Adjuvant Clodronate for Breast Cancer

Clodronate is a first generation bisphosphonate (a.k.a. clodronic acid, marketed under the Brand names of Bonefos, Clasteon, Difosfonal, Loron, Mebonat and Ossiten in Europe & the U.K., Canada, and elsewhere, not yet commercially available in the US, where the FDA deems it “approvable” as of 2005 ) that shares with its more famous cousin Fosamax the ability to inhibit bone resorption and is thus used for treating osteoporosis to increase bone mass and reduce fractures. Because of the propensity of these agents to adsorb mineral and inhibit bone resorption, they have also been applied to treat cancer metastases to the bone, as well as to lower cancer associated hypercalcemia since the 1980’s.  So why is it appearing in my blog as an “off-label” treatment for cancer? Well, it can be used in cancer as other bisphosphonates, but usually in a palliative sense to control bone metastases and/or hypercalcemia associated with cancer, but not as a standalone treatment for the cancer itself.  However, there is compelling data for Clodronate’s use as an adjuvant agent, especially in breast cancer.

In a pioneering double-blind controlled study of Clodronate in treating breast cancer metastatic to the bone, Canadian researchers Paterson et al. (1993) noted reduced bone-related morbidity in treated patients and recommended that Clodronate be further investigated for potentially reducing bone metastasis as an adjuvant treatment for those who are at risk.  Not long thereafter, Diel et al. (1998) from the University of Heidelberg published a landmark trial in the New England Journal of Medicine on the subject and found in the 302 patient randomized trial that adjuvant clodronate at 1600 mg a day reduced not only bone metastases in breast cancer, but reduced other organ metastasis as well as the risk of death.  Subsequent, a Finnish study published in 2001 unexpectedly showed a decrease in survival in clodronate treated breast cancer patients, thus confounding the topic.  With accumulating evidence in favor, the FDA issued an approvability letter in 2005 for the use of clodronate as an adjuvant treatment in breast cancer. Finally in 2006, a larger randomized double-blinded placebo controlled multi-center study of over one thousand patients over 5 years confirmed reduced skeletal metastasis as well as possibly favorable survival in breast cancer patients (esp those with Stage II or III disease rather than Stage I) receiving clodronate as adjuvant over the initial 2 years.

There are quite a few discussions and review of the use of clodronate for breast cancer online and there is no doubt remaining controversy based on the earlier Finnish trial and a more recent meta-analysis which found no attributable benefit to the drug.  Furthermore, the drug is not commercially available in the US and not FDA approved despite its approvability, and these all hinder more wide-scaled use of the drug.  Lately, there has also been increasing concern for the risk of osteonecrosis of the jaw as a complication of long-term bisphosphonate use, but unlike other bisphosphonates, the risk of ONJ with clodronate is extremely low at 0 – 0.5% (rare cases reported only) after taking it for 2 years (see Mayo Clin Proc 2007; 82:516-522), and this should not be a major deterrent in those considering its use.

My Take

Given some of the favorable trial results above and the very safe and relatively inexpensive (under $200 per month from Canada) nature of the drug, in addition to its benefit in reducing bone loss in breast cancer patients simultaneously receiving anti-estrogen therapy, I think Clodronate ought to be seriously considered as adjuvant treatment for Stage II and III breast patients, and I have been recommending it for the past 5 years.  It is not available in the US, but can be obtained from Canada, Mexico, Europe and Asia. Newer generation bisphosphonates may have more potent anti-cancer potential (See my more recent blog on gammadelta cell therapy as well as amino bisphosphonates if interested) and may in the future replace Clodronate for this use, so I eagerly await further trials in the area of using bisphonates as adjuvant therapy for breast cancer.