported by the recognition that the immune and bone systems in fact share regulatory mechanisms and progenitor molecules.

Some researchers have postulated that osteoporosis has an autoimmune component. Rosen is not sure: "It's not really an autoimmune disease. There's a semblance to autoantibodies or autoimmune disease, and definitely there is something happening with the gut microbiome. In certain circumstances there is marrow inflammation, which can be pathogenic, but the connection is still not clear."

Keller noted, however, that people with autoimmune diseases such as rheumatoid arthritis and type 1 diabetes are at increased risk of osteoporosis, and it's possible the two types of conditions share inflammatory characteristics. "A lot more work is needed to understand the immune-bone connection," she said.

Risk Factors

According to Rosen, no strong new risk factors have been established. Recent research, however, is looking at the possible role of endocrine disruptors in widely used household products and the environment. One report, for example, suggested that endocrine disruptors such as phthalates may destabilize the crucial cellular balance of proliferation, differentiation, and functioning of osteoblasts and osteoclasts, as well as alter calcium metabolism by impairing the secretory activity of the endocrine glands and hormone signaling.

Those authors noted that these effects have more impact on children and adolescents during critically sensitive periods of osteogenesis. "All available measures should be taken in order to limit the influence of endocrine disruptors both in utero and postnatal development," the team wrote.

Meanwhile, the classic non-modifiable predisposing parameters remain older age, female sex, slight build, white or Asian race, failure to achieve peak bone mass in youth, and early natural or surgical menopause.

Environmental determinants for bone loss broadly comprise poor nutrition, eating disorders, too-low body mass index, suboptimal intake of calcium and vitamin D, and inadequate exposure to vitamin D-stimulating sunlight.

Smoking, and excessive intake of alcohol are also detrimental, while the impact of high consumption of caffeine is unclear, although it appears to accelerate calcium excretion.

In addition, low levels of weight-bearing activity, including from forced immobility through illness or injury, have a bone-weakening effect.

Augmenting the impact of genetics/family history, race, age, gender, body build, and lifestyle, bone loss is also secondarily exacerbated by other medical conditions. These include rheumatic, enteropathic, and liver and blood diseases, as well as the drugs used chronically to treat them, Jan de Beur said.

Diabetes medications, proton pump inhibitors, androgen inhibitors for prostate cancer, and aromatase inhibitors for breast cancer are just a few. Among the most common culprits are glucocorticoids, which inhibit osteoprotegerin synthesis by osteoblasts, thereby enhancing osteoclast proliferation and bone resorption.

"Even having a segment of bowel resected for some reason can impact calcium absorption and promote bone loss," she said.

Warning Signs

Often the first symptom of osteoporosis is a fracture, one that occurs with low-force injury. Sometimes the following problems will provide an earlier clue: unexplained back pain, which could result from osteoporosis-weakened or collapsed vertebrae in the spine, or a noticeable shrinking from previous adult height. A stooped kyphotic posture, the so-called dowager's hump, can signal an osteoporotic compression fracture in the spine.

"We have made tremendous strides in understanding the etiology of osteoporosis and effectively treating it in the past 2 decades," Jan de Beur noted. "But the biggest challenge remains screening – fewer than 50% [of those eligible] are screened, while all women over age 65 and men over age 70 should be screened regardless of risk factors."

"The indications for screening are really quite vast," said Keller, adding that the biggest hurdle is that osteoporosis remains underdiagnosed and undertreated both in the U.S. and around the world.

A fractured hip is fatal 25% of the time and disabling 50% of the time, Jan de Beur cautioned. "A fracture is basically a skeletal heart attack, but people who suffer them are often not assessed and treated for osteoporosis."

Today's treatments can reduce fracture risk by 75%, but without screening or assessment at the time of fracture, many vulnerable people are not being captured, she said. "So we can move the needle now by screening for osteoporosis and evaluating and treating after fractures."