Longevity Briefs: Can This Cancer Drug Prevent Bone Ageing?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Cellular senescence is a state in which cells stop dividing but remain active, releasing harmful inflammatory molecules known as the senescence-associated secretory phenotype (SASP). Senescence occurs when a cell has divided too many times, and it helps to protect against cancer – if a cell starts dividing uncontrollably, senescence will soon shut it down. The inflammatory molecules serve as a signal for the immune system to destroy the senescent cells.

Senescent cells and the SASP contribute to many age-related diseases which, paradoxically, includes cancer. Senescence might protect against cancer when we are young, but as senescent cells build up faster than the immune system can remove them in old age, the SASP becomes a boon for cancer cells. Scientists are now interested in targeting senescent cells to help treat not just cancer, but a range of age-related diseases in which the SASP is thought to play a role. One such disease is osteoporosis – a loss of bone mass and strength that is thought to be driven in part by senescence disrupting the balance between bone-forming osteoblasts and bone-resorbing osteoclasts. In this study, researchers screened existing drugs for their ability to affect senescence and thereby prevent bone loss in mice.

The discovery:

It turns out that many cancer drugs developed before we knew the importance of senescence were actually working partly by suppressing it. Here, researchers screened multiple drug candidates by testing them on senescent cells and identified another example of a cancer drug that suppresses senescence: cabozantinib. They then tested the effects of cabozantinib on osteoblast and osteoclast progenitor cells in cell culture.

They found that cabozantinib reduced the number of senescent cells in both progenitor cell types. It also reversed the activation of key proteins (p53, p21, p16) involved in cellular senescence and reduced the release of SASP factors. However, while cabozantinib promoted the differentiation of bone-forming osteoblasts from their progenitor cells, it had the opposite effect on the differentiation of bone-resorbing osteoclasts.

The team then tested cabozantinib in ovariectomized mice. Such mice are deficient in estrogen, which plays an important role in bone maintenance. These mice therefore develop osteoporosis for similar reasons that women are more at risk of osteoporosis after the menopause. For 8 weeks, groups of 5 ovariectomized mice received either cabozantinib every two days or a control treatment, while another 5 mice received a sham operation. As expected, mice that underwent ovariectomy lost bone density compared to sham operated mice, but this was significantly lessened in mice receiving cabozantinib. There was also no statistically significant difference in osteoblast and osteoclast numbers between sham operated mice and the mice receiving cabozantinib.

Unfortunately, cabozantinib did not significantly impact osteoporosis when treatment was started two months after ovariectomy, suggesting that this treatment is only works in a preventative manner.

The implications:

This research suggests that cabozantinib could be employed as a drug to prevent osteoporosis in those at risk. While cabozantinib has some potentially serious side effects at the doses employed in cancer treatment, the researchers note that the relative doses required to affect osteoporosis were four to nine times lower than clinically approved doses, which might cut down the risk of side effects sufficiently.

Regardless of whether you’re at risk of osteoporosis or not, maintaining a diet rich in calcium and vitamin D and engaging in weight-bearing exercises are effective ways to maintain bone mass.