Cannabis compounds blamed for bone loss

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Nature.com Published online: 23 May 2005; | doi:10.1038/news050523-1

Cannabis compounds blamed for bone loss by Roxanne Khamsi

Mouse study gives hope for osteoporosis drugs.

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.