Cancer Chemotherapy & Biotherapy: Principles & Practices, 4th Edition

Bisphosphonates

Matthew R. Smith

INTRODUCTION

Bone metastases are a major cause of morbidity for many patients with advanced-stage cancers. The complications of bone metastases include hypercalcemia, pain, fracture, and spinal cord compression. Most complications of bone metastases result from excessive osteoclast activation.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. These agents are used to treat benign diseases associated with excessive bone resorption, including Paget's disease and osteoporosis. Bisphosphonates are also an important part of the management for many cancer patients. Bisphosphonates are the treatment of choice for hypercalcemia of malignancy. Bisphosphonates decrease the risk of skeletal complications for patients with multiple myeloma and patients with bone metastases from breast cancer, prostate cancer, and other solid tumors. In addition, bisphosphonates may prevent development of bone metastases in women with high-risk primary breast cancer.

PHARMACOLOGY

Bisphosphonates are synthetic analogs of pyrophosphate characterized by a phosphorus-carbon-phosphorus backbone that renders them resistant to hydrolysis (Fig. 26.1). The properties of bisphosphonates are determined by the R1 and R2 carbon side chains.1 Most bisphosphonates contain a hydroxyl group at the R1position that confers high-affinity binding to calcium phosphate. The R2 side chain is the critical determinant of antiresorptive potency (Table 26.1). Bisphosphonates that contain a primary amino group (pamidronate and alendronate) are approximately 100-fold more potent than first-generation bisphosphonates that do not contain an amino group (etidronate and clodronate). Bisphosphonates that contain a secondary or tertiary amino group (ibandronate, risedronate, and zoledronic acid) are among the most potent bisphosphonates, with approximately 10,000-fold more activity than etidronate.

Bisphosphonates are poorly absorbed. Bioavailability is less than 1% after oral administration. Bisphosphonates bind calcium, and calcium-containing foods, beverages, and medications alter drug absorption. Oral administration is associated with gastrointestinal toxicity.

Bisphosphonates are not metabolized. They are eliminated by renal excretion. Bisphosphonates have potential renal toxicity related to total drug dose and rate of intravenous administration. Renal toxicity results from the R1 carbon side chain. Because most bisphosphonates share the same R1 hydroxyl side chain, renal toxicity is a potential adverse effect of all bisphosphonates.

Bisphosphonates are adsorbed to calcium phosphate (hydroxyapatite) crystals in bone. Approximately one half of an intravenously administered dose accumulates in the skeleton. Bisphosphonates preferentially bind to sites of active bone remodeling. Bisphosphonates become biologically inactive after they are incorporated into quiescent bone, and repetitive administration appears to be required to maintain inhibition of bone resorption.

Etidronate (Didronel), pamidronate disodium (Aredia), and zoledronic acid (Zometa) are marketed for oncology in the United States (Table 26.2). Clodronate (Ostac) and ibandronate (Bondronat) are marketed for oncology in other countries but are not available in the United States.

MECHANISMS OF ACTION

Bisphosphonates inhibit osteoclast-mediated bone resorption by several mechanisms. Etidronate and clodronate are metabolized to cytotoxic analogs of adenosine triphosphate. More potent nitrogen-containing bisphosphonates (risedronate, pamidronate, zoledronic acid) inhibit farnesyl diphosphate synthase, a key enzyme in the mevalonate pathway, and decrease prenylation of essential GTP-binding proteins. Bisphosphonates also increase osteoblast secretion of two important cytokines: (1) an inhibitor of osteoclast recruitment and (2) transforming growth factor-β, a signal for osteoclast apoptosis.

Figure 26.1 General structure of bisphosphonates. The biological activity of bisphosphonates depends on the P-C-P group and the structure of the R1 and R2 side chains.

The growth of bone metastases involves reciprocal interactions between tumor cells and metabolically active bone.2 Development and progression of bone metastases involves tumor cell adhesion to bone, invasion, new blood vessel formation, and proliferation. Preclinical studies suggest that bisphosphonates inhibit each of these steps.3, 4 The clinical relevance of the observed antitumor properties of bisphosphonates in preclinical models is not known.

TABLE 26.1 PRECLINICAL POTENCY OF SELECTED BISPHOSPHONATES

Generic Name

Trade Name

Relative Potency

Etidronate

Didronel

1

Clodronate

Ostac

10

Pamidronate

Aredia

100

Ibandronate

Bondronat

10,000

Zoledronic acid

Zometa

10,000

TABLE 26.2 FDA-APPROVED BISPHOSPHONATES FOR ONCOLOGY

Generic Name

Trade Name

Approved Indication(s) in Oncology

Etidronate

Didronel

Hypercalcemia

Pamidronate

Aredia

Hypercalcemia

Multiple myeloma

Metastatic breast cancer

Zoledronic acid

Zometa

Hypercalcemia

Multiple myeloma

Any solid tumor with bone metastases

HYPERCALCEMIA

Hypercalcemia of malignancy results primarily from increased release of calcium from bone. In the presence of bone metastases, calcium is released from the skeleton by local osteoclast-mediated bone destruction. In addition, hypercalcemia of malignancy may result from tumor secretion of PTHrP.5 PTHrP causes hypercalcemia by osteoclast activation and decreased renal calcium excretion. Many malignancies produce PTHrP, including breast cancer, squamous cell carcinoma, renal cell carcinoma, multiple myeloma, and some types of lymphoma.

Treatment with intravenous pamidronate disodium (90 mg) achieves normocalcemia in more than 90% of patients with hypercalcemia of malignancy.6Pamidronate achieves more complete and longer lasting responses than clodronate. In a double-blind study, 41 patients with hypercalcemia of malignancy persisting after 48 hours of saline rehydration were randomly assigned to receive intravenous pamidronate (90 mg) or intravenous clodronate (1,500 mg).7Nineteen of 19 patients (100%) treated with pamidronate achieved normocalcemia compared with 16 of 20 patients (80%) given clodronate. The median duration of normocalcemia was 28 days after pamidronate therapy compared with 14 days after clodronate treatment (P < .01).

Ibandronate appears comparable to pamidronate for hypercalcemia of malignancy. Seventy-two patients with hypercalcemia of malignancy (corrected serum calcium > 2.7 mmol) were treated with either ibandronate (2 or 4 mg) or pamidronate (15, 30, 60, or 90 mg).8 The dose was dependent on the severity of hypercalcemia. The rates of normocalcemia were similar with ibandronate and pamidronate (77% vs. 76%, P = .30). The mean decreases in serum calcium were also similar for ibandronate and pamidronate. The median time to increase in serum calcium was longer for ibandronate than pamidronate (14 vs. 4 days, P = .03).

Zoledronic acid is superior to pamidronate for hypercalcemia of malignancy. In a double-blind study, 287 patients with moderate to severe hypercalcemia of malignancy (corrected serum calcium 3.0 mmol) were randomly assigned to zoledronic acid (4 or 8 mg) or pamidronate (90 mg).9 Both doses of zoledronic acid were superior to pamidronate. The rate of normalization of serum calcium at day 10 was 87% for zoledronic acid versus 70% for pamidronate. The median duration of normocalcemia was greater than 30 days for zoledronic acid and 18 days for pamidronate.

Bisphosphonates should be administered to all patients with hypercalcemia of malignancy and a corrected serum calcium level greater than 3.0 mmol.10Bisphosphonates should also be administered to symptomatic patients with more moderate hypercalcemia.

MULTIPLE MYELOMA

Multiple myeloma is a malignancy characterized by osteolytic bone lesions and accumulation of mature plasma cells in the bone marrow. Osteoclasts are activated through local release of osteoclast-stimulating factors by myeloma and stromal cells. The growth of myeloma cells in the skeleton is promoted by bone production of interleukin 6 and other growth factors.

Eight large randomized trials of bisphosphonate administration for multiple myeloma have been reported (Table 26.3).

In a Canadian study, 166 patients with previously untreated multiple myeloma were randomly assigned to receive either daily oral etidronate disodium (5 mg/kg) or placebo indefinitely.11 All patients were treated with intermittent oral melphalan and prednisone. No significant differences were seen in skeletal outcomes (fracture, hypercalcemia, bone pain) between the two groups.

Three randomized studies evaluated the efficacy of oral clodronate in multiple myeloma. In a Finnish study, 336 patients with previously untreated disease were randomly assigned to receive daily oral clodronate (2,400 mg) or placebo for 2 years.12 All patients were treated with intermittent oral melphalan and prednisolone. No significant differences were noted between the two groups in rates of fracture or hypercalcemia. Bone pain and analgesic usage were also similar in both groups. The proportion of patients with progression of osteolytic bone lesions was lower in the clodronate-treated group than in the control group (12% vs. 24%, P = .026).

In an open-label German study, 170 previously untreated patients were randomly assigned to receive daily oral clodronate (1,600 mg) or no bisphosphonate for 1 year.13 All patients were treated with intravenous melphalan and oral prednisone. Less than one half of the participants completed the 1-year study. No difference was observed in the rate of radiographically apparent disease progression in bone. A trend was seen toward fewer new sites of bone involvement in the clodronate-treated group.

In a Medical Research Council study, 536 patients with previously untreated multiple myeloma were randomly assigned to receive either daily oral clodronate (1,600 mg) or placebo.14 All patients were treated with primary chemotherapy. Overall survival, time to first skeletal event, hypercalcemia, and need for radiation therapy to bone were no different in the two groups. The proportion of patients with vertebral and nonvertebral fractures was significantly lower in the clodronate-treated group than in the placebo-treated group.

Two randomized studies of pamidronate for multiple myeloma have been reported. In a Danish-Swedish cooperative group study, 300 previously untreated patients were randomly assigned to receive daily oral pamidronate (300 mg) or placebo.15 All patients were treated with intermittent melphalan and prednisone. Fewer episodes of severe pain were observed in the pamidronate-treated group. After a median of 18 months, the two groups showed no significant differences in skeleton-related morbidity, incidence of hypercalcemia, or survival.

In a Myeloma Aredia Study Group trial, 392 patients with Durie-Salmon stage III multiple myeloma and at least one osteolytic lesion were treated with antimyeloma therapy and either placebo or pamidronate (90 mg intravenously every month for 9 months).16 The proportion of patients who had any skeletal events (pathologic fracture, irradiation of or surgery on bone, or spinal cord compression) was significantly lower in the pamidronate group than in the placebo group (24% vs. 41%, P < .001). The patients who received pamidronate had significant decreases in bone pain and improved quality of life. Overall survival was similar for both groups. Among patients receiving second-line chemotherapy at study entry, median survival was significantly longer in the pamidronate-treated group than in the placebo-treated group (21 vs. 14 months, P = .041).

TABLE 26.3 MAJOR RANDOMIZED CONTROLLED TRIALS OF BISPHOSPHONATES FOR MULTIPLE MYELOMA

Study (Reference)

N

Treatment

Result

Canadian (11)

166

Etidronate vs. placebo

No difference in skeletal morbidity

Finnish (12)

336

Clodronate vs. placebo

No difference in skeletal morbidity

German (13)

170

Clodronate vs. placebo

Trend toward fewer new bone lesions

Medical Research Council (14)

536

Clodronate vs. placebo

Reduced proportion of patients with fracture

Danish-Swedish (15)

300

Pamidronate vs. placebo

No difference in skeletal morbidity; improved pain

Myeloma Aredia Study (16)

377

Pamidronate vs. placebo

38% decrease in skeletal morbidity rate

Myeloma Ibandronate (17)

214

Ibandronate vs. placebo

No differences in skeletal-related events

Zometa Protocol 10 (18)

1,648

Zoledronic acid vs. pamidronate

Noninferiority study in breast and myeloma; similar clinical outcomes overall

A Myeloma Ibandronate Study Group trial assessed the efficacy of ibandronate in patients with advanced-stage multiple myeloma.17 Two-hundred and fourteen patients with multiple myeloma stage II or III were randomly assigned to receive either intravenous ibandronate (2 mg) or placebo monthly for 12 to 24 months in addition to conventional chemotherapy. The incidence of skeletal-related events, the skeletal morbidity rate, and survival were similar between the ibandronate and placebo groups. In exploratory analyses, strong suppression of bone turnover markers was associated with better clinical outcomes.

Zometa Protocol 10 was designed to demonstrate that zoledronic acid was not inferior to pamidronate for patients with breast cancer or multiple myeloma.18Approximately 1,600 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 via a 15-minute intravenous infusion or 90 mg of pamidronate via a 2-hour intravenous infusion every 3 to 4 weeks for 12 months.18 The primary efficacy endpoint was the proportion of patients experiencing at least one skeletal- related event over 13 months. The zoledronic 8-mg group was discontinued because of excess renal toxicity. The proportion of patients with at least one skeletal-related event was similar in all treatment groups. The median time to the first skeletal-related event 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. Safety, including incidence of renal impairment, was similar for the zoledronic acid 4-mg and pamidronate groups.

The American Society of Clinical Oncology has published clinical practice guidelines on the role of bisphosphonates in myeloma.19 The authors of the guidelines conclude that bisphosphonates provide a meaningful supportive benefit to multiple myeloma patients with lytic bone disease. The authors also conclude that further research is warranted to address the following issues: (1) when to start and stop bisphosphonate therapy, (2) how to integrate its use with other treatments for lytic bone disease, (3) how to evaluate its role in the treatment of myeloma patients without lytic bone involvement, (4) how to distinguish between symptomatic and asymptomatic bony events, and (5) how to better determine the costs and benefits of bisphosphonate therapy.

BREAST CANCER

Several large randomized trials have evaluated the effect of bisphosphonate therapy on skeletal events in women with breast cancer and bone metastases (Table 26.4).

In a double-blind Canadian study, 173 women with breast cancer metastatic to bone were randomly assigned to receive either daily oral clodronate (1,600 mg) or placebo.20 No significant difference in survival was found between the two groups. The combined rate of skeletal events was 28% lower in the clodronate-treated group (P < .001). Treatment with clodronate resulted in significant reduction in the incidence of hypercalcemia, number of vertebral fractures, and number of vertebral deformities.

TABLE 26.4 MAJOR RANDOMIZED CONTROLLED TRIALS OF BISPHOSPHONATES FOR METASTATIC BREAST CANCER

Study (Reference)

N

Treatment

Result

Canadian (20)

173

Clodronate vs. placebo

28% decrease in skeletal events

Netherlands (21)

161

Pamidronate vs. no bisphosphonate

38% reduction in skeletal morbidity rate

Aredia Multinational (22)

224

Pamidronate vs. no bisphosphonate

48% increase in median time to skeletal progression

Aredia Protocol 18 (23)

380

Pamidronate vs. placebo

37% reduction in skeletal morbidity rate

Aredia Protocol 19 (24)

371

Pamidronate vs. placebo

42% reduction in skeletal morbidity rate

Zometa Protocol 10 (18)

1,648

Zoledronic acid vs. pamidronate

Noninferiority study in breast and myeloma; similar clinical outcomes overall; trend toward better outcomes in breast cancer subset

Ibandronate 4265 (26)

466

Ibandronate vs. placebo

Significant improvement in skeletal morbidity period rate

Oral ibandronate (27)

564

Ibandronate vs. placebo

Significant improvement in skeletal morbidity period rate

In an open-label study in the Netherlands, 161 women with predominantly osteolytic metastases were randomly assigned to receive daily oral pamidronate (300 to 600 mg) or no bisphosphonate.21 Treatment with pamidronate resulted in a statistically significant 38% reduction in skeletal morbidity. The benefit of treatment appeared to be dose-dependent, although significant gastrointestinal toxicity was observed at the higher dose.

Three randomized studies of intravenous pamidronate therapy have been reported. In an open-label Aredia Multinational Cooperative Group Study, 295 women with progressive bone metastases were randomly assigned to receive either pamidronate (45 mg intravenously every 3 or 4 weeks) or no bisphosphonate until skeletal disease progression.22 All women were treated with standard chemotherapy. Among 224 evaluable patients, treatment with pamidronate resulted in a statistically significant 48% increase in time to skeletal disease progression. Decreases in other skeleton-related events were not significant. The lack of significant improvements in other skeletal events may reflect the low dose of pamidronate used and the discontinuation of treatment at skeletal disease progression.

In the Protocol 18 Aredia Breast Cancer Study, 372 women who had metastatic breast cancer and at least one lytic bone lesion and who were receiving hormonal therapy were randomly assigned to receive either placebo or pamidronate (90 mg intravenously every 4 weeks) for 24 cycles.23 The skeletal morbidity rate (ratio of number of skeletal events to time on study) was significantly reduced at 12, 18, and 24 cycles in women treated with pamidronate (P= .028, .023, and .008, respectively). At 24 cycles, the proportion of patients with any  skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to first skeletal complication was longer in patients treated with pamidronate than in those receiving placebo (P = .049). No significant difference in survival was seen.

In the Protocol 19 Aredia Breast Cancer Study, 380 women with metastatic breast cancer and at least one lytic bone lesion were treated with cytotoxic chemotherapy and either placebo or pamidronate (90 mg intravenously every month for 12 months).24 The median time to the occurrence of the first skeletal complication (pathologic fractures, need for radiation to bone or bone surgery, spinal cord compression, and hypercalcemia requiring treatment) was greater in the pamidronate group than in the placebo group (13.1 vs. 7.0 months, P = .005). In addition, the proportion of patients in whom any skeletal complication occurred was lower in the pamidronate treatment group (43% vs. 56%, P =.008). The pamidronate group showed significantly less increase in bone pain (P = .046) and deterioration of performance status (P = .027) than the placebo group.

As noted in the section on multiple myeloma, Zometa Protocol 10 was designed to demonstrate that zoledronic acid was not inferior to pamidronate for patients with breast cancer or multiple myeloma.18Approximately 1,600 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 via a 15-minute intravenous infusion or 90 mg of pamidronate via a 2-hour intravenous infusion every 3 to 4 weeks for 12 months.18 The primary efficacy endpoint was the proportion of patients experiencing at least one skeletal-related event over 13 months. The zoledronic 8-mg group was discontinued because of excess renal toxicity. Overall, the incidence of skeletal-related events, time to first skeletal-related event, and skeletal morbidity rate were similar between the groups. In the subset of 1,130 patients with breast cancer, treatment with zoledronic acid was associated with improved outcomes.25

Three randomized controlled trials evaluated the efficacy of ibandronate in metastatic breast cancer. In one study, 466 patients with metastatic breast cancer were randomly assigned to intravenous ibandronate (4 mg or 6 mg) versus placebo.26 The primary efficacy endpoint was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal related events. Secondary endpoints were bone pain scores and analgesic use. Compared with placebo, no statistically significant differences were noted in any parameter with 4 mg ibandronate. In contrast, subjects in the ibandronate 6 mg group had significantly lower SMPR (-20%, 1.19 vs. 1.48, P = 0.004) and longer median time to first SRE (51 vs. 33 weeks, P = 0.018) compared to placebo. Using a multivariate Poisson regression model, the mean reduction in the relative risk of SREs was 40% compared with placebo (P = 0.003). Secondary endpoints, pain score, analgesic use and QOL deterioration, were also significantly lower for 6 mg ibandronate compared to placebo.

In the two other studies, 564 patients with metastatic breast cancer were randomly assigned to receive oral ibandronate (50 mg/day) or placebo for up to 96 weeks. In pooled analyses of the two studies, the ibandronate group had significant improvement in mean SMPR compared to placebo (0.95 vs. 1.18, P < 0.004).27 By multivariate Poisson's regression analyses, ibandronate significantly reduced the risk of SRE by 38% compared with placebo (P < 0.001). The secondary endpoints, bone pain score, analgesic use, and QOL scare reduction, were significantly more favorable in the ibandronate group than in the placebo group (P = 0.001, P < 0.02 and P = 0.032, respectively).

Three randomized controlled trials have evaluated the effect of clodronate on the development of bone metastases on women with high-risk primary breast cancer. Two of the three studies suggest that bisphosphonates reduce the incidence and number of new bony and visceral metastases in women with high-risk primary breast cancer. In one study of 302 women with primary breast cancer and immunohistochemical evidence of tumor cells in the bone marrow, administration of clodronate (1,600 mg by mouth daily for 2 years) reduced the incidence of distant metastases by 50% (P < .001).28 The incidence of both osseous and visceral metastases was significantly lower in the clodronate-treated group than in the control group (P = .003). The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3). In another study, 1,069 women with operable breast cancer were randomized to receive oral clodronate (1,600 mg/day) or a placebo for 2 years starting within 6 months of primary treatment.29 The primary endpoint was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (hazard ratio, 0.77; 95% CI, 0.56 to 1.08; P = .13). During the medication period there was a significant reduction in the occurrence of bone metastases (hazard ratio, 0.44; 95% CI, 0.22 to 0.86; P = .016). The occurrence of nonosseous metastases was similar, but there was a significant reduction in mortality in favor of clodronate during the total follow-up period. A third randomized controlled trial failed to demonstrate efficacy of adjuvant clodronate. Two-hundred and ninety-nine women with primary node-positive breast cancer were randomized to clodronate (n = 149) or control groups (n = 150).30 Clodronate 1,600 mg daily was given orally for 3 years. The incidence of bone metastases was similar in both groups. Clodronate was associated with greater risk of nonskeletal metastases and shorter disease-free survival. Additional studies are required to evaluate the role of bisphosphonates as adjuvant therapy for breast cancer and other malignancies.

The American Society of Clinical Oncology has published clinical practice guidelines on the role of bisphosphonates in breast cancer.31 The authors of the guidelines conclude that bisphosphonates provide a supportive, albeit expensive and non-life-prolonging, benefit to many patients with bone metastases. The authors also conclude that additional information is needed about (1) when to stop therapy, (2) alternative doses or schedules for administration, and (3) how to best coordinate bisphosphonates with other palliative therapies.

PROSTATE CANCER

Most bone metastases in men with prostate cancer appear osteoblastic by radiographic imaging. Osteolytic and osteoblastic lesions represent two extremes of a spectrum, however, and morphologic studies suggest that most bone metastases from prostate cancer are characterized by both excess bone formation and bone resorption. Pathological acceleration of bone remodeling results in disorganized bone with impaired biomechanical properties.

Osteoblastic metastases from prostate cancer have increased osteoblast number and activity, increased bone volume, and increased the bone mineralization rate.32 Osteoclast number and activity are increased in osteoblastic metastases in bone adjacent to metastases and in distant uninvolved bone.32, 33Biochemical markers of osteoclast activity are elevated in men with osteoblastic metastases from prostate cancer.34 Although osteoclast activity is increased in men with prostate cancer, it is unclear whether osteoclast activation precedes bone formation, as in normal bone remodeling, or osteoclast activation is secondary to excessive osteoblast activity in the metastases. Markers of osteoclast activity independently predict the risk for subsequent skeletal complications,35 suggesting that cancer-mediated osteoclast activation not only accompanies bone metastases but also contributes to the clinical complications of metastatic disease. These observations form the rationale for osteoclast-targeted therapy in men with prostate cancer and blastic bone disease.

Three contemporary studies have evaluated the efficacy of bisphosphonates in men with hormone-refractory metastatic prostate cancer (Table 26.5).

In the zoledronic acid 039 study, 643 men with androgen-independent prostate cancer and asymptomatic/minimally symptomatic bone metastases were assigned randomly to zoledronic acid (4 mg intravenously every 3 weeks) or placebo.36 All men continued androgen-deprivation therapy throughout the study and received additional antineoplastic therapy at the discretion of the investigator. The primary study endpoint was the proportion of men who experienced one or more skeletal-related events (pathological fracture, spinal cord compression, surgery or radiation therapy to bone, or change in antineoplastic treatment to treat bone pain). By fifteen months, at least one skeletal-related event occurred in 44% of men who received placebo and 33% of men who received zoledronic acid (P = .02). The median time to first skeletal-related event differed significantly between men who received zoledronic acid and men who received placebo (>420 vs. 321 days; P = .01). The study was not designed to evaluate the effect of zoledronic acid on survival. Median time to death, however, was longer in the zoledronic group than in the placebo group (546 vs. 464 days, P = .09).

TABLE 26.5 CONTEMPORARY RANDOMIZED TRIALS OF BISPHOSPHONATES FOR MEN WITH HORMONE-REFRACTORY METASTATIC PROSTATE CANCER

Study (Reference)

N

Treatment

Result

Zometa 039 (36)

643

Zoledronic acid vs. placebo

Significant decrease in skeletal-related events

Study 032/INT 05 (38)

350

Pamidronate vs. placebo

No significant difference in pain, analgesic use, or skeletal-related events

NCIC Pr06 (37)

204

Mitoxantrone and prednisone ± clodronate

No significant difference in palliative response

The two other contemporary randomized, controlled trials for men with hormone-refractory prostate cancer were negative. In the National Cancer Institute of Canada Pr06 study, 204 men with androgen-independent prostate cancer and symptomatic bone metastases were assigned randomly to two treatments: mitoxantrone, prednisone, and intravenous clodronate versus mitoxantrone, prednisone, and placebo.37 The primary study endpoints were pain scores and analgesic use. Pain scores, analgesic use, duration of palliative benefit, and overall survival did not differ significantly between the groups. In a pooled analyses of two multicentered trials, protocol 032 and INT 05, 350 men with androgen-independent prostate cancer and symptomatic bone metastases were assigned randomly to either intravenous pamidronate or placebo every 3 weeks for 27 weeks.38 Pain scores, analgesic use, proportion of men with at least one skeletal-related event by 27 weeks, and survival were similar in the pamidronate and placebo groups.

Only one study has evaluated the efficacy of bisphosphonates in men receiving initial hormone therapy for metastatic prostate cancer. In the Medical Research Council Pr05 study, 311 men who were starting or responding to primary androgen-deprivation therapy were assigned randomly to either oral clodronate (2,080 mg/day) or placebo.39 All the men continued primary androgen-deprivation therapy. The relative risk of skeletal disease progression or prostate cancer death was lower in the clodronate group, although the difference was not significant. Adverse events were more common among men treated with clodronate. Gastrointestinal problems and elevated serum concentrations of lactate dehydrogenase were the most common adverse events.

Each of the contemporary randomized, controlled trials in prostate cancer has potential limitations. Inadequate sample size, use of less potent bisphosphonates, and endpoint definition may account for the lack of statistically significant benefits in the MRC Pr05, NCIC Pro6, and Protocol 032/INT 05 studies. In addition, the advanced disease state of subjects in the NCIC Pr06 and Protocol 032/INT 05 may have contributed to the inability to demonstrate any benefit.

OTHER MALIGNANCIES

Only one large randomized controlled trial has evaluated the efficacy of bisphosphonates for patients with bone metastases from other malignancies. In the Zometa Protocol 11 study, 773 patients with bone metastases from lung cancer or other solid tumors (except breast or prostate cancer) were randomly assigned to receive zoledronic acid or placebo every 3 weeks for 9 months.40 Concurrent antineoplastic therapy was administered at the discretion of the treating physician. The primary efficacy analysis was proportion of patients with at least one skeletal-related event. At 9 months, the proportion of subjects with a skeletal related event was 38% for the zoledronic acid group versus 44% for the placebo group (P = .13). The median time to first event was significantly longer for the zoledronic acid group than the placebo group (230 vs. 163 days; P = .02). Multiple event analyses showed that the risk of skeletal-related events was significantly decreased with zoledronic acid (hazard ratio, 0.73; P = .017). The results of this study contributed to the broad approval of zoledronic acid for the treatment of patients with bone metastases from any solid tumor.

A retrospective analysis of the Zometa Protocol 11 data assessed the efficacy and safety of zoledronic acid in the subset of 74 patients with metastatic renal cell carcinoma.41 Zoledronic acid (4 mg intravenously every 3–4 weeks) was found to significantly reduce the proportion of patients with skeletal-related event (37% vs. 74% for placebo, P = .015). Similarly, zoledronic acid significantly reduced the mean skeletal morbidity rate (2.68 versus 3.38 for placebo, P = .014) and extended the time to the first event (median not reached vs. 72 days for placebo, P = .006). The median time to progression of bone lesions was significantly longer for patients who were treated with zoledronic acid (P = .014).

CONCLUSION

Bisphosphonate therapy has become an important part of supportive care for patients with advanced malignancies. Potent bisphosphonates administered by the intravenous route are the treatment of choice for patients with hypercalcemia of malignancy. Bisphosphonates reduce the skeletal morbidity associated with multiple myeloma and breast cancer with osteolytic bone metastases. Treatment with bisphosphonates reduces pain in patients with symptomatic bone metastases from other primary sites.

In addition to having an established role in supportive care, bisphosphonates show the potential to change the natural history of some cancers. Several studies suggest that adjuvant treatment with bisphosphonates may prevent or delay new bone metastases in women with high-risk primary breast cancer.

 

REFERENCES

1. Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer 1997;80:1652–1660.

2. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2002;2:584–593.

3. Clezardin P. The antitumor potential of bisphosphonates. Semin Oncol 2002;29:33–42

4. Green JR. Antitumor effects of bisphosphonates. Cancer 2003;97: 840–847.

5. Rankin W, Grill V, Martin TJ. Parathyroid hormone-related protein and hypercalcemia. Cancer 1997;80:1564–1571.

6. Body JJ, Dumon JC. Treatment of tumour-induced hypercalcaemia with the bisphosphonate pamidronate: dose-response relationship and influence of tumour type. Ann Oncol 1994;5:359–363.

7. Purohit OP, Radstone CR, Anthony C, et al. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995;72:1289–1293.

8. Pecherstorfer M, Steinhauer EU, Rizzoli R, et al. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate. Support Care Cancer 2003;11:539–547.

9. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558–567.

10. Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol 1998;16:3890–3899.

11. Belch AR, Bergsagel DE, Wilson K, et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol 1991;9: 1397–1402.

12. Lahtinen R, Laakso M, Palva I, et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet 1992;340:1049–1052.

13. Clemens MR, Fessele K, Heim ME. Multiple myeloma: effect of daily dichloromethylene bisphosphonate on skeletal complications. Ann Hematol 1993;66:141–146.

14. McCloskey EV, MacLennan IC, Drayson MT, et al. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 1998;100:317–325.

15. Brincker H, Westin J, Abildgaard N, et al. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo-controlled trial. Danish-Swedish Co-operative Study Group. Br J Haematol 1998;101:280–286.

16. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996; 334:488–493.

17. Menssen HD, Sakalova A, Fontana A, et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 2002;20:2353–2359.

18. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377–387.

19. Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20: 3719–3736.

20. Paterson AH, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59–65.

21. van Holten-Verzantvoort AT, Kroon HM, Bijvoet OL, et al. Palliative pamidronate treatment in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:491–498.

22. Conte PF, Latreille J, Mauriac L, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group. J Clin Oncol 1996;14:2552–2559.

23. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846–854.

24. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996;335:1785–1791.

25. Rosen LS, Gordon DH, Dugan W Jr, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36–43.

26. Body JJ, Diel IJ, Lichinitser MR, et al: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14: 1399–1405.

27. Body JJ, Diel IJ, Lichinitzer M, et al: Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133–1137.

28. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–363.

29. Powles T, Paterson S, Kanis JA, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–3224.

30. Saarto T, Blomqvist C, Virkkunen P, et al. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19:10–17.

31. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042–4057.

32. Clarke NW, McClure J, George NJ. Osteoblast function and osteomalacia in metastatic prostate cancer. Eur Urol 1993;24:286–290.

33. Clarke NW, McClure J, George NJ. Morphometric evidence for bone resorption and replacement in prostate cancer. Br J Urol 1991;68:74–80.

34. Garnero P, Sornay-Rendu E, Claustrat B, et al. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 2000;15:1526–1536.

35. Berruti A, Dogliotti L, Bitossi R, et al. Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline. J Urol 2000;164:1248–1253.

36. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458–1468.

37. Ernst D, Tannock I, Venner P, et al. Randomized placebo controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone alone in patients with hormone refractory prostate cancer (HRPC) and pain: National Cancer Institute of Canada Clinical Trials Group study [abstract]. Proc ASCO 2002;705:A177.

38. Small EJ, Smith MR, Seaman JJ, et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003;21.

39. Dearnaley DP, Sydes MR, Mason MD, et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003;95:1300–1311.

40. Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial. Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150–3157.

41. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962–969.