A recent article in the British Journal of Cancer indicated that women taking bisphosphonates prescribed for osteoporosis had about a 30% reduction in breast cancer occurrence.
Bisphosphonates have a core molecular structure similar to a naturally occurring compound, pyrophosphate, essentially a diphosphate moiety. However, in a bisphosphonate, a carbon atom replaces an oxygen atom linking the two phosphates groups in pyrophosphate. The carbon atom stabilizes this “diphosphate”, which would otherwise be rapidly broken down by cellular enzymes. The carbon atom also provides two other bonds to which many different chemical groups can be linked. Numerous chemical groups have been linked to the carbon atom, particularly chemical groups with a nitrogen atom, in an attempt to generate bisphosphonates with greater and greater efficacy.
Bisphosphonates have been used primarily to minimize bone destruction in many diseases, especially osteoporosis, but also including cancer metastases to the bone, very common in prostate cancer. The two phosphate groups of the bisphosphonates are highly negatively charged and therefore bisphosphonates migrate to and accumulate at the bone mineral, where there are many positive charges, particularly from the calcium ions. The bisphosphonates are then taken up by osteoclasts, cells that absorb bone. Inside the osteoclasts, the bisphophonates inhibit an enzyme termed, farnesyl pyrophosphate synthase. This enzyme is important for generating a small lipid molecule that is covalently attached to proteins, called Ras proteins, that are required for cell division. The lipid molecule facilitates the positioning of the Ras proteins to the inside of the cell membrane, which is mostly constituted with lipids itself. Thus, the lipid molecule attached to the Ras protein essentially dissolves into the cell membrane, bringing the Ras protein in very close proximity to other proteins that are also located just inside the cell membrane and that are required for normal Ras function. Without the lipid molecule, termed a prenyl group, the Ras protein is not positioned properly for interactions with its partner proteins and cell division does not occur properly. The osteoclasts thus undergo programmed cell death, termed apoptosis. The fewer number of osteoclasts means less bone resorption.
As might be obvious from the above, interfering with Ras prenylation could reduce cell proliferation in other cases, such as cancer. In fact, there is very active field of cancer biology related to the development of Ras prenylation inhibitors and these drugs are entering clinical trials now or very soon. However, the bisphosphonates have been used extensively and much is known about the related safety issues. Thus, the authors of the British Journal of Cancer article, among others, have considered the possible usefulness of the bisphosphonates preventing cancer. The answer to this question is not obvious, in particular because the bisphosphonates accumulate at the bone mineral and may not have a big impact on distant tissues.
The authors of the British Journal of Cancer article reviewed the bisphosphonate use among women who were diagnosed with breast cancer during 2003-2006. Their results indicated that the risk of being diagnosed with breast cancer, during the use of bisphosphonates, over 3 months to several years, was reduced by a maximum of 30%. Furthermore, the greater the period of bisphosphonate usage, the greater the reduction in breast cancer diagnosis risk.
While the results are encouraging, particularly given the understanding that bisphosphonate can reduce Ras stimulation of cell proliferation, the study has many limitations that need to be researched before the true usefulness of bisphosphonates in reduced breast cancer occurrence can be understood. In fact, there are so many limitations to a report of this kind that, no matter how encouraging from a basic research point of view, they cannot all be listed here. However, here are a few. First, the risk reduction was seen among current bisphosphonate users; the sample size of previous users was too small to allow conclusions. A larger study with patients who are no longer taking bisphosphonates can now be justified. Second, there is no information about overall mortality, either due to breast cancer or due to unintended consequences of bisphosphonate usage, during such a short time period. Finally, many mechanistic issues remain unresolved. For example, T-cell proliferation could be inhibited by bisphosphonates, and in several human conditions where T-cell proliferation is impaired, cancers develop, for example Kaposi’s sarcoma in AIDS.
Recent British Journal of Cancer article on bisphosphonates and breast cancer
