New targets in osteoporosis

BOSTON—Osteoporosis is a condition in which bone density is slowly lost as a person ages. As balance issues are also common among the elderly, this significantly increases the likelihood of a fracture, which is one of the leading causes of hospitalization for older individuals. Unfortunately, however, there is no treatment for osteoporosis, only preventive recommendations such as increased calcium intake, weight-bearing exercise and some medications. According to the International Osteoporosis Foundation, in persons over the age of 50, one in three women and one in five men will sustain bone fractures due to osteoporosis. Women are at higher risk of osteoporosis because while estrogen protects bones, the production of estrogen decreases significantly after the onset of menopause.

In a new study, researchers have identified 518 genome-wide loci that account for 20 percent of the genetic variance linked to estimated bone mineral density. Their work was published in Nature Genetics in a paper titled “An atlas of genetic influences on osteoporosis in humans and mice.”

“Our findings represent the largest genetic study of genetic associations with the density of bone. This large study provides potential future targets for drug development to treat osteoporosis,” said Dr. Douglas Kiel, one of the authors on the study and Director of the Geriomics Program at the Hinda and Arthur Marcus Institute for Aging Research at Hebrew SeniorLife and Professor of Medicine at Harvard Medical School.

The researchers used heel quantitative ultrasound in 426,824 study participants to look for genetic factors related to bone mineral density (BMD), and of the 518 identified loci, 301 were newly discovered. Of those, 13 were bone fracture loci, which the authors noted in the paper are “associated with estimated BMD (eBMD) in ~1.2 million individuals.” In addition, they also “identified target genes enriched for genes known to influence bone density and strength … from cell-specific features, including chromatin conformation and accessible chromatin sites.”

“We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs [single nucleotide polymorphisms] to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development,” the authors wrote.

“Although it might seem overwhelming to sort through the many genes we found to be associated with bone density, we are able to focus on those with the greatest effect to potentially target for drug development,” explained Kiel. “Another value of our study is that it can be used to estimate a person’s risk for having weaker bones, thereby alerting them to the need for adapting healthy lifestyle choices such as physical activity and diet, and to make sure they get screened with bone density testing.”

“Our patients need additional therapies to treat their osteoporosis, and genetic studies like ours can identify new biologic pathways related to bone that can be leveraged to develop new drugs capable of preventing fractures,” he added.

New therapeutic options are always a benefit. At present, bisphosphonates are commonly prescribed for those with osteoporosis. As noted in a 2010 article in Therapeutic Advances in Chronic Disease, bisphosphonates are “stable analogs of naturally occurring inorganic pyrophosphate. The bisphosphonates share a common chemical structure with side chain variations that convey differences in their pharmacological properties, such as affinity for bone mineral and inhibitory effect on osteoclastic bone resorption … Randomized placebo-controlled clinical trials have shown that bisphosphonates reduce fracture risk in postmenopausal women with osteoporosis and have a generally excellent safety record.” Bisphosphonates do have the rare side effects of osteonecrosis of the jaw and atypical fractures near the top of the femur, which can leave patients wary of long-term use, according to Harvard Medical School.

The greater tendency for women to suffer from osteoporosis than men may also have impacted treatment options, as a Healthbeat piece by Harvard Medical School noted that “Men may, however, have fewer treatment choices at this time because some drugs have been tested only in women.” Alendronate (Fosamax) has proven effective in men, Harvard Medical School reports.