BREAST CANCER � Bisphosphonates have five potential uses in women with breast cancer: preventing or delaying skeletal complications in patients with documented osteolytic bone metastases, palliation of bone pain, delaying the appearance of bone metastases in patients with high-risk early stage disease (ie, adjuvant treatment), prevention of bone loss in women receiving adjuvant systemic therapy (who often have premature menopause), and direct cytotoxicity. Direct cytotoxicity may account for some of the clinical benefit observed with bisphosphonates in patients with breast cancer. Bisphosphonates induce apoptosis in human breast cancer cell lines in vitro , and also block the growth of bone marrow metastases in animals bearing prostate cancer xenografts .

Most clinical studies of bisphosphonates in patients with breast cancer have evaluated their utility in reducing skeletal-related events in patients with bone metastases.

Intravenous pamidronate � An initial double-blind trial included 382 women with breast cancer receiving systemic chemotherapy who had osteolytic metastases . Intravenous pamidronate (90 mg/month for two years) delayed the appearance of clinical skeletal complications (median time to first skeletal complication 14 versus 7 months with placebo) but had no effect on survival. The differences in overall skeletal complications continued to favor the pamidronate group and remained statistically significant at all endpoints up to 24 months.

A similar double-blind trial conducted by the same group of investigators included 372 women with metastatic breast cancer and lytic bone metastases who were receiving concurrent hormone therapy . The time to first skeletal complication was prolonged with pamidronate compared with placebo (median 10.4 versus 6.9 months, p = 0.049), and the proportion of women with skeletal complications was reduced (56 versus 67 percent, p = 0.027).

In contrast to these results, at least three studies in women with advanced breast cancer, but without clinically evident bone metastases, have failed to demonstrate any reduction in the incidence of skeletal events from prophylactic bisphosphonates .

The optimal dose of intravenous pamidronate to prevent skeletal events in women with breast cancer is unknown. The use of 60 rather than 90 mg once monthly in clinical practice is based upon a Swedish trial, in which 404 women with skeletal metastases from advanced breast cancer received either intravenous pamidronate (60 mg every four weeks) or placebo . Despite a significantly longer time to progression of pain, time to develop hypercalcemia, and cumulative number of skeletal events in the pamidronate group, its use was not associated with a significant reduction in the incidence of pelvic or long bone fractures or a delay in the need for bone radiation or surgery. However, it is possible that the slightly lower dose of pamidronate in this study contributed to the lesser benefit. Treatment guidelines from the American Society of Clinical Oncology support the use of 90 mg every three to four weeks .

  Optimal duration of treatment � The duration of benefit for monthly intravenous pamidronate in women with osteolytic bone metastases is unknown. Drug administration for at least six months is necessary before an effect is seen on skeletal morbidity outcomes . At least two studies suggest that prevention of skeletal complications and palliation of symptoms persist with up to 3.6 years of continued therapy . In one report, the fracture rate beyond two years was no greater than during the first two years of treatment . As noted below, a potential complication, particularly with higher than standard doses, is the nephrotic syndrome .

Intravenous zoledronic acid � Zoledronic acid, a new generation high potency parenteral bisphosphonate, is a promising new agent for decreasing the risk of skeletal events in women with breast cancer and osteolytic (and osteoblastic) metastases . Benefit has been shown in at least two randomized controlled trials:

• In one trial, 412 women with breast cancer and osteolytic bone metastases were randomly assigned to monthly treatment with zoledronic acid at one of two dose levels (4 or 8 mg over 15 minutes) or pamidronate (90 mg over two hours) . The 8 mg dose was subsequently reduced to 4 mg because of elevated serum creatinine levels

The percentage of patients who experienced at least one skeletal event was similar (46 versus 50 percent), but patients treated with 4 mg zoledronic acid had a slightly but significantly lower risk of a skeletal event after two years of treatment, compared to the pamidronate group (relative risk 0.80, 95% CI, 0.66-0.97) . Benefit was maintained through the duration of follow-up.

• More impressive results were noted in a Japanese trial that randomly assigned 228 women with bone metastases from breast cancer to zoledronic acid (4 mg over 15 months monthly) or placebo . The rate of skeletal-related events (pathologic fracture, spinal cord compression, need for bone surgery or radiation) was significantly lower in the treated group (30 versus 50 percent), as was the time to develop a first skeletal-related event. There was no evidence of renal dysfunction in patients treated with zoledronic acid.

Oral bisphosphonates � In breast cancer, randomized double-blind studies of oral bisphosphonates have evaluated the treatment of bone metastases, prophylaxis in women thought to be at high risk for bone metastases, and reducing early bone loss in women receiving adjuvant systemic chemotherapy.

  Bone metastases � In the first of these trials, 173 patients with breast cancer and bone metastases were randomly assigned to receive either oral clodronate (1600 mg/day) or placebo for 18 months . There were no significant differences between the groups in the incidence of hypercalcemia, symptomatic progression requiring radiotherapy, or fractures.

Ibandronate is a high potency bisphosphonate which can be administered intravenously or orally. The efficacy of oral ibandronate (50 mg once daily) was shown in two placebo-controlled trials involving a total of 564 women with breast cancer and bone metastases . In a pooled analysis, ibandronate was associated with a significant reduction in the overall risk of a skeletal event (hazard ratio 0.62), and in the need for radiation or surgery, but it did not significantly reduce the incidence of vertebral or nonvertebral fractures.

  Prophylaxis against bone metastases: metastatic disease � A second trial, which included 133 women with metastatic breast cancer without bone metastases, tested a prophylactic strategy of clodronate (1600 mg/day) versus placebo . Despite the finding of fewer skeletal metastases (32 versus 63, p = 0.005), and skeletal-related clinical events (68 versus 106, p<0.01) in the women receiving clodronate, the proportion of patients developing skeletal metastases (23 versus 28 percent) or experiencing clinical manifestations of metastatic bone disease (44 versus 57 percent) were not statistically different between the groups.

Prophylaxis against bone metastases: adjuvant setting � Data evaluating the efficacy of bisphosphonate therapy in the adjuvant setting are conflicting. In a study in which 302 women with primary breast cancer and tumor cells in the bone marrow (a risk factor for the development of distant metastases) were randomly assigned to placebo or clodronate (1600 mg/day) for two years . At a median follow-up of 36 months, clodronate therapy was associated with a lower incidence of distant bony or other metastases (13 versus 29 percent), fewer bone metastases per patient (3.1 versus 6.3), and a lower three year mortality rate (3.8 versus 15.2 percent).

Benefit was also noted in a second trial in which 1079 women with primary operable breast cancer were randomly assigned to adjuvant clodronate or no treatment for two years . Overall, clodronate was associated with a significant reduction in the incidence of bone metastases during therapy (2.3 versus 5.2 percent, hazard ratio [HR] 0.44, 95% CI, 0.22-0.86) but not thereafter. Although the occurrence of non-bony metastases did not differ from the placebo group, clodronate was associated with a significantly lower mortality rate during the total follow-up period (18.5 versus 23.9 percent, p = 0.047). In a companion study, significant increases in bone mineral density (BMD) were noted in the clodronate group (see below).

However, conflicting results were reported in a Finnish study in which 299 women with node-positive breast cancer were randomly assigned to adjuvant chemotherapy or hormone therapy with or without clodronate (1600 mg daily for three years) . The use of clodronate was associated with no improvement in the frequency of skeletal metastases (21 versus 17 percent), a significantly higher rate of extraskeletal metastases (43 versus 25 percent), and significantly worse survival (70 versus 83 percent).

Prophylaxis against bone loss � In premenopausal women, adjuvant chemotherapy may be associated with premature menopause and early bone loss. Randomized trials evaluating the benefit of short-term prophylactic administration of a bisphosphonate suggest potential benefit from this approach :

• In a subset of 498 women enrolled on a trial discussed above, in which 1079 women with primary operable breast cancer were randomly assigned to adjuvant clodronate or no treatment for two years , the effects of clodronate on BMD of the spine and total hip were evaluated . Clodronate had a protective effect on bone mass during therapy, but thereafter, rates of bone loss were similar to that of the placebo group. however, the net effect was that at five years, women treated with clodronate had a higher BMD than controls.

A smaller trial in which 45 women receiving chemotherapy for early breast cancer were randomly assigned to seven courses of intravenous clodronate or no clodronate failed to document a significant difference in BMD at six or 12 months. Mean bone loss in the lumbar spine at 6 months was -0.5 versus -1.4 percent in the clodronate and control groups; the corresponding values at 12 months were -3.9 and -3.6 percent, respectively. The small size of this study and the short treatment duration may have compromised the ability to detect a benefit from clodronate.

• More recently, benefit was also suggested for prophylactic pamidronate (60 mg IV every three months for one year) in a small randomized placebo-controlled trial carried out in 40 premenopausal women receiving adjuvant chemotherapy for early breast cancer . Tamoxifen was administered to a similar proportion of women in the pamidronate and control groups (67 and 74 percent, respectively). There was a significant treatment effect at both 6 and 12 months; BMD stabilized in the lumbar spine at both time points in the treated group, while it decreased in placebo-treated patients (mean difference from baseline at 12 months was +1.9 versus -3.2 percent). Benefit was most pronounced in the women who became amenorrheic (11 subjects in each arm).

• A similar degree of benefit was noted with the oral agent risedronate (two years of 30 mg daily for two of every 12 weeks) in a small placebo-controlled trial involving 53 women with breast cancer and premature menopause. In contrast to the significant degree of BMD loss in the placebo group, those receiving prophylactic risedronate had an increase in BMD. However, on treatment withdrawal, bone loss ensued, although a significant difference was still evidence when the groups were compared one year after treatment discontinuation.

Taken together, these data suggest potential utility for bisphosphonates for preventing bone loss in premenopausal women who become menopausal after receiving adjuvant chemotherapy. However, the optimal timing of bisphosphonate therapy in such cases is unclear. The Cancer and Leukemia Group B has completed a trial in which zoledronic acid is started at the onset of adjuvant chemotherapy or one year later. Until the results of this trial are available, most clinicians recommend calcium and vitamin D supplementation and a baseline bone density if a patient remains menopausal for at least six months after adjuvant chemotherapy. Bisphosphonates are then started if justified by finding a T score of -1 to -2.5. (See "Overview of the management of osteoporosis in women").

Palliation of bone pain � The degree of analgesic benefit provided by bisphosphonates in women with breast cancer and symptomatic bone metastases is difficult to ascertain. Although the placebo-controlled trials described above support a modest reduction in metastatic bone pain with oral and intravenous bisphosphonates, their role in patients undergoing radiation therapy or failing radiation therapy for symptomatic bone metastases has not been determined.

One observational study suggested a marked analgesic effect with higher than standard dose ibandronate (4 mg intravenously daily for four days) in 18 patients with opioid-resistant symptomatic bone metastases. This was achieved without substantial renal toxicity. However, larger confirmatory trials are needed before such therapy can be considered outside of the confines of a clinical trial.

Summary and recommendation � Based upon the above studies, and systematic overviews of the literature, the routine use of intravenous bisphosphonates have lessened the impact of skeletal complications in women with breast cancer and skeletal metastases, decreasing the frequency of pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. They have not been shown to have any survival impact in this disease. The role of oral bisphosphonates remains unclear.

  ASCO guidelines � Clinical practice guidelines for the use of bisphosphonates in women with breast cancer have been published by ASCO , and were updated in November 2003  :

• For women with radiographic lytic metastatic bone disease, intravenous pamidronate (90 mg over two hours every three to four weeks) or zoledronic acid (4 mg over 15 minutes every three to four weeks) is recommended. There is insufficient evidence to recommend one over the other, although zoledronic acid is more convenient because it can be administered over a shorter period of time. We agree with this recommendation.

In women with metastatic breast cancer and pain due to an osteolytic metastasis, intravenous bisphosphonate may also be of benefit to relieve pain when used in conjunction with systemic chemotherapy or hormone therapy.

Serum creatinine should be monitored prior to each dose, and serum calcium, electrolytes, magnesium and hemoglobin/hematocrit should also be monitored regularly, but there is no need to perform routine assessments for albuminuria, as with myeloma

• We suggest starting bisphosphonate therapy in women with an abnormal bone scan and normal radiographs, but with evidence of bone destruction on CT or MRI.

• For women with only an abnormal bone scan but no radiographic evidence of bone destruction on plain radiographs, CT, or MRI, there is insufficient evidence to start bisphosphonates.

• For women with no evidence of bone metastases, the use of bisphosphonates is not recommended.

• Once begun, we recommend that bisphosphonates be continued until there is evidence of a substantial decline in the patient's overall performance status.

PROSTATE CANCER � In prostate cancer, the rationale for bisphosphonate therapy is less obvious since bone metastases are predominantly osteoblastic. Nevertheless, fractures do occur.  In vitro and in vivo studies in animal models suggest an inhibitory effect of zoledronic acid on both osteolytic and osteoblastic prostate cancer metastases. Another reason for bone fractures in men with advanced prostate cancer is that men who are receiving androgen deprivation therapy (ADT) for advanced disease frequently show evidence of increased bone resorption and osteoporosis.

Thus, bisphosphonates have four potential uses in men with advanced prostate cancer: delaying skeletal progression, protecting the bone from loss in density that can accompany treatment with ADT, direct antitumor effects, and palliation of bone pain.

Delay skeletal progression � At least five studies and a systematic review of the literature have explored the adjuvant use of potent bisphosphonates to delay skeletal progression in men with advanced prostate cancer, with conflicting results:

Support for a beneficial effect on reducing the risk of skeletal complications from intravenous zoledronic acid was obtained in a trial in which 643 men with prostate cancer with bone metastases who were progressing while on ADT (three-fourths symptomatic) were randomly assigned to zoledronic acid 4 mg, 8 mg (later reduced to 4 mg because of excess renal toxicity), or placebo, infused every three weeks . Bone pain continued to increase in all groups, albeit at a significantly faster rate in the placebo group. However, there was a significant reduction in the frequency of skeletal-related events (SREs, vertebral and nonvertebral bone fractures, need for radiation therapy) in men receiving zoledronic acid 4 mg (33 versus 44 percent). This translated to a significant 43 percent reduction in the odds ratio of developing a bone fracture. Only about one-third of the men in each group completed the study (mostly because of disease progression), which may have interfered with the ability to document more impressive treatment-related effects. However, there was little impact of therapy on analgesic scores or quality of life issues.

Nevertheless, in a later report after an average 24 months follow-up, the difference in the rate of SREs persisted (38 versus 49 percent), and the median time to develop an SRE was significantly longer in the treated group (488 versus 321 days) .

Based in large part upon this trial, zoledronic acid is approved for use by the United States Food and Drug Administration in men with bone metastases from prostate cancer who are failing hormone therapy. . In contrast, the European Committee for Proprietary Medicinal Products has approved the drug for all men with prostate cancer and bone metastases.

In contrast, two trials of intravenous pamidronate showed no benefit of this weaker bisphosphonate in reducing skeletal events (and relieving bone pain) for prostate cancer patients with metastatic bone disease. A pooled analysis was performed on two multicenter trials involving a total of 378 men with bone pain secondary to metastatic prostate cancer who were randomly assigned to pamidronate (90 mg every three weeks for 27 weeks) or placebo . There were no significant differences between the pamidronate and placebo groups with respect to self-reported pain measurements, analgesic use, proportion of patients with a skeletal-related event (pathologic fracture, radiation or surgery to bone, spinal cord compression, hypercalcemia) or mobility at 9 or 27 weeks.

The factors responsible for the discrepant results from these trials are not well understood.

Two other trials have failed to demonstrate a significant benefit from oral bisphosphonates in men with metastatic prostate cancer:

• In one study, 311 men either beginning or responding to standard hormonal treatment for advanced prostate cancer were randomly assigned to oral clodronate (2,080 mg daily) or placebo. The primary end point was the time to symptomatic progression or death from prostate cancer. With an average follow-up of 59 months, fewer men receiving clodronate had reached the primary end point (112 versus 124), but this did not reach the level of statistical significance (hazard ratio, 0.79, p = 0.066) . Similarly, the median time to progression or death was longer in the treated patients (23.6 versus 19.3 months), but the difference was not statistically significant.

• Clodronate also failed to significantly improve pain or improve the duration of palliative benefit from chemotherapy in a trial that randomly assigned men with HRPC and bone pain to mitoxantrone and prednisone with and without clodronate. The median duration of palliation was not longer in the group receiving clodronate (6.2 versus 6.4 months).

Prevention of treatment-related bone loss � Bisphosphonates may prevent the high bone turnover with loss of bone density that can result from chronic androgen deprivation therapy in men with prostate cancer.

The magnitude of the benefit of bisphosphonates is illustrated by the following observations:

• In one trial, 47 men with metastatic prostate cancer were randomly assigned to leuprolide with or without concurrent pamidronate (60 mg IV over two hours every 12 weeks). All men received calcium and vitamin D supplements, and were evaluated after one year with dual energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT). The men receiving prophylactic pamidronate had no significant change in bone density, while those receiving leuprolide alone had a mean decrease in bone mineral density of 3.3 and 1.8 percent at the lumbar spine and hip by DXA, and an 8.5 percent decrease in mean trabecular bone mineral density of the lumbar spine by QCT.

• In another report, zoledronic acid (4 mg every three months for one year) was compared to placebo in men initiating androgen deprivation therapy for nonmetastatic prostate cancer. Mean bone mineral density in the lumbar spine increased by an average of 5.6 percent in men receiving zoledronic acid, while it decreased an average of 2.2 percent in those given placebo.

  Recommendation � Supplementation with calcium and vitamin D should be recommended for all men beginning androgen deprivation for advanced prostate cancer. Clinicians should consider baseline measurements of bone density, and periodic reassessment during therapy. The optimal timing of bisphosphonate therapy is unclear; some suggest that it be considered only when osteoporosis becomes evident on serial bone density studies or in the patient who presents with an osteoporotic bone fracture. This topic is discussed in detail elsewhere.

Palliation of bone pain � The benefit of bisphosphonates for palliation of bone pain in men with metastatic prostate cancer is unclear. At least two randomized trials (one using zoledronic acid, the other pamidronate) have failed to demonstrate a clear benefit for either agent. This topic is discussed in detail elsewhere.

Recommendations � The routine use of zoledronic acid is recommended in men hormone refractory prostate cancer and bone metastases to decrease the frequency of skeletal events. Only zoledronic acid (and not other bisphosphonates) has been approved for his indication by the United States Food and Drug Administration. Not all physicians caring for patients with metastatic prostate cancer agree with this recommendation

For all men beginning androgen deprivation for advanced prostate cancer who are at risk for treatment-related osteoporosis, calcium and vitamin D supplements should be prescribed as well as a moderate exercise regimen. Clinicians should consider baseline measurements of bone density, and periodic reassessment during therapy. The optimal timing of bisphosphonate therapy is unclear in this setting. Largely because of its expense, many clinicians suggest that it be considered only when osteoporosis becomes evident on serial bone density studies or in the patient presenting with an osteoporotic bone fracture. The United States Food and Drug Administration has not approved any bisphosphonate for use in this setting. Some clinicians preferentially use alendronate in this setting.

OTHER CANCERS � Bone metastases are frequent and cause substantial morbidity in other malignancies, particularly non-small cell lung cancer (NSCLC). However, few studies have evaluated the utility of bisphosphonates for metastatic cancers other than multiple myeloma, breast, and prostate cancer. A benefit for zoledronic acid in a wide variety of other metastatic malignancies was suggested in one double-blind trial, in which 773 patients with skeletal metastases from cancers other than breast and prostate (49 percent NSCLC) were randomly assigned to zoledronic acid (4 or 8 mg) or placebo every three weeks for nine months. The percentage of patients with osteolytic versus osteoblastic bone metastases was not stated.

Zoledronic acid (4 mg) was associated with a significant reduction in the number of skeletal-related events (pathologic fracture, spinal cord compression, radiation or surgery to bone, or hypercalcemia, 38 versus 44 percent), and a significantly longer time to the first event (230 versus 163 days). These benefits persisted at approximately the same magnitude, and long-term treatment (approximately 21 months) was safe and well tolerated in a later update of this series .

Recommendation � Intravenous bisphosphonates such as zoledronic acid (4 mg over 15 minutes monthly) reduce skeletal complications in patients with bone metastases from a wide variety of tumors (with the exception of prostate cancer), and should be considered as adjuvant treatment for such patients.

RISKS OF BISPHOSPHONATE THERAPY � Prolonged therapy with bisphosphonates is generally well tolerated. However, patients should be periodically monitored for a number of complications, including nephrotic syndrome, renal insufficiency, hypocalcemia, and osteonecrosis (avascular necrosis) of the jaw.