The skeleton is the most common site of metastatic disease in breast and prostate cancers, and tumor-induced bone destruction can complicate any neoplasm. The clinical consequences of cancer-mediated bone destruction are a source of misery for these patients. The term “skeletal-related events” (SREs) refers to the major complications of tumor bone disease: pathologic fractures, need for radiotherapy, need for bone surgery, spinal cord compression, and hypercalcemia. Across all tumor types, patients with breast cancer have the highest incidence of skeletal complications. Major complications will be observed in up to one third of patients whose first relapse is in bone (1,2). Taken from data in placebo groups of randomized bisphosphonates trials, the mean skeletal morbidity rate in breast cancer (i.e., the mean number of SREs per year) varies between 2.2 and 4.0 and is around 1.5 in advanced prostate cancer (2,3).

Bone destruction due to metastatic infiltration is essentially mediated by the osteoclasts. The propensity of cancer cells to proliferate in bone is best explained by a “seed and soil” concept (4). Breast cancer cells (the “seed”) appear to secrete factors, such as parathyroid hormone-related protein (PTHrP), potentiating the development of metastases in the skeleton, which constitutes a fertile “soil” rich in cytokines and growth factors that stimulate cancer cells growth. Local production of PTHrP and of other osteolytic factors by cancer cells in bone stimulate osteoclastic bone resorption, essentially through the osteoblasts. Tumor factors thus alter the ratio between osteoprotegerin (OPG), whose production is decreased, and RANK ligand (receptor activator of NF-_KB ligand), whose production is increased (5). The net result of such imbalance in these key regulatory factors of bone resorption is an increase in osteoclast proliferation and activity. In prostate cancer, histomorphometric analyses of bone biopsies and studies on biochemical markers of bone turnover demonstrated that enhanced bone formation in osteosclerotic lesions is accompanied by a marked increase in osteoclast-mediated bone resorption. These considerations explain why bisphosphonates have been so extensively used in oncology. These compounds are indeed able to interrupt the vicious circle between cancer cells, bone cells, and bone matrix by inducing osteoclast apoptosis. They also exert direct antitumoral effects whose clinical relevance remains unknown.

Tumor-induced hypercalcemia was the first successful therapeutic application of bisphosphonates. Cancer hypercalcemia can now be successfully treated in at least 90% of the cases by rehydration and bisphosphonates (6).

Pain is the most frequent symptom of bone metastases. Bisphosphonates are useful co-analgesics for the treatment of moderate to severe metastatic bone pain. The current opinion is that the intravenous route has to be selected for the treatment of bone pain, but placebo-controlled trials have shown that all bisphosphonates can exert analgesic effects, whether they are given orally or intravenously. The analgesic effect of bisphosphonates in prostate cancer appears to be less than that in advanced breast cancer (3). The administration of a high “loading” dose of the bisphosphonate ibandronate could be especially useful in patients with severe bone pain, but this new concept must be further tested (7). Pain is now viewed more as a subjective SRE in long-term bisphosphonate trials, and the marked decrease in radiotherapy needs in these trials is a surrogate marker for clinically significant pain relief.

Placebo-controlled trials with oral or intravenous bisphosphonates have shown that their prolonged administration can reduce the frequency of SREs in patients with bone metastases from breast cancer (3). For patients with metastatic breast cancer demonstrated on plain films, computed tomography (CT) or magnetic resonance imaging (MRI), it is generally recommended to start bisphosphonates before the first bone complication occurs. Placebo-controlled trials have established that, when administered over a prolonged period by the oral route (clodronate and ibandronate) or by the intravenous route (pamidronate, ibandronate, and zoledronic acid), bisphosphonates reduce the skeletal morbidity rate by 25% to 40% in patients with breast cancer metastatic to the skeleton. Clodronate is now viewed as less effective than other bisphosphonates for the prevention of SREs. It has been shown in a large-scale controlled 2-year comparative trial between pamidronate and zoledronic acid that this latter compound has a superior efficacy, as the likelihood of getting an event during therapy is reduced by 20% in breast cancer, according to a multiple event analysis (8,9) (Fig. 7.1, upper panel). Zoledronic acid is also more convenient to administer than pamidronate (15-min vs. 2-hr infusion). However, zoledronic acid is not more efficient than pamidronate in myeloma patients (Fig. 7.1, upper panel). Importantly, the dose of 8 mg of zoledronic acid is not more effective than the 4-mg dose level, which probably indicates that we have reached the maximal efficacy of bisphosphonates in that setting. Rare cases of renal insufficiency have been reported in patients receiving zoledronic acid therapy. This has led to the recommendation that serum creatinine, and more recently creatinine clearance, be checked before each zoledronic acid infusion to adjust the dose. Conversely, ibandronate is well tolerated and, in phase III trials, this compound had a renal-safety profile similar to that of placebo. Repeated 6-mg monthly ibandronate infusions or oral ibandronate, 50 mg once daily, also constitute efficient strategies to reduce the morbidity rate of bone metastases from breast cancer (10,11). Multiple event analysis showed that oral or intravenous ibandronate led to a statistically significant 38% to 40% reduction in the risk of SREs compared with placebo, which appears to be comparable to the effect of zoledronic acid (Fig. 7.1, middle and lower panels) (9).

In prostate cancer, monthly zoledronic acid infusions have been shown to reduce the skeletal morbidity rate by about one third in patients with hormone-refractory disease (12) (Fig. 7.1

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