Metastatic
bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all,
tumor types providing a rational target for treatment. The
clinical course of metastatic
bone disease in
multiple myeloma, breast and
prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone
pain, fractures, hypercalcaemia, and
spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam
radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced
cancers. However, it is now clear that the
bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement.
Pamidronate (
Aredia(TM)) is the most widely evaluated
bisphosphonate and is recommended for most patients with
multiple myeloma or
breast cancer with bone
metastases. Current research aims include the evaluation of new potent
bisphosphonates such as
zoledronic acid (
Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity.
Zometa may also have some direct anticancer activity. Preclinical studies with
Zometa have demonstrated its potential in malignant
bone disease. Clinical studies in treatment of
hypercalcemia of
malignancy have been completed, as have Phase I and II trials in patients with
cancer and pre-existing bone
metastases. Three randomized, double-blind, controlled Phase III trials are now ongoing to establish the efficacy and safety of
Zometa in treatment of bone
metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in
cancer induced
bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of
bisphosphonate in metastatic
bone disease and their use in the prevention and treatment of
osteoporosis in
cancer patients. In vitro suggestions of direct anti-
cancer activity and some promising clinical data in early
breast cancer have resulted in considerable interest in the possible adjuvant use of
bisphosphonates to inhibit the development of bone
metastases.