New Understanding in why Common Drugs Cause Bone Loss

Research teams have come up with a possible explanation of why some commonly used drugs increase a patient’s risk of breaking bones.

Two studies published in the June issue of Cell Metabolism focus on the drugs :glucocorticoids and insulin sensitizer rosiglitazone. The drugs work through different mechanisma as therapies for inflammatory disease and diabetes and also lead to bone loss in different ways, according to the studies.

The researchers teams are from the University of Texas Southwestern Medical Center and the Fritz-Lipmann Institute in Germany. The both agree, according to a press relase, that the new molecular understanding of what happens to bones could lead to the design of drugs with fewer side effects.

"People taking a high dose of glucocorticoids can be pretty sick with rheumatoid arthritis or severe asthma, for example, and in that case their systemic fracture risk doubles," said Jan Tuckermann of the Fritz-Lipmann Institute, in a press release. "For a young person, that might be OK because their risk is very low to start, but, as you become older, it's a real problem."

Glucocorticoids represent a class of steroid hormone and their receptors are found in cells all over the body, including in the bones. Prior to the studies, scientists didn't know which bone cells were important in producing the side effects on bone loss.

Bone is constantly being remodeled through a balance between the activities of bone-building osteoblasts and bone-resorbing osteoclasts. Tuckermann's team found that glucocorticoids act on the osteoblast side of that equation. Studies in mice showed that animals lacking glucocorticoid receptors in their osteoblasts didn't show the same bone loss that glucocorticoids normally bring.

Through Tuckerman’s study, the team found when glucorticoids remain in their lone state (when they do not form dimmers) they may play a role in inflammation. Prior to the study many had suspected that the side effects of glucorticoids resulted when the receptor formed dimmers to influence glucose. The team found, the answer was not so clear cut. Additionally, the team found that the ill effects in bone stem from the transcription factor AP-1. This means it may now be possible to fine-tune glucocrticoid drugs that do not lead to AP-1 interaction.

The goal of the second study, led by Yihong Wan of UT Southwestern, was to undersane why long-term use of rosiglitazone in diabetic patients makes their bones more fragile, especially when these patients are already at increases risk of bone fractures.

The drug acts through the peroxisome proliferator-activated receptor g (PPARg). The receptor plays diverse roles in fat cell development, lipid metabolism and insulin sensitivity and emergine evidence suggests that PPARg plays in important rolw in bones. Previous studies found the receptor suppresses the bone-building activities of osteoblasts and speeds up the differentiaition and activity of osteoclasts to break down more bone.

The team found that the drug’s side effects on bone involve the transcriptional coactivator PGC1b, which coordinates with the molecular actor ERRa. Animals lacking PCG1b in their osteoclasts grow completely resistant to the drug-induced bone loss.

The new information could help to produce new drugs, Wan said, in a press release.