In multiple myeloma, bone impairment is the most frequent clinical feature of the disease, with over 80 % of these patients presenting with pain .
More than 80% of bone metastases are located in the axial skeleton, with the vertebrae, ribs, and hips as the most frequently involved sites .
The balanced activity of osteoblasts and osteoclasts is the basis for physiologic bone remodeling. Activated osteoclasts are responsible for the resorption of bone, while osteoblasts form bone at the same site . Bone metastases are classified as osteolytic, osteoblastic, or mixed, according to the primary mechanism of interference with normal bone remodeling. In many cases, both osteolytic and osteoblastic processes are involved. Thus, the classic view of bone metastases as either osteolytic or osteoblastic acknowledges the two extremes of a process wherein both biological situations coexist, with a clinical prevalence of the one over the other . The pathogenesis of osteolytic damage is far from elucidated. Osteolysis is mediated by osteoclasts and does not result from the direct action of tumor cells on bone. Bone-derived transforming growth factor beta (TGF-β) and the tumor-derived parathyroid hormone-related protein (PTHrP) seem to be the major mediators involved in osteolytic metastases . Osteoclasts are activated through the action of receptor activator of nuclear factor kb ligand (RANKL) on the RANK receptor, which is expressed on the cell membrane of osteoclast precursors. Osteolysis is suppressed by osteoprotegerin (OPG), which inhibits RANKL binding to the RANK receptor . The ratio of RANKL to OPG regulates osteoclast activity. Both RANKL and osteoprotegerin are potential targets for therapeutic interventions against the formation of bone metastases.
The improved survival of cancer patients that has been obtained over the past 30 years through improved diagnostic and therapeutic interventions may determine a higher risk to develop bone metastases during the natural history of their disease. Consequently, the long-term effects of treatment on the skeleton have become an important clinical problem and a specific rationale for the use of bone-targeted treatments.
The main goals in the management of patients with bone metastases are to treat the underlying malignancy and intervene to prevent skeletal complications. Options include surgery, radiation, chemotherapy, hormonal, and biologically targeted therapies, and bisphosphonates.
3.2 Bisphosphonates in Bone Metastasis
Following their administration, bisphosphonates bind hydroxyapatite crystals of the bone matrix, reaching very high local concentrations in the resorption lacunae, where they are internalized by the osteoclasts. This results in the disruption of a number of biochemical processes crucial to osteoclast function and ultimately leads to apoptotic cell death . The molecular mechanism of action of bisphosphonates has been well elucidated: nitrogen-containing bisphosphonates inhibit enzymes of the mevalonate pathway that are responsible for the post-translational modification of a number of proteins, including small GTPases such as Ras and Rho. The inhibition of farnesyl diphosphate synthase blocks the prenylation of proteins, leading to a loss of downstream signaling essential for osteoclast functioning . Non-nitrogen containing bisphosphonates, such as clodronate, have a different mode of action and induce osteoclast apoptosis through the generation of cytotoxic ATP analogues .
Recent studies also suggest that bisphosphonates have direct apoptotic effects on tumor cells and that this effect is enhanced by a combination with other anticancer agents .
Bone metastases often lead to skeletal complications, such as pain, pathological fractures requiring surgery and/or radiation to bone, spinal cord compression, or hypercalcemia of malignancy. Many of these complications are associated with life-altering morbidity and can negatively impact survival times. Pathological fractures are the most common skeletal events, reflecting the fragility of these patients’ bones and the burden of bone pain. Many patients will have to receive radiation to bone in order to treat bone pain and to prevent complications. Moreover, skeletal events are associated with a loss of mobility and social functioning, a decrease in the quality of life, and a substantial increase in medical costs .
To date, bisphosphonates are the key treatment option for reducing, delaying, and preventing the skeletal complications associated with bone metastases, thus maintaining and restoring patient’s mobility and function in addition to reducing pain . Health economic studies on bisphosphonates indicate that they are an effective treatment considering drug costs, quality of life benefits (especially due to bone pain reduction), and incidence and costs of skeletal complications . Nonetheless, the choice of bisphosphonates for a given clinical setting should be evidence based .
3.3 Breast Cancer
Factors that negatively affect normal bone homeostasis in patients with breast cancer may be related to either the cancer itself or its treatment.
In patients with early breast cancer treated in the adjuvant setting, treatments are the predominant cause of bone loss and increased fracture risk; these include use of ovarian ablation or endocrine therapy and chemotherapy. Endocrine therapies enhance bone loss rates either by lowering estrogen levels, as ovarian suppression and aromatase inhibitors do, or by interfering with estrogen signaling (e.g., tamoxifen in premenopausal women). Some chemotherapeutic agents may directly affect bone, resulting in a rapid decrease in bone mineral density; however, indirect effects of chemotherapy, such as induced ovarian dysfunction in premenopausal women leading to premature menopause, are more common.
Moreover, approximately 70% of patients with advanced breast disease develop bone metastases and are subject to some of the highest rates of skeletal morbidity and poor quality of life.
For all of the above reasons, the most significant trials examining the efficacy of bisphosphonates have been performed in breast cancer patients with bone metastases.
Paterson et al.  reported a randomized study of 173 patients with bone metastases from breast cancer treated with standard anti-cancer treatment(s) with or without clodronate, an oral bisphosphonate. In patients who received clodronate, there was an overall 28% reduction in skeletal morbidity. Indeed, the greatest benefit was registered for a significant reduction in the total number of hypercalcemic episodes, in the incidence of vertebral fractures, and in the rate of vertebral deformity.
Conte et al. reported the results of a multi-center study that randomized 295 patients with breast cancer and bone metastases to receive chemotherapy with or without intravenous pamidronate (45 mg) administered every 3 weeks. The median time to disease progression in bone was increased by 48% in patients who received pamidronate (249 vs. 168 days); marked pain relief was reported by 44% of pamidronate patients and by 30% of controls. The infusions were well tolerated, with no major toxicities reported .
Two larger double-blind, placebo-controlled trials of 90 mg pamidronate infusions administered every 3–4 weeks in addition to chemotherapy or endocrine therapy confirmed the efficacy of pamidronate for patients with breast cancer and lytic bone metastases.
Theriault et al.  randomized 372 women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy to receive 90 mg of pamidronate or placebo. The skeletal morbidity rate was significantly reduced in pamidronate-treated patients. The proportion of patients with skeletal complications was 56% in the pamidronate group and 67% in the placebo group. The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo. Pamidronate was well tolerated.
In a second randomized trial, by Hortobagyi et al., 380 women with stage IV breast cancer receiving cytotoxic chemotherapy and with at least one lytic bone lesion were given either placebo or pamidronate (90 mg i.v.) The median time to the occurrence of the first skeletal complication was greater in the pamidronate group than in the placebo group (13.1 vs. 7.0 months), and the proportion of patients in whom any skeletal complication occurred was lower (43 vs. 56%). There was a significantly lower increase in both bone pain and deterioration of performance status in the pamidronate group than in the placebo group .
Zoledronic acid is a highly potent, new-generation bisphosphonate that has demonstrated greater potency than pamidronate in preclinical testing and can be safely administered via a 15 min infusion. In a placebo-controlled trial in Japan, Kohno et al. randomly assigned 228 women with bone metastases from breast cancer to treatment with zoledronic acid or placebo every 4 weeks. Zoledronic acid reduced the rate of skeletal-related events (SRE) by 39% compared with placebo. The percentage of patients with at least one SRE was significantly reduced by 20% in the zoledronic acid group (29.8 vs. 49.6% for placebo). Zoledronic acid was well tolerated, with a safety profile similar to placebo .
Zoledronic acid was compared with pamidronate in a randomized, non-inferiority double-blind, phase III trial. The 1648 patients with either Durie-Salmon stage III multiple myeloma or advanced breast cancer and at least one bone lesion were randomly assigned to treatment with either 4 or 8 mg of zoledronic acid, administered via a 15-min intravenous infusion or 90 mg of pamidronate administered via a 2 h intravenous infusion every 3–4 weeks for 12 months. The primary efficacy endpoint was the proportion of patients experiencing at least one SRE over 13 months. The results showed that the proportion of patients with at least one SRE was similar in all treatment groups. Median time to first SRE was approximately 1 year in each treatment group. The skeletal morbidity rate was slightly lower in patients treated with zoledronic acid than in those treated with pamidronate, and zoledronic acid (4 mg) significantly decreased the incidence of event rate following radiation therapy to bone, both overall and in breast cancer patients receiving hormonal therapy. Pain scores decreased in all treatment groups in the presence of stable or decreased analgesic use. Zoledronic acid (4 mg) and pamidronate were equally well tolerated.  After 25 months of follow-up, zoledronic acid had reduced both the overall proportion of patients with SREs and the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications, including malignant hypercalcemia, by an additional 16%. In breast carcinoma patients, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by 20% and by an additional 30% in patients receiving hormonal therapy .
Ibandronate is a new, potent amino-bisphosphonate available in oral and infusion formulations. In a phase III study, Body et al. compared the efficacy of ibandronate with that of placebo as intravenous therapy in metastatic bone disease due to breast cancer. The 466 patients were randomized to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) of ibandronate every 3–4 weeks for up to 2 years. The primary efficacy parameter was the number of 12 week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use, and safety were evaluated monthly. The results showed that the SMPR was lower in both ibandronate groups than in the placebo group; the difference was statistically significant for the ibandronate 6 mg group (p = 0.004 vs. placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also had lower bone pain scores and analgesic use. Treatment with ibandronate was well tolerated .
Oral ibandronate has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, 564 patients with breast cancer and bone metastases were randomized to receive oral ibandronate 50 mg or placebo once daily for up to 96 weeks. The primary end point was again the SMPR, defined as the number of 12-week periods with new skeletal complications. Oral ibandronate significantly reduced the mean SMPR compared with placebo (0.95 vs. 1.18). There were also significant reductions in the mean number of events requiring radiotherapy (0.73 vs. 0.98) or surgery (0.47 vs. 0.53). The incidence of mild treatment-related nausea/vomiting was slightly higher in the ibandronate group than in the placebo group, but very few serious drug-related adverse events were reported .
The use of an oral agent is obviously attractive to both patients and health care providers but comparative data with other bisphosphonates are needed before a move away from intravenous treatment can be recommended.
A potential preventive effect of oral bisphosphonates was studied in retrospective analyses of large cohorts of women with osteoporosis. Interestingly, women who received bisphosphonates for osteoporosis had a 32% relative reduction in the overall risk of breast cancer compared with those who not receiving bisphosphonates. These correlations suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can prevent breast cancer. However, these results were generated from retrospective studies and in the absence of a prospective, randomized study of prevention [20, 21].
Gnant et al. investigated the effect of adding 3 years of zoledronic acid every 6 months to combination treatment either with tamoxifen and goserelin or with anastrozole and goserelin in 1803 premenopausal women with early, endocrine-responsive breast cancer . The addition of zoledronic acid to endocrine therapy led to a relative reduction of 36% in the risk of disease progression compared with endocrine therapy alone and, although not significant, there was a trend toward improved overall survival. In addition, emerging evidence suggests that zoledronic acid has anti-tumor and anti-metastatic properties, including the inhibition of angiogenesis, tumor-cell invasion, adhesion in bone, and the induction of apoptosis .
A definite adjuvant role for bisphosphonates will require much larger randomized studies, such as the NSABP B34 study, with oral clodronate vs. placebo in 3300 patients with stage I–III breast cancer, or the AZURE trial, a large study of adjuvant zoledronic acid in 3360 patients with stage II/III breast cancer.