Drs. Ramaswamy and Shapiropresent a timely and comprehensivereview of the potentialuses of bisphosphonates and theirindications in the prevention and treatmentof bone metastasis. The reviewprovides a concise summary of thepathophysiology of skeletal metastasesand describes emerging biologicprinciples that open the door for novel,highly targeted therapeutic interventions.It is generally accepted thatrelative osteoclast hyperactivity resultsin excess bone resorption, which isthe basic process behind bone metastasis,osteoporosis, and hypercalcemiaof malignancy. Osteoprotegerin,the receptor activator of nuclear factor–kappa B (RANK), and the kappa Bligand (RANK-L) have critical rolesin osteoclastogenesis. In addition,parathyroid hormone–related proteinalso plays a major role in osteoblastactivation and production of RANKLas well as terminal osteoclast differentiationand activation.
Drs. Ramaswamy and Shapiro present a timely and comprehensive review of the potential uses of bisphosphonates and their indications in the prevention and treatment of bone metastasis. The review provides a concise summary of the pathophysiology of skeletal metastases and describes emerging biologic principles that open the door for novel, highly targeted therapeutic interventions. It is generally accepted that relative osteoclast hyperactivity results in excess bone resorption, which is the basic process behind bone metastasis, osteoporosis, and hypercalcemia of malignancy. Osteoprotegerin, the receptor activator of nuclear factor- kappa B (RANK), and the kappa B ligand (RANK-L) have critical roles in osteoclastogenesis. In addition, parathyroid hormone-related protein also plays a major role in osteoblast activation and production of RANKL as well as terminal osteoclast differentiation and activation.
Research is ongoing into the mechanisms by which exogenous osteoprotegerin and anti-parathyroid hormone-related protein antibodies suppress osteoclast activity and, secondarily, bone resorption. Bisphosphonates were initially developed for the treatment of osteoporosis, Paget's disease, and malignant hypercalcemia. They now have a crucial role in the management of all skeletal complications of cancer.
Ramaswamy and Shapiro describe the clinical trials that defined the role of bisphosphonates in the management of bone metastases and address such key issues as selection of patients likely to benefit from therapy, the timing and duration of therapy, and the financial implications of widespread long-term use. Clinical trials of bisphosphonates described 2 years of treatment, but no studies to date have investigated differing lengths of therapy. Current practice is to continue bisphosphonate treatment indefinitely even if metastasis to bone is progressive, based on the assumption that active cancer continuously produces osteoclast-activating substances (eg, parathyroid hormone-related protein, prostaglandin E2, interleukins, tumor necrosis factor) and continued "suppressive therapy" may delay disease progression. This eminently reasonable hypothesis, however, has not been adequately tested.
Fortunately, bisphosphonates are well tolerated, so long-term treatment is fairly nontoxic. While renal dysfunction is a known possible side effect of chronic therapy, a small study in which 22 patients were treated for a mean of 3.6 years documented normal renal function. Nevertheless, long-term bisphosphonate therapy requires additional monitoring to determine the efficacy and safety profile of chronic therapy.
Based on our current knowledge of the mechanism of action of bisphosphonates, it seems reasonable to assume that these agents could be used to prevent bone metastases. However, as the authors describe in detail, data from clinical trials addressing this indication are conflicting. To resolve the discrepancy in these results, a trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP-34) is investigating clodronate for the prevention of bone metastases in patients with localized breast cancer. This trial is intended to be definitive in determining whether bisphosphonate therapy is associated with a long-term reduction in the incidence of bone metastases.
One concern about this trial, however, centers on the use of clodronate, as the currently recommended standard of practice for the treatment of bone metastasis entails the use of intravenous zoledronic acid or pamidronate. Multiple preclinical studies have documented that clodronate is significantly less potent than zoledronic acid or pamidronate, and using a less potent bisphosphonate-especially one administered orally-might fail to show a statistically significant benefit for the intervention. These considerations might lead some to question the outcome of NSABP-34, especially if the results are negative.
Another important indication for bisphosphonate therapy in cancer patients is the prevention and management of osteoporosis. Younger women who receive chemotherapy are at high risk of developing premature ovarian failure, a condition that becomes permanent in more than two-thirds of patients. Ovarian ablation and suppression in premenopausal women are also being investigated with increasing enthusiasm.
In addition, 75% of newly diagnosed patients with breast cancer are more than 50 years old. Although tamoxifen has been shown to prevent bone mineral loss in postmenopausal women, newer agents such as the third-generation aromatase inhibitor anastrozole (Arimidex) have been shown to enhance the incidence of osteoporosis and fractures, most likely by lowering estrogen levels. The recently reported Arimidex, Tamoxifen Alone or in Combination (ATAC) trial demonstrated at 33- and 47-month follow-up that although the decrease in the rate of breast cancer relapse in those treated with anastrozole was statistically significant compared with tamoxifen (with a relative risk reduction of 17%), the rate of fractures was significantly higher in the anastrozole group (5.9% vs 3.7%).
Clinical trials of goserelin (Zoladex) and other gonadotropin analogs have also shown a reduction in bone density. Thus, it is important to monitor bone mineral density in breast cancer patients who are at risk of osteoporosis, especially those in whom estrogen deprivation is a therapeutic goal. Calcium supplementation and weight-bearing exercise should be recommended, and if appropriate, bisphosphonates should be prescribed.
The authors briefly mention the current research on the antitumor and antiangiogenesis effects of bisphosphonates. This exciting area of research will be very influential in further expanding the clinical applications of bisphosphonate therapy. To date, several in vitro studies have demonstrated that bisphosphonates can exert direct proapoptotic and cytostatic effects on tumor cells. These effects were initially demonstrated in myeloma cells, but similar results were documented in breast cancer cells. Zoledronic acid was shown to be several times more potent than pamidronate and two orders of magnitude more potent than clodronate. Antitumor effects, by induction of apoptosis, were demonstrated by DNA fragmentation, downregulation of bcl-2, and particular changes in nuclear morphology.
Synergistic antitumor effects were documented in breast cancer cells when zoledronic acid was combined with paclitaxel and tamoxifen. Zoledronic acid, but not pamidronate, has been shown to markedly inhibit human umbilical vein endothelial cells cultured with the basic fibroblast growth factor or vascular endothelial growth factor (VEGF). Recent results also document a decrease in basal VEGF levels up to 7 days after the infusion of pamidronate for the treatment of bone metastases.
Despite our increased understanding of the mechanisms of action and biologic and clinical effects of bisphosphonates, many questions remain unanswered. As we further elucidate the complete mechanisms of action and identify predictive markers of bone disease, our ability to target therapy will improve. Clinical trials are needed to further the understanding of the antitumor effects of bisphosphonates. With the development of multiple approaches to inhibiting osteoclast recruitment and activity, it is likely that combination approaches will be developed for the treatment of bone metastases, with agents that target modulators of bone resorption such as parathyroid hormone-related protein, RANK-L, or RANK.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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