Bone health

Bisphosphonates have benefits beyond bone

Wednesday, 26 Aug 2015

There is overwhelming evidence that bisphosphonates act on cells outside bone and may have an anti-tumour effect in soft tissue, Professor Mike Rogers has told ESA-SRB delegates.

In a conversation with the limbic, Professor Rogers said attention on this class of drugs had largely focussed on bone for the last 40 years.

“We need to take a broader view and get a better understanding of their effects in other tissues and the mechanisms of action,” he said.

Professor Rogers, head of the Bone Therapeutics Group at the Garvan Institute of Medical Research in Sydney, said preclinical data from cell culture and animal models of breast and other soft tissue cancers had suggested anti-tumour activity more than 15 years ago.

“During the last five years we have also seen very intriguing clinical data from large randomised controlled trials, mostly in breast cancer,” he said.

For example, in 2014 the AZURE study reported that the addition to zoledronic acid to standard care in postmenopausal women with stage II or III breast cancer improved invasive disease-free survival, but there were no benefits in pre- or peri-menopausal patients.

Although bisphosphonates are approved for the treatment of skeletal complications of advanced cancer involving bone, they are not yet approved for use in earlier disease.

Professor Rogers and his colleagues have been exploring the mechanisms to explain possible anti-tumour effects in soft tissue.

They demonstrated an apparent toxic effect on cultured tumour cells some years ago, but more recent work suggests that the mechanisms are more complex.

In a study which was published in Cancer Discovery (2015; 5: 35-42) earlier this year, his laboratory used the very sophisticated technique of real-time 2-photon microscopy in living mice with induced breast cancer.

Fluorescently-tagged bisphosphonate was injected into a tail vein and, within minutes, seen to diffuse into the tumour tissue from the leaky, disorganised tumour vasculature.

The bisphosphonate bound to granular microcalcifications within the tumour tissue which were then rapidly consumed by tumour-associated macrophages.

“These data represent the first compelling in vivo evidence that bisphosphonates can target immune cells in tumours outside the skeleton,” he said.

“We know that macrophages are involved in tumour biology and stimulate tumour growth. The effect of bisphosphonate on tumour-associated macrophages is a likely mechanism for the anti-tumour activity outside the skeleton.”

The research team also identified a patient with breast cancer in which radio-labelled bisphosphonate was localised to the primary breast tumour, and the resected tumour was subsequently shown to be infiltrated with tumour-associated macrophages and contain similar granular microcalcifications to those seen in the mouse tumours.

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