Use of Bisphosphonates in Patients With Metastatic Bone Disease

Introduction

Metastatic cancer in bone is a major cause of misery for afflicted patients and may be associated with severe bone pain, fractures, hypercalcemia, and, less commonly, spinal cord compression and neurologic injury. Although chemotherapy, hormonal manipulation, or radiation treatment may be used to palliate patients with bone metastases, substantial morbidity from progressive skeletal involvement remains a common problem.

Tumor-induced osteolysis or lytic bone disease is mediated by osteoclast activation. Osteoclasts can be activated directly by products produced by tumors or indirectly through other nonmalignant cells.

Bisphosphonates inhibit bone resorption by reducing osteoclastic activity. These agents have been shown to be effective in treating cancer-related hypercalcemia and Paget’s disease of bone, both of which are associated with increased bone resorption. Based on these findings, clinical trials were initiated to explore the use of bisphosphonates in patients with osteolytic bone metastases.

This article summarizes the results of these clinical trials, with particular focus on recent, large, randomized, double-blind trials conducted in patients with bone metastases from breast cancer or multiple myeloma. As background to this discussion, a brief review of the pharmacology of bisphosphonates is provided.

Pharmacology of Bisphosphonates

Pyrophosphates are natural compounds that contain two phosphonate groups bound to a common oxygen. In vitro, these compounds are potent inhibitors of bone resorption. However, when used in vivo, pyrophosphates are readily hydrolyzed by phosphatases, which renders them ineffective in reducing bone resorption.[1,2]

If one simply substitutes a carbon for the oxygen, the pyrophosphate molecule becomes resistant to hydrolysis and yet remains active as an inhibitor of bone resorption. With the carbon substitution, these synthetic compounds, known as bisphosphonates, contain two additional chains of variable structure (called R1 and R2; see Figure 1), which have given rise to a large number of different drugs (Table 1).

Most bisphosphonates contain a hydroxyl group at the R1 position, which gives them high affinity for calcium crystals and bone mineral. Marked differences in antiresorptive potency result from differences at the R2 site. Newer bisphosphonates, such as zol-edronate and ibandronate, show nearly four to five logs more potency than first-generation agents, such as etidronate(Drug information on etidronate) (Didronel).

Bisphosphonates are poorly absorbed orally (usually < 1%), probably due to their very poor lipophilic nature. Certain foods, beverages, and medications can significantly alter drug absorption. These agents also are poorly tolerated orally and have significant gastrointestinal toxicity, particularly esophagitis and esophageal ulcers. Thus, compliance has been a significant problem with this route of administration.

The bisphosphonates are eliminated almost exclusively through renal excretion. Significant nephrotoxicity can occur with these compounds, although this is clearly related to the drug dose and rate of infusion when given intravenously. Importantly, renal dysfunction results from the R1 group, so that more potent newer bisphosphonates with different R2 groups offer the opportunity for more convenient dosing schedules without significant nephrotoxicity.

Because bisphosphonates have high affinity for bone mineral, the drugs are highly concentrated in bone (approximately half of the intravenous dose). In addition, these drugs preferentially bind to bones that have high turnover rates. Thus, bisphosphonates are concentrated at the exposed bone surface, which is actively remodeling. They also bind more avidly with highly active trabecular bone than with cortical bone, which has a much lower bone turnover rate.

Once bisphosphonates become a part of bone that is not remodeling, they are biologically inactive. As a result, continued administration of these drugs is required to achieve the desired lasting inhibition of bone resorption.

Bisphosphonate Treatment of Bone Metastases

Because multiple myeloma and breast cancer are often accompanied by bone involvement with osteolytic bone destruction, most clinical trials of bisphosphonates have involved these two forms of cancer. However, recent trials are assessing the effects of bisphosphonates in treating bone metastases from other cancers, such as carcinoma of the prostate.

Multiple Myeloma

Multiple myeloma is characterized by the accumulation of terminally differentiated plasma cells in the bone marrow, and is accompanied by a marked increase in osteoclast activity and proliferation. This increase in osteoclast activity is mediated by the release of osteoclast-stimulating factors.[3,4] These factors are produced locally in the bone marrow microenvironment by cells of both tumor and nontumor origin.

Bone pain, the major clinical manifestation of multiple myeloma, is related to osteolytic bone destruction. Even patients who respond to chemotherapy may exhibit progression of skeletal disease.[5,6]

Although early studies of bisphosphonates in patients with myeloma suggested a reduction in bone pain and healing of lytic lesions, the trials involved few patients and were open-label in design.[7-9] Six large randomized trials of long-term bisphosphonate therapy have now been published; these involved the use of either the first-generation bisphosphonates etidronate or clodronate or the second-generation aminobisphosphonate pamidronate(Drug information on pamidronate) (Aredia).[5,10-14]

Etidronate--In a Canadian study of etidronate,[5] 173 newly diagnosed patients were entered, and 166 patients were randomized. All patients received intermittent oral melphalan(Drug information on melphalan) (Alkeran) and prednisone(Drug information on prednisone) as primary chemotherapy. Patients were then randomized to receive either daily oral etidronate (5 mg/kg) or placebo until death or termination of treatment due to side effects.

Although significant height loss occurred in both placebo- and etidronate-treated patients, no difference was found between the two arms. Similarly, there were no differences between the two arms with respect to the other outcome measures (new fractures, hypercalcemic episodes, and bone pain).

Clodronate--Three large randomized trials using oral clodronate in myeloma patients have been published. In a Finnish trial,[11] 350 newly diagnosed, previously untreated patients were entered, 336 of whom were randomized to receive either clodronate (2.4 g) or placebo daily for 2 years. All patients also received intermittent oral melphalan and prednisolone(Drug information on prednisolone).

Only 204 (61%) patients had had radiographs at both study entry and after 2 years. Given this limitation, the proportion of patients with progression of lytic lesions was lower in the clodronate-treated group than in the placebo group (12% vs 24%; P = .026). However, the two groups did not differ with regard to the progression of overall pathologic fractures, as well as both vertebral and nonvertebral fractures. In addition, the number of patients who developed hypercalcemia was comparable in the two arms. Changes in pain index and use of analgesics were similar in both arms.

Clodronate has also been evaluated in an open-label randomized German trial.[12] In this study, 170 previously untreated patients were randomized to receive either no bisphosphonate or oral clodronate (1.6 g/d) for 1 year. All of the patients were also treated with intravenous melphalan on day 1 and oral prednisone on days 1 through 4 every 4 weeks. Unfortunately, 52% of the participants prematurely terminated treatment despite the short length of the study (1 year).

Patients in the two arms showed no difference in the progression of bone disease, as assessed by plain radiographs. However, there was a trend toward a reduced number of new progressive sites in the clodronate-treated group after 6 months (P = .06), as well as 12 months (P = .09). The proportion of patients who were pain-free and who were not using analgesics was higher in the clodronate group. Because of the open design of this trial, one should be cautious in interpreting the results relative to analgesic usage and pain evaluation. No difference in performance status was observed.

Recently, the Medical Research Council (MRC) published the results of a large trial that randomized 536 patients with recently diagnosed myeloma to receive either oral clodronate (1.6 g) or placebo daily in addition to alkylator-based chemotherapy.[13] The primary end points of the trial were unclear. However, after combining the proportion of patients who developed either nonvertebral fractures or severe hypercalcemia (including those who left the trial due to severe hypercalcemia), the investigators found a lower incidence of these combined events in the clodronate-treated patients than in the placebo-treated patients (P = .021). Nevertheless, the overall number of patients who developed hypercalcemia was similar in the two arms.

In addition, the number of patients who experienced nonvertebral fractures was lower in the clodronate group (P = .036). Although vertebral fractures reportedly occurred significantly less frequently in clodronate-treated patients than in placebo recipients, only half of patients underwent even one post-baseline radiograph.

Back pain and poor performance status did not differ significantly between the two groups except at one time point (24 months). The proportion of patients requiring radiotherapy was similar in the two groups. There also were no differences between the groups in time to first skeletal event or overall survival.

It is somewhat surprising that this trial showed any benefit, given the negative results of the Finnish trial, which used a higher daily dose (2.4 g) of oral clodronate. The results of the MRC trial are limited by the lack of clearly defined, predetermined, specific primary and secondary end points. The lack of impact of this drug on time to first skeletal event and use of radiotherapy is also problematic.

Pamidronate--Compared with etidronate and clodronate, pamidronate is 100- and 10-fold more potent, respectively, in preventing bone resorption in vitro. This agent is a potent inhibitor of bone resorption at doses that do not affect bone mineralization.[14] In multiple myeloma patients, results of open-label trials lasting up to 24 months suggested that pamidronate disodium might be effective in reducing skeletal complications of multiple myeloma.

Based on these results, a randomized, double-blind study was conducted to determine whether monthly 90-mg infusions of pamidronate would reduce skeletal events in patients with mul-tiple myeloma who were receiving chemotherapy, as compared with placebo.[10,15] This study included 392 patients with Durie-Salmon stage III multiple myeloma and at least one osteolytic lesion. Unlike the etidronate and clodronate trials, which involved untreated patients, patients in the pamidronate trial were required to receive an unchanged chemotherapy regimen for at least 2 months before enrollment.

Patients were stratified according to the type of antimyeloma therapy they were receiving at trial entry: first-line chemotherapy (stratum 1) or second-line or higher chemotherapy (stratum 2). Within each stratum, patients were randomized to receive either pamidronate disodium (90 mg) or placebo, each administered as a 4-hour intravenous infusion at intervals of 4 weeks for 21 months.

Because of the expected loss of patients on the trial, it was preplanned to analyze the primary efficacy variable (skeletal events) after 9 cycles of treatment and to analyze survival and safety after 21 cycles. However, patients continued to be followed for skeletal events during the entire 21 cycles of randomized treatment. Both the primary end point, skeletal events (pathologic fractures, spinal cord compression associated with vertebral compression fracture, surgery to treat or prevent pathologic fracture or spinal cord compression associated with vertebral compression fracture, or radiation to bone), and secondary end points (hypercalcemia, bone pain, analgesic drug use, performance status, and quality of life) were assessed monthly.

A total of 392 patients were enrolled in the study (205 patients received pamidronate and 187 patients received placebo), although efficacy was based on 377 patients. However, all 392 patients were included in the safety assessments and survival analyses. The chemotherapeutic regimens in the two groups were similar at study entry and during the trial.

After nine cycles of therapy, the proportion of patients having any skeletal event was 41% in the placebo group but only 24% in the pamidronate group (P < .001). In addition, median skeletal morbidity (defined as the number of skeletal events per year) was half as high in pamidronate-treated patients as in placebo recipients (P < .001). During the first nine treatment cycles, the proportion of pamidronate-treated patients with skeletal events was lower in both stratum 1 (first-line therapy) and stratum 2 (second-line or higher therapy).

During these first nine cycles, patients who received pamidronate had significant decreases in bone pain and required no increase in analgesic usage. The pamidronate-treated patients also showed no deterioration in performance status or quality of life at the end of 9 months.

Similar to the results after 9 cycles of therapy, the proportion of patients developing any skeletal event and skeletal morbidity continued to remain significantly lower in the pamidronate group than in the placebo group during the additional 12 randomized treatment cycles. However, the two treatment groups did not differ with respect to the percentage of patients with healing or progression of osteolytic lesions.

Overall survival in all 392 patients was not significantly different between the two treatment groups. Although median survival did not differ between the treatment groups in stratum 1 patients, median survival time was 21 months for stratum 1 patients treated with pam-idronate vs 14 months for their counterparts treated with placebo (Figure 2).

In a double-blind, randomized trial, a Danish-Swedish cooperative group compared oral pamidronate (300 mg/d) to placebo in 300 newly diagnosed myeloma patients who were also receiving intermittent melphalan and prednisone.[16] After a median duration of 18 months, there were no significant differences between the two arms with respect to either the primary end point, skeletal-related morbidity (defined as bone fracture, surgery for impending fracture, vertebral collapse, or increase in the number and/or size of lytic lesions) or secondary end points (hypercalcemic episodes or survival). Fewer episodes of severe pain and less height loss were observed in the pamidronate-treated patients, however.

Treatment Recommendations--Results of these trials show that the adjunctive use of bisphosphonates in addition to chemotherapy is superior to chemotherapy alone in patients with stage III multiple myeloma with respect to lessening bone complications. Bisphosphonate treatment should now be considered for all patients with multiple myeloma and at least one osteolytic lesion.

The three large long-term studies of clodronate show little impact of the oral form of this drug on skeletal complications. In addition, the lack of efficacy of oral pamidronate suggests that this route of administration is unlikely to produce positive results in multiple myeloma patients. Thus, the current drug of choice at present in the United States is intravenous pamidronate. Although 90 mg monthly is efficacious, the optimal duration and dose of intravenous pamidronate are unknown. However, based on published results, patients should receive at least 21 months of treatment.[15]

Whether intravenous pamidronate is effective in earlier-stage disease or in patients without bone disease is unknown. However, recent in vitro studies suggest that pamidronate may possess antimyeloma properties, as demonstrated by its ability to induce apoptosis of myeloma cells[17] and suppress the production of interleukin-6, an important myeloma growth factor, by bone marrow stromal cells from myeloma patients.[18]