Bisphosphonates (BPs) are potent inhibitors of osteoclast-mediated
bone resorption, and it is well accepted that
tumor cells in bone, especially
breast cancer and myeloma cells, can stimulate osteoclast formation and activity leading to the release of
growth factors or
cytokines, which will further stimulate
cancer cells' growth and their secretion of osteolytic factors. BPs are now the standard treatment for
cancer hypercalcemia, for which a dose of 90 mg of
pamidronate or 1500 mg of
clodronate is recommended; the former compound is more potent and has a longer lasting effect. Repeated
pamidronate infusions exert clinically relevant
analgesic effects in more than half of patients with metastatic bone
pain. Recent data suggest that non-responding patients should perhaps be treated with higher doses. The optimal dose actually remains to be defined, especially as it is thought that it is probably a function of the disease stage. Regular
pamidronate infusions can also achieve a partial objective response according to conventional UICC criteria and they can almost double the objective response rate to
chemotherapy. Lifelong administration of oral
clodronate to patients with
breast cancer metastatic to bone reduces the frequency of morbid skeletal events by more than one-fourth. Two double-blind randomized placebo-controlled trials comparing monthly 90 mg
pamidronate infusions to placebo infusions for 1-2 years in addition to
hormone or
chemotherapy in patients with at least one lytic bone
metastasis have shown that the mean skeletal morbidity rate could be reduced by 30-40%. The results obtained with intravenous BPs are generally viewed as better than those obtained with oral
clodronate. However, preference can be given to the oral route when BPs are started early in the process of metastatic
bone disease in a patient receiving
hormone therapy. According to the recently published ASCO guidelines,
pamidronate 90 mg i.v. delivered over 2 h every 3-4 weeks can be recommended in patients with metastatic
breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic
therapy with hormonal
therapy or
chemotherapy. Furthermore, the ASCO Panel considered it "reasonable" to start i.v. BPs in women with localized
pain whose bone scans were abnormal and plain radiographs normal, but not when an abnormal bone scan is asymptomatic. The pertinence of these criteria is discussed below. Because BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic
antineoplastic drugs, and they should not be stopped when metastatic
bone disease is progressing. However, criteria to determine whether and for how long an individual patient benefits from their administration are lacking. New
biochemical markers of
bone resorption might help identify those patients continuing to benefit from
therapy. Even better results have been achieved in patients with
multiple myeloma, and the general consensus is that BPs should be started as soon as the diagnosis of lytic disease is made in myeloma patients. On the other hand, data are scanty in
prostate cancer, but large-scale trials with potent BPs are ongoing or planned in such patients. Similar results to those achieved with
pamidronate have been obtained with monthly 6-mg infusions of the newer BP
ibandronate in patients with
breast cancer metastatic to bone. The tolerance of
ibandronate could be better, and the
drug has the potential to be administered as a 15- to 30-min infusion.
Zoledronate can also be administered safely as a 15-min 4-mg infusion, and large scale phase III trials have just been completed. These newer BPs will simplify the current therapeutic schemes and improve the cost-effectiveness ratio; they also have the potential to improve the therapeutic efficacy, at least in patients with an aggressive osteolytic disease or when given as adjuvant
therapy. For that matter, initial data with
clodronate indicate that they have the potential to prevent the development of bone
metastases, but the use of BPs in the adjuvant setting must still be viewed as experimental.