BioEd Online

Cannabinoid compounds found naturally in the body could accelerate the bone-wasting disease osteoporosis, according to British researchers.

The research raises hopes that a class of osteoporosis drugs could be developed to stop cannabinoid chemicals binding to receptors on the surface of cells, which might prevent bone loss.

About one in two women over 50 years old will be affected by osteoporosis at some point. Scientists think that the sudden drop in oestrogen levels they experience during the menopause can trigger the disease. Although hormone replacement therapy can help to slow the onset of osteoporosis, scientists are searching for a drug that will completely stop the disease without the side-effects of these hormones. Previous research has linked hormone therapies to increased risks of breast cancer and stroke.

The British researchers speculated that cannabinoids could be involved in the disease, because related molecules have already been found to affect bone growth. They tested the idea in mice that had had their ovaries removed to simulate the hormone-loss of menopause. One group of these mice was otherwise normal, but a second group had been genetically engineered to lack a crucial receptor for cannabinoid molecules.

The scientists found that these mutant mice had 16% more bone-strengthening minerals than the control group. Moreover, when the normal mice received small doses of drugs to block the cannabinoid receptors, they were also protected from bone loss. The researchers report their results in the journal Nature Medicine¹.

Building blocks

To find out exactly how cannabinoids might be accelerating the disease, the team studied a group of cells called osteoclasts. These cells normally release acid to dissolve old, weakened bone, allowing the chemical building-blocks to be recycled to make fresh bone. But overactive osteoclasts can lead to osteoporosis by destroying more bone than is created, thinning the bones and raising the risk of fractures.

The researchers added chemicals that block cannabinoid receptors to a culture of bone-marrow cells. They found that osteoclast production was halved, proof that, when denied cannabinoids, these cells' destructive activities can be slowed.

"No one really knows for sure how oestrogen affects the bone," says biologist Stuart Ralston of the University of Edinburgh, UK, who worked on the study. But he speculates that decreased oestrogen levels may cause the production of natural cannabinoids in bones, and thus boost the degrading action of osteoclasts. He adds that more research is necessary to fully understand the link.

Pharmaceutical companies such as Paris-based Sanofi-Aventis have already tested appetite-suppressing drugs that work by blocking cannabinoid receptors, and the research team believes that similar drugs could prevent bone loss.

Bone of contention

The researchers also suggest that the cannabinoid compounds found in marijuana could predispose people to osteoporosis. "I have to stress that our study is only in mice," says Ralston, "but our results predict that you would have increased bone loss, and that would be bad."

However, Raphael Mechoulam of the Hebrew University of Jerusalem in Israel, who has also investigated the influence of cannabinoids on bone, is doubtful. "It has to be checked," he says, adding that the compounds inhaled by cannabis smokers differ markedly from those made naturally in cells. And although the cannabinoids from drugs spread throughout the body, natural versions form only where they are needed.

Mechoulam says that further research should clarify the specific role of cannabinoid receptors in bone tissue. In fact, his initial studies of the problem indicate that cannabinoids actually produce a positive effect on bone regeneration, the exact opposite of the British team's finding. Mechoulam thinks that genetic differences between the mice used in the study could explain this difference.