Osteoporosis

In Sweden, around 70 000 fragility-related fractures occur every year. For older women, hip fractures alone require more days of hospitalisation than heart attacks, breast cancer or diabetes. The overall aim of our project is to identify and study risk factors that may help explain why Sweden and Norway have the highest incidence of fragility fractures in the world. Known risk factors have not been able to explain this. We studied both genetic and environmental factors, but focused on dietary factors, especially vitamins A and D. This led us to identify a previously unknown risk factor - too much vitamin A (retinol), which seemed to be a remnant from the cod liver oil era. Our findings have led to a reduction in the level of retinol in food supplements both in the US and in the EU. In Norway, the level of retinol in cod liver oil has been reduced by 70%. Sweden was previously the only country in Europe to fortify low-fat dairy products. This fortification was removed in 2008 and the following year the classic AD drops became D-drops only.

Already a century ago, it was found that toxic levels of vitamin A could cause spontaneous fractures in laboratory animals. No other known substance has this deleterious effect on the skeleton, which appears to be mainly due to a reduction in the circumference - and therefore strength - of the bones.

We are trying to elucidate in detail the cellular and molecular mechanisms behind the effects of vitamin A, but we are also studying whether retinol in the blood is inversely associated with the circumference of the tubular bones in humans. If, at the same time, bone density is unaffected, as seen in animal experiments, this could be a new type of ‘osteoporosis’, as the definition of osteoporosis is based on bone density.

It is estimated that about half of all cancer patients develop metastases, and about half of these are in the bones. Despite the prevalence of bone metastases, there is no real cure (with a few exceptions). The tumour spreads through the blood, but exactly what happens next is not fully understood. Interestingly, there are two different types of bone metastases. They are either mainly bone-degrading or bone-forming and stimulate two different cells in the bone tissue. We want to investigate whether some drugs currently used for other diseases can inhibit either of these two types of cells and thus bone metastases.

An established model for studying bone-degrading metastases of malignant melanoma will be used. In preliminary experiments we can see clear metastases in vertebrae. We will now study whether 1) melphalanflufenamide (Pepaxti), a new drug for a cancer that arises in the bone marrow (myeloma), and 2) old heart drugs, which have been shown to dissolve cancer cells that have clumped together (and metastasise more easily), can inhibit melanoma metastasis. We will then test drugs in models of prostate cancer bone-forming metastases, including palovarotene, which is used to treat a rare inherited disease that causes extra bone tissue to form in the body.

Our aim is to provide important new insights into how cancer cells metastasise to the bone. It is hoped that this will eventually lead to new drugs that can prevent or slow down bone metastases.