Bone lesions due to metastatic disease undermine

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and the Benefits of Bone-Targeted Therapy

Allan Lipton

Several cancers, including those originating in the breast, prostate, and lung, exhibit a propensity to metastasize to bone, resulting in debilitating skeletal complications. These sequelae, such as intractable pain, pathologic fractures, spinal compression, and hypercalcemia, greatly erode the patients’ quality of life. Bisphosphonates, a class of antiresorptive drugs, are now the mainstay of the treatment of skeletal-related events in myeloma bone disease and many solid cancers with bone metastases. Current evidence indicates that newer-generation nitrogen-containing bisphospho-nates, particularly zoledronic acid, are potent inhibitors of bone resorption. In addition, increased understanding of the pathogenesis of bone metastasis has resulted in the development of several bone-targeted therapies including a monoclonal antibody targeting the receptor activator of nuclear factor (NF)-␬B ligand (RANKL). In this review, clinical evidence regarding the efficacy and safety of currently available bone-targeted therapies including bisphosphonates and anti-RANKL monoclonal antibody in the treatment of bone metastasis due to breast cancer, prostate cancer, lung cancer, and multiple myeloma bone disease will be summarized.

Semin Oncol 37 (Suppl 2):S15-S29 © 2010 Elsevier Inc. All rights reserved.

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one lesions due to metastatic disease undermine the structural integrity of the bone and are asso-ciated with substantial morbidity and debilitat-ing complications.1 These sequelae, including severe bone pain, pathologic fractures, spinal cord compres-sion, leukoerythroblastic anemia, bone deformity, and hypercalcemia of malignancy (HCM), have a devastat-ing impact on quality of life and are associated with increased health care costs. The annual incidence of skeletal complications is 1.5\– 4.0 events per year in patients with bone metastasis.2,3

Hypercalcemia occurs in advanced stage disease, and is associated with dysfunction of the gastrointesti-nal tract, kidneys, and central nervous system that can reach potentially life-threatening proportions.1In most instances, hypercalcemia is causally linked to increased osteoclastic bone resorption, either multifocal manifes-tations or as a generalized process, in response to tumor-derived growth factors and cytokines. Moreover, the loss of bone integrity due to metastasis results in rib fractures, vertebral collapse, and pathologic fractures. While the last is not as common as the other two, it is

associated with the most incapacitating effects; sites of pathologic fractures commonly involve the hip and the proximal ends of the long bone and often require orthopedic surgery. Development of spinal cord com-pression is a catastrophic event that requires vigilant monitoring, early diagnosis, and urgent decompression interventions to allow neurologic recovery. Bone pain is a common cancer-related complication that can be intractable in severe cases, and is linked to the rate of bone resorption.

Several treatment strategies are currently employed in the management of bone metastasis, including sur-gery, radiation, chemotherapy, and treatment with a bisphosphonate class of antiresorptive drugs.4 While radiotherapy or surgery intervention are used with pal-liative intent and have been favorably associated with better quality of life and longer survival times, their curative potential is limited since they do not target the underlying pathobiology of the disease. Bisphospho-nates are analogues of pyrophosphates that bind avidly to metabolizing bone and inhibit several components of the bone resorptive process, including induction of osteoclast apoptosis, inhibition of osteoclast formation, and recruitment. Based on their considerable clinical activity, bisphosphonates are now an integral part of the current armamentarium for the treatment of skele-tal complications related to metastatic bone disease. There are several bisphosphonates currently available and they exhibit varying structures, mechanism of ac-tion, and potencies. The early-generation

bisphospho-Milton S. Hershey Medical Center, Penn State University, Hershey, PA. Publication of this article was supported by an educational grant from

Novartis Pharmaceuticals Corporation.

Address correspondence to Allan Lipton, MD, PO Box 850 H-46, Her-shey, PA 17033– 0850. E-mail:alipton@hmc.psu.edu

0270-9295/ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2010.10.002

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nates such as clodronate do not contain nitrogen and are metabolized by osteoclasts. In contrast, later-gener-ation bisphosphonates, such as pamidronate and zoledronic acid, are nitrogen-containing agents that are internal-ized by osteoclasts and lead to inhibition of farnesyl-diphosphonate (FPP) synthase that regulates activity of key guanosine triphosphatases (GTPases) required for osteoclast function.5 Of the nitrogen-containing bis-phosphonates, current evidence indicates that zoledronic acid is the most potent in terms of FPP synthase inhibition and antiresorptive activity. Recent advances in under-standing of the pathogenesis of bone metastasis in different cancer settings have led to the development of rational bone-targeted therapies.4 Several such emerging bone-targeted agents are currently being de-veloped and are in varying stages of clinical testing. Considering the crucial role of the receptor activator of nuclear factor (NF)-␬B ligand (RANKL) in osteoclasto-genesis,6 a fully human monoclonal RANKL anti-body denosumab is being actively investigated in solid tumors and multiple myeloma. This review attempts to summarize the clinical data regarding the efficacy and safety of currently available bone-targeted therapies in the treatment of bone metastasis due to breast cancer, prostate cancer, lung cancer, and multiple myeloma bone disease.

BREAST CANCER Bisphosphonates in the Treatment of Bone Metastasis

Randomized clinical trials have demonstrated that prolonged administration of oral or intravenous (IV) bisphosphonates significantly reduces the frequency of skeletal-related events (SREs) in patients with bone metastases from breast cancer. Although clodronate has demonstrated considerable activity in terms of re-duction of SREs and palliation in the treatment of bone lesions of breast cancer, questions remain regarding the durability and survival effects. In a randomized placebo-controlled trial, clodronate therapy resulted in significant reduction of the total number of hypercal-cemic episodes (28 events v 52 events; P ⬍.01), the rate of vertebral fractures (84 v 124 events per 100 patient-years; P⬍.025), and the rate of vertebral defor-mity (168 v 252; P ⬍.001) compared with placebo.7 The combined event rate for all skeletal morbidity rate (SMR) was significantly reduced with clodronate ther-apy (218.6 v 304.8; P⬍.001)7(Table 1).7–20 However, these benefits did not translate into significant differ-ences in survival. Considering that the statistical meth-ods used to analyze differences in events per 100 pa-tient-years between the clodronate and placebo groups might potentially overestimate treatment effects, the results of this study were later reanalyzed to measure the time to first SRE and survival; however, median

survival time was still similar between the treatment groups.21Kristensen et al reported that oral clodronate therapy in 100 patients with metastatic breast cancer led to significant reduction in the time to the first SRE and incidence of fractures compared to control8 (Table 1). However, these benefits were not durable and declined after 15 months of treatment. Another trial of 137 patients with osteolytic bone metastases from breast cancer demonstrated that addition of clo-dronate therapy to either chemotherapy or hormonal therapy resulted in a significant reduction in median time to first SRE (244 days v 180 days; P⫽ .05), pain intensity (P ⫽ .01), and analgesic usage (P ⫽ .02) compared to the control group.9 In these studies, no significant differences were observed in the incidence of adverse events between the two treatment groups. Several trials have evaluated the safety and efficacy of pamidronate in the treatment of bone metastases in patients with breast cancer. Early clinical trials, albeit small nonrandomized trials, indicated the clinical ben-efit of pamidronate in terms of progression of bone disease and improvement in bone pain in patients with advanced breast cancer and osteolytic lesions.22–25 Sub-sequently, a randomized study of patients with bone metastases from breast cancer demonstrated that addi-tion of pamidronate to chemotherapy resulted in sig-nificant prolongation of median time to progression (249 days v 168 days; P⫽ .02) and significant reduction in pain (44% v 30%; P⫽ .025) compared to those that received chemotherapy alone10(Table 1).

The clinical benefit of pamidronate was confirmed in a randomized, multicenter trial (Protocol 19 Aredia Breast Cancer Study Group) initiated by Hortobagyi et al to evaluate the long-term effectiveness and safety of infrequent intravenous pamidronate therapy over a pe-riod of 2 years in 382 patients with metastatic breast cancer and osteolytic bone lesions11 (Table 1). Land-mark analysis of the trial showed that monthly infu-sions of pamidronate therapy resulted in significant reductions in the proportion of patients with SRE com-pared to placebo at 15, 18, 21, and 24 months (P⬍.001), which were consistent with data at end of 1 year.2 The median time to first SRE was also signifi-cantly increased with pamidronate therapy compared to placebo (13.9 months v 7 months; P⬍.001).11 How-ever, there was no difference in survival between the two groups. Moreover, long-term treatment did not have any adverse effects. These findings showed that long-term treatment with bisphosphonates was safe and effective as adjunct therapy with standard chemo-therapy in the palliative management of metastatic breast cancer.

Subsequently, Hultborn et al demonstrated that pam-idronate therapy in 404 women with skeletal metasta-ses from breast cancer resulted in significantly fewer SREs (P⬍.01) and significantly increased time to pro-gression of pain (P ⬍.01) and hypercalcemic events

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Table 1. Bone-Targeted Therapy in Patients With Breast Cancer

Study Treatment Results

Clodronate therapy

Paterson et al7 Placebo v oral clodronate (1,600 mg/d)

2 terminal hypercalcemic episodes (17 v 7; P⬍.05);

2 vertebral fractures (124 events v 84 events per 100 patient years; P⬍.025); 2 rate of vertebral deformity (252 v 168;

P⬍.001);

2 SMR (304.8 to 218.6; P⬍.001); 1 time to first SRE (4.9 months v

9.9 months; P⫽ .022); No change in survival time Kristensen et al8 No treatment v oral clodronate

(1,600 mg/d)

1 time to first SRE (P⬍.015); 2 occurrence of fractures (P⬍.023); SRE effects are not durable

Tubiana-Hulin et al9 Placebo v oral clodronate (1,600 mg/d)

1 time to first SRE (180 days v 244 days;

P⫽ .05);

2 pain intensity (P⫽ .01); 2 analgesic usage (P⫽ .02) Pamidronate therapy

Conte et al10 Placebo v pamidronate (45 mg

IV every 3 weeks)

1 time to progression of disease (168 days

v 249 days; P⫽ .02; 1 by 48%);

1 pain relief (30% v 44% of patients;

P⫽ .025)

Hortobagyi et al11 Placebo v pamidronate (90 mg IV every 3–4 weeks; for 2 years)

2 patients with SRE at 15, 18, 21, and 24 months (P⬍.001);

1 time to first SRE (7.0 months v 13.9 months; P⬍.001);

No change in survival

Hultborn et al12 Placebo v pamidronate (60 mg

IV every 4 weeks)

2 SRE (P⬍.01);

1 time to progression of pain (P⬍.01); 1 time to hypercalcemic events (P⬍.05); 1 PS scores (P⬍.05);

No change in fracture or paralysis due to vertebral compression

Theriault et al13 Placebo v pamidronate (90 mg IV every 4 weeks; for 2 years)

2 SMR at 12 months (P⫽ .028), 18 months (P⫽ .023) and 24 months (P⫽ .008);

2 skeletal complications (67% v 56%;

P⫽ .027)

Lipton et al14 Pooled analysis of the

Hortobagyi et al11and Theriault et al13trials 2 in skeletal complications (64% v 51%; P⬍.001); 2 mean SMR (3.7 v 2.4; P⬍.001) Ibandronate therapy

Body et al15 Placebo v ibandronate (6 mg

IV every 3–4 weeks; 2 years)

2 SMPR (2 by 20%; 1.48 events v 1.19 events per patient year; P⫽ .004); 2 time to first SRE (33.1 weeks v

50.6 weeks; P⫽ .018);

2 number of new bone events (2 by 38%)

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(P ⬍.05) compared with placebo.12 However, no sig-nificant difference in pathologic fractures of long bones or pelvis, or paralysis due to vertebral compression was observed between the two groups. In another confir-matory trial (Protocol 18 Aredia Breast Cancer Study

Group), Theriault et al demonstrated that pamidronate therapy in 372 patients with at least one osteolytic bone lesion from breast cancer treated with hormone therapy significantly reduced the primary endpoint of SMR at 12 cycles (P⬍.028), 18 cycles (P ⬍.023), and

Table 1. Continued

Study Treatment Results

Body et al16 Placebo v ibandronate

(50 mg/ day; oral; 96 weeks)

2 mean SMPR (1.18 v 0.95; P⫽ .004); 2 risk of SRE (HR⫽ 0.62; P ⫽ .0001); No significant difference in percentage of

patients with SRE or time to SRE Zoledronic acid therapy

Kohno et al17 Placebo v zoledronic acid

(4 mg IV every 4 weeks for 1 year)

2 SRE (P⫽ .027);

2 in percentage of patients withⱖ SRE (49.6% v 29.8%; P⫽ .003);

delayed time to first SRE (364 days v median not reached; P⫽ .007); 2 risk of SRE (2 by 41%; RR⫽ 0.59;

P⫽ .019);

2 bone pain (45% v 32% of patients) Pamidronate v zoledronic acid therapy

Rosen et al18 Pamidronate (90 mg IV) v

zoledronic acid (4 mg IV) every 3–4 weeks

Prolonged time to first SRE (174 days v 310 days; P⫽ .013);

2 risk of skeletal events (2 by 20%; HR⫽ 0.801; P ⫽ .037);

2 risk of skeletal events in patients with osteolytic lesions (2 by 30%;

HR⫽ 0.704; P ⫽ .010) Denosumab therapy

Body et al19 Pamidronate (90 mg IV) v

denosumab (0.1, 0.3, 1.0 or 3.0 mg/kg SC) in patients with multiple myeloma or breast cancer

Sustained 2 in urinary and serum NTX in denosumab treated patients

Stopeck et al20 Zoledronic acid (4 mg IV) v denosumab (120 mg SC) every 4 weeks

Delayed time to first on-study SRE (HR⫽ 0.82; P ⬍.0001 noninferiority;

P⫽ .01 superiority);

delayed time to first and subsequent on-study SRE (rate ratio 0.77; P⫽ .001); delayed time to first radiation to bone

(HR⫽ 0.74; P ⫽ .01);

delayed time to first on-study SRE or HCM (HR⫽ 0.82; P ⫽ .007);

2 mean SMR (0.58 v 0.45, respectively;

P⫽ .004);

2 patients experiencingⱖ1 on-study SRE (denosumab: 30.7% [95% CI, 27.9%, 33.5%]) (zoledronic acid: 36.5% [95% CI, 33.5%, 39.4%]).

Abbreviations: IV, intravenous; SC, subcutaneous; PS, performance status; SRE, skeletal-related event; SMPR, skeletal morbidity period rate; SMR, skeletal morbidity rate; HR, hazard ratio; RR, risk ratio; NTX, N-telopeptide levels; HCM, hypercalcemia of malignancy; CI, confidence interval.

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24 cycles (P ⬍.008) in the pamidronate group com-pared to placebo (Table 1). At the end of 2 years, the proportion of patients with any skeletal complication was 56% with pamidronate therapy versus 67% for treatment with placebo (P ⫽ .049).13 No statistical difference was observed in survival between the two groups. A pooled analysis at 2 years follow-up of the Hortobagyi et al and Theriault et al trials reaffirmed that pamidronate therapy resulted in significant reductions in percentage of patients with skeletal complications (51% v 64%; P ⬍.001) and mean SMR (2.4 v 3.7;

P ⬍.001) compared to control.14 Median time to first SRE was nearly 6 months longer in the pamidronate group compared to placebo (12.7 months v 7 months;

P⬍.001). Although there were substantial differences

in the extent of reduction in skeletal morbidity that might be attributable to differences in patient popula-tions, these trials led to pamidronate being established as standard supplemental therapy in preventing skele-tal complications and symptom palliation in patients with osteolytic lesions of metastatic breast cancer be-ing treated with chemotherapy or hormonal therapy.

Based on preclinical evidence of 50 –100 times higher potency exhibited by ibandronate in compari-son to pamidronate, both oral and intravenous ibandr-onate formulations were evaluated for treatment of patients with skeletal metastases due to breast can-cer.15,16In a pooled analysis of two placebo-controlled phase III clinical trials that evaluated oral ibandronate 50 mg once daily therapy in patients with skeletal metastases from bone cancer, oral ibandronate therapy significantly decreased the mean skeletal morbidity pe-riod rate (SMPR) compared to placebo (0.95 v 1.18;

P ⫽ .004)16 (Table 1). Oral ibandronate significantly decreased the risk of SRE by 38% compared to placebo (hazard ratio [HR] ⫽ 0.62; P ⬍.0001). However, oral ibandronate did not significantly decrease the percent-age of patients with SREs (45% v 52%; P⫽ .122) or the time to the first SRE (median 21 months v 15 months;

P ⫽ .089). In another pooled analysis that included

both IV ibandronate and oral ibandronate trials, Tripa-thy et al showed that both IV ibandronate and oral ibandronate significantly reduced the SMPR (P⫽ .004) compared with placebo, and reduced bone pain. In a multivariate analysis, the mean reduction in the relative risk of new bone events were comparable between intravenous and oral administration.26 Due to the lack of unequivocal demonstrations of clinical activity with ibandronate therapy, its clinical use is limited in breast cancer.

The third-generation bisphosphonate, zoledronic acid, is considered to be a more potent bisphosphonate compared to pamidronate, as evidenced from preclin-ical data, and requires a relatively short infusion time. Based on these favorable features, a large randomized phase III trial was undertaken to directly compare zoledronic acid (4 mg IV 15-minute infusion every 3– 4

weeks) to the then standard pamidronate therapy (90 mg IV 2-hour infusion every 3– 4 weeks) in 1,130 patients with breast cancer who had bone metastasis including osteolytic, mixed, or osteoblastic18(Table 1). In the total breast cancer population, both zoledronic acid and pamidronate reduced the overall proportion of patients with an SRE (43% v 45%) to a similar extent. However, in the subset of patients with at least one osteolytic lesion, treatment with zoledronic acid re-duced the proportion of patients with an SRE com-pared to pamidronate (48% v 58%), although this trend did not reach statistical significance (P⫽ .058). More-over, significant reduction in the time to first SRE was achieved with zoledronic acid compared to pamidr-onate (median, 310 days v 174 days; P⫽ .013). Multi-ple event analysis, which is proposed to provide a comprehensive assessment of skeletal morbidity, dem-onstrated a 20% reduction in the risk of skeletal events (HR⫽ 0.801; P ⫽ .037) with zoledronic acid compared to pamidronate in all patients, with an even greater reduction the lytic subgroup (HR ⫽ 0.70; P ⫽ .010). These results suggested that zoledronic acid was supe-rior to pamidronate in treatment of patients with bone metastases from breast cancer. Moreover, in an explor-atory analysis of this trial, 68% of the patients who had experienced at least one SRE prior to study entry were associated with an increased risk for the development of an on-study SRE compared to patients with no prior SREs (58% v 32%), implying that early initiation of bisphosphonate therapy might be beneficial and must not be reserved till occurrence of first SRE.

Subsequently, a registrational, randomized, placebo-controlled trial of zoledronic acid in Japan in 228 women with breast cancer bone metastases showed that zoledronic acid led to a significant 39% reduction in the rate of SRE compared to placebo (risk ratio [RR]⫽ 0.61; P⫽ .027), and a 40% decrease in the percentage of patients with at least one SRE (29.8% v 49.6%;

P⫽ .003)17(Table 1). Placebo was deemed an appro-priate comparator since no other bisphosphonates were approved in Japan in this disease and patient setting. Zoledronic acid also significantly decreased the time to first SRE (median not reached v 364 days;

P⫽ .007). A significant reduction in the risk of SREs

was associated with zoledronic acid in this study

compared to placebo (RR ⫽ 0.59; P ⫽ .019).

Zoledronic acid also reduced bone pain (32% v 45%), with only 6% of patients in the zoledronic acid group experiencing grade 3 or 4 bone pain compared to 20% of patients in the placebo group. While caution-ing the hazards of cross-trial interpretations, it must be noted that the magnitude of clinical benefit from treatment with zoledronic acid in this trial appeared to be higher than that from pamidronate and ibandr-onate treatment.11,13

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Novel Targeted Agents in

the Treatment of Bone Metastasis

The investigational bone-targeted human anti-RANKL monoclonal antibody denosumab is the furthest along in clinical testing. It was initially compared to pamidr-onate in patients with multiple myeloma (N⫽ 25) or breast cancer (N ⫽ 29) with radiologically confirmed bone lesions, where patients either received deno-sumab (0.1, 0.3, 1.0, or 3.0 mg/kg subcutaneously [SC]) or pamidronate (90 mg IV), and the effect on bone metabolism was assessed using changes in bone mark-ers urinary and serum N-telopeptide levels (NTX).19 In this study, a significant reduction in median urinary NTX was observed after 1 day of both denosumab and pamidronate. While this decrease was sustained with higher doses of denosumab until 84 days of follow-up, it was not durable in the pamidronate group. These results suggested that denosumab conferred a much longer inhibitory activity on bone resorption compared to standard doses of pamidronate.

A prospective large placebo-controlled randomized trial was initiated to compare the effects of denosumab to zoledronic acid in delaying or preventing bone me-tastases in 2,046 patients with breast cancer and bone metastases that had not been previously treated with bisphosphonates. Patients were randomized to receive either denosumab (120 mg SC) plus placebo (IV), or placebo (SC) plus zoledronic acid (4 mg IV) every 4 weeks20(Table 1). Denosumab significantly delayed the primary endpoint of time to first on-study SRE com-pared to zoledronic acid (HR⫽ 0.82; P ⬍.0001 nonin-feriority; P⫽ .01 superiority) and the time to first and subsequent on-study SRE (rate ratio⫽ 0.77; P ⫽ .001). Denosumab therapy also demonstrated a significant delay in the time to first radiation on bone (HR 0.74;

P⫽ .01) and time to first on-study SRE or HCM (HR ⫽

0.82; P⫽ .007) compared to zoledronic acid therapy. Moreover, denosumab therapy reduced the mean SMR compared to zoledronic acid (0.45 v 0.58; P⫽ .04). At the time of analysis of the primary data, the proportion of patients experiencing at least one on-study SRE was lower in the denosumab arm (30.7% v 36.5%) com-pared to zoledronic acid. Acute-phase reactions during the initial 3 days of the study were reported by 10% of the patients on denosumab treatment and 27% of pa-tients on zoledronic acid. Based on these study results,

denosumab appears to be more effective than

zoledronic acid in delaying the first on-study SRE, and in reducing SMR, time to first radiation to bone, and the proportion of patients with SREs.

PROSTATE CANCER Bisphosphonates in the Treatment of Prostate Cancer

Although prostate cancers are predominantly scle-rotic or osteoblastic, they also have an osteolytic

com-ponent that might be responsive to bisphosphonates. Consequently, several trials have investigated clod-ronate, pamidclod-ronate, and zoledronic acid in patients with prostate cancer. While several early clinical trials indicated that intravenous clodronate might have anal-gesic effects in patients with bone pain associated with metastatic bone disease from prostate cancer, subse-quent trials failed to show convincing clinical activity in preventing skeletal complications, delaying symp-tomatic bone progression, or in palliative responses in prostate cancer, which might be attributable to differ-ences in patient populations, dosage used, and baseline pain levels.27–32 In the placebo-controlled, random-ized PR05 trial in 311 men with bone metastases from prostate cancer who were either commencing or responding to first-line hormone therapy, oral clo-dronate 2,080 mg/d therapy for 3 years resulted in a 21% reduction in risk of bone progression-free survival (BPFS; HR⫽ 0.79; P ⫽.066) and a 20% reduction in risk of death (HR ⫽ 0.80; P ⫽.082) compared with pla-cebo; however, both were not statistically signifi-cant32(Table 2).27–39However, clodronate therapy sig-nificantly lowered the risk of worsened World Health Organization (WHO) performance scores compared to those treated with placebo (HR ⫽ 0.71; P ⫽.008). Nonetheless, patients in the clodronate group exhib-ited an elevated risk for adverse events, with high levels of gastrointestinal toxicities and increased lactate dehydro-genase levels. Based on the bulk of current evidence, the role of clodronate therapy in prostate cancer is uncertain. Two multicenter, randomized, placebo-controlled trials evaluated the effect of pamidronate in the treat-ment of bone metastases in 378 patients with hormone-refractory prostate cancer (HRPC).33Pooled analysis of these two trials showed no statistically or clinically significant differences in pain scores compared with placebo at 9 or 27 weeks in the total population (Table 2). Although a subset of patients with stable or decreas-ing analgesic use achieved significant pain relief at 9 weeks, this was no longer significant at 27 weeks of treatment. Moreover, pamidronate also had no effect on the proportion of patients with SRE at 9 weeks and 27 weeks. Pamidronate was generally well tolerated; the most common adverse events in both groups in-cluded bone pain, nausea, anorexia, and fatigue.

In contrast to the disappointing data with clodr-onate and pamidrclodr-onate in prostate cancer, zoledronic acid has demonstrated efficacy in terms of analgesic effects and reduction in SREs.34 In a randomized, pla-cebo-controlled trial conducted to test the efficacy of zoledronic acid in reducing the incidence of SREs in men with metastatic HRPC, patients were randomized to receive either zoledronic acid (4 mg IV every 3 weeks for 15 months) or placebo (Table 2). After 24 months on the study, a significantly lower percentage of patients who received zoledronic acid treatment had at least one SRE compared to those that received

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pla-cebo (38% v 49%; difference⫽ ⫺11%; 95% confidence interval [CI], ⫺20.2% to ⫺1.3%; P ⫽.028). Consis-tently, the annual incidence of SREs was lower in the zoledronic acid group compared to placebo (0.77 v 1.47; P⫽ .005). A significant prolongation in the me-dian time to first SRE was achieved in the zoledronic acid treatment group (488 days v 321 days; P⫽ .009) compared to placebo. Treatment with zoledronic acid also significantly decreased the risk of developing a skeletal complication by 36% compared to placebo (RR ⫽ 0.64; P ⫽ .002). Moreover, zoledronic acid treatment significantly decreased bone pain compared

to placebo. Zoledronic acid was well tolerated with mild to moderate adverse effects including mild-to-mod-erate fatigue, myalgia, and fever. These results represent the first compelling demonstrations of durable activity with any bisphosphonate therapy in prostate cancer.

Other Bone-Targeted

Therapies in Prostate Cancer

Besides bisphosphonates, several bone-specific agents, including denosumab, atrasentan, and ZD4054 (zibo-tentan), are either being evaluated or rationally de-Table 2. Clinical Trial Data of Bone-Targeted Therapy in Prostate Cancer

Study Patients Treatment Results

Clodronate therapy

Ernst et al27 Men with advanced prostate cancer with bone pain

Placebo v clodronate (600 mg or 1,500 mg IV) for 2 weeks and switched to alternate treatment for 2 weeks

1 analgesic effect with clodronate

Dearnaley et al28(PR05 trial) Men with bone metastases from prostate cancer on first-line hormone therapy

Placebo (n⫽ 156 patients) v clodronate (2,080 mg/d; oral; 3 years; n⫽ 155 patients)

Clodronate therapy showed: no difference in OS and PFS; 2 in worsened WHO PS (P⫽ .008) 1 risk of adverse events;

1 lactate dehydrogenase levels Ernst et al31 Patients with HRPC treated

with mitoxantrone and prednisone (MP)

Placebo v clodronate (1,500 mg IV) every 3 weeks

No difference observed in the palliative response

Pamidronate therapy

Small et al33 Patients with HRPC Placebo or pamidronate (90 mg IV every 3 weeks for 27 weeks)

No difference in palliative response to pain No difference in SRE and SMR

Zoledronic acid therapy

Saad et al34 Patients with HRPC Placebo or zoledronic acid (4 mg IV every 3 weeks) for 15 months

Zoledronic acid showed:

2 in number of patients with at least one SRE (difference⫽ ⫺11%; P ⫽.028); 2 in annual incidence of SRE (1.47 v 0.77;

P⫽ .005);

1 median time to first SRE (321 days v 488 days; P⫽ .009); 36% 2 in risk of SRE (RR⫽ 0.64; P⫽ .002); 2 incidence of SRE; 2 bone pain Denosumab therapy

Fizazi et al35 Patients with bone metastases from prostate cancer, multiple myeloma and other solid tumors

IV bisphosphonate every 4 weeks v 180 mg denosumab SC every 4 or 12 weeks

Higher proportion of patients showed 2 in uNTX (31% v 69%) with denosumab; 2 in on study SRE

Atrasentan therapy

Carducci et al36(phase II trial) Men with metastatic HRPC Placebo or atrasentan (2.5 mg; oral) or atrasentan (10 mg; oral)

1 in median TTP both atrasentan dose groups;

1 median time to PSA progression in the 10 mg atrasentan group (71 days v 155 days; P⫽ .002)

Carducci et al37 Patients with metastatic HRPC

Placebo or atrasentan (10 mg; oral) No change in TTP, TTPSA, or OS Nelson et al38 Patients with nonmetastatic

HRPC

Placebo or atrasentan (10 mg; oral) No statistically significant difference in TTP, TTPSA, or OS

2 in rise of BALP (P⫽ .001) ZD4054 (zibotentan)

James et al39 Men with metastatic HRPC Placebo or ZD4054 (10 mg; oral; daily) or ZD4054 (15 mg; oral; daily)

No difference in median TTP in treatment groups;

1 in OS with ZD4054

Abbreviations: SRE, skeletal-related event; RR, risk ratio; uNTX, urinary N-telopeptide levels; WHO PS, World Health Organization performance status; OS, overall survival; PFS, progression-free survival; TTP, time to progression; TTPSA, time to prostate-specific antigen; PSA, prostate-specific antigen; BALP, bone-specific alkaline phosphatase; SC, subcutaneous; IV, intravenous.

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signed for the treatment of bone lesions due to metastatic prostate cancer. In a randomized phase II trial, 111 patients with bone metastases from pros-tate cancer, other solid tumors, or multiple myeloma and high urinary NTX values were treated with IV bisphosphonates every 4 weeks or subcutaneous de-nosumab 180 mg every 4 weeks or 12 weeks35(Table 2). Of the entire study group, 45% represented patients with prostate cancer, all of whom had received prior treatment with zoledronic acid.33 After 13 weeks of treatment, 69% of patients who received denosumab therapy achieved the primary endpoint of urinary NTX levels⬍50 compared to 19% of patients that received IV bisphosphonate; this trend was sustained even at week 25. The median time to reduction of urinary NTX values to⬍50 was 10 days in the denosumab group v 88 days in the IV bisphosphonate group (P⬍.001). A lower proportion of patients with prostate cancer who received denosumab experienced an on-study SRE compared to patients receiving IV bisphosphonate (3%

v19%). Only one grade 4 adverse event of asymptom-atic reversible hypophosphatemia was reported in pa-tients receiving denosumab therapy. Several ongoing phase III studies are further evaluating the role of denosumab in patients with prostate cancer who have not been previously treated with bisphosphonates, or in patients with castration-resistant prostate cancer and bone metastases.

Based on preclinical evidence, endothelin-1 recep-tor blockade with atrasentan or ZD4054 may represent an attractive treatment option for osteoblastic bone disease in prostate cancer metastases. A placebo-con-trolled, randomized phase II trial demonstrated that atrasentan had favorable tolerability and delayed time to progression of disease in 288 asymptomatic patients with HRPC compared to placebo36(Table 2). Although the primary endpoint of median time to progression (TTP) was not significantly prolonged in the intent-to-treat (ITT) population, it was found to be significantly increased in the assessable population with both drug doses (10 mg and 2.5 mg). Median time to prostate-specific antigen (PSA) progression in the 10-mg atra-sentan group was twice that of the placebo group in both the ITT and the assessable populations (155 days

v71 days; P⫽ .002). Primary adverse events included headache, rhinitis, and peripheral edema in the atra-sentan group. Based on these encouraging results, Carducci et al conducted a phase III placebo-con-trolled trial to evaluate the efficacy and safety of atrasentan 10 mg in patients with metastatic HRPC.37 Disappointingly, atrasentan did not decrease TTP (HR⫽ 0.89; P ⫽ .136), time to PSA progression (HR ⫽ 0.84; P ⫽ .366), or overall survival (OS) (HR ⫽ 0.97;

P⫽ .775) compared with placebo. In another

placebo-controlled, international phase III trial, reported by Nelson et al, in 941 patients with nonmetastatic HRPC who had adequate androgen suppression, and no

evi-dence of metastatic progression but increasing PSA levels, atrasentan 10 mg resulted in a nonsignificant prolongation of median TTP (764 days v 671 days; P⫽ .288) and median time to initial diagnosis of skeletal metastases (1,008 days v 757 days; P⫽ .103) compared to placebo.38There was no difference in OS between the treatment arms. However, atrasentan therapy resulted in significant reductions in PSA doubling time (P ⫽ .031) and was significantly slowed rise in bone-specific alkaline phosphatase (BALP) (P ⫽ .001). An ongoing phase III trial by the Southwest Oncology Group (SWOG-0421) is evaluating atrasentan in combination with docetaxel in patients with metastatic HRPC.40

Preliminary investigations of safety and efficacy of two doses of oral ZD4054 (10 mg or 15 mg) from a placebo-controlled, randomized multicenter phase II study in 312 patients with metastatic HRPC were re-cently presented39 (Table 2). At the time of primary analysis, the median TTP was not significantly different between the treatment groups. However, a clear statis-tically significant survival benefit emerged in subse-quent analysis with 10 mg ZD4054 therapy compared to placebo (HR⫽ 0.55; P ⫽ .008), but the differences in TTP remained insignificant. Adverse events were as expected for an endothelin-A receptor (ETAR) antago-nist including peripheral edema, headaches, and nasal congestion.

MULTIPLE MYELOMA Bisphosphonates in the

Treatment of Myeloma Bone Disease

Clodronate therapy has demonstrated particular clinical efficacy in myeloma bone disease. In the Finn-ish Leukemia Study Group placebo-controlled random-ized trial in patients with multiple myeloma, 350 pa-tients were treated with either placebo or clodronate 2,400 mg/d in addition to melphalan/prednisolone for 2 years; only 68 of these patients did not present with overt skeletal disease41 (Table 3).19,41–50 A significantly lower proportion of patients showed increased pro-gression of osteolytic bone lesions in the clodronate treatment group compared to placebo (12% v 24%, P⫽ .026). While there was no significant difference in the incidence of vertebral fractures between the two groups (30% v 40%), significantly greater pain relief was experienced with clodronate therapy compared to placebo (54% v 24%; P ⬍.001). In the randomized Medical Research Council (MRC) trial reported by Mc-Closkey et al, the use of clodronate 1,600 mg daily in addition to chemotherapy was separately evaluated in newly diagnosed patients with and without overt skel-etal disease at study entry42 (Table 3). An approxi-mately 50% decrease in the proportion of patients with severe hypercalcemia (5.1% v 10.1%; P⫽ .06) or non-vertebral fractures (6.8% v 13.2%; P ⫽ .04) were

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achieved with clodronate therapy. Additionally, clodr-onate treatment decreased the frequency of back pain (10.9% v 19.9%, P ⫽ .05) and height loss (2.0 cm v 3.4 cm, P⫽ .01) compared to placebo at 24 months. While OS was similar between clodronate and pla-cebo therapy at a median follow-up of 8.6 years, it appeared that baseline absence of vertebral fractures might be associated with better survival.43 These results suggested that long- term usage of oral clodr-onate may slow the progression of skeletal disease in multiple myeloma.

Berenson et al demonstrated that monthly infusions

of pamidronate 90 mg in patients with advanced mul-tiple myeloma and at least one osteolytic lesion who had responded to last chemotherapy significantly re-duced incidence of vertebral and nonvertebral frac-tures and requirement for radiotherapy44 (Table 3). Pamidronate therapy resulted in significantly lower in-cidence of skeletal events (38% v 51%; P ⫽ .015), decrease in mean number of SREs (1.3 v 2.2; P⫽ .008), and prolongation of median time to first skeletal event (21 months v 10 months; P ⬍.0001) compared to placebo. While OS was similar between the two treat-ment groups in the total population, a subset analysis

Table 3. Treatment of Myeloma Bone Disease

Study Patients Treatment Results

Clodronate therapy

Lahtinen et al41 Patients with multiple myeloma treated with melphalan-prednisolone

Placebo or clodronate (2,400 mg/d; 2 years)

2 proportion of patients with bone lesions (P⫽ .026);

1 pain relief (P⬍.001); No difference in vertebral fracture

occurrence McCloskey et al42,43 Patients recently diagnosed

with multiple myeloma

Placebo or clodronate (1,600 mg, oral, daily) in addition to chemotherapy 2 by 50% in hypercalcemia (P⫽ .06); 2 by 50% in nonvertebral fractures (P⫽ .04); 2 vertebral fractures (P⫽ .01); 2 height loss (P⫽ .01); 2 pain (P⫽ .05); No change in OS Pamidronate therapy

Berenson et al44 Patients with stage III multiple myeloma and at least one osteolytic lesion

Placebo v pamidronate (90 mg IV; monthly; 21 cycles)

2 SRE (51% v 38%; P⫽ .015); No change in OS

Brincker et al45 Patients with newly diagnosed multiple myeloma who required chemotherapy

Placebo or pamidronate (300 mg, oral, daily) in addition to chemotherapy

No difference in skeletal morbidity; No effect on OS;

1 pain relief (P⫽ .02);

2 reduction of body height (P⫽ .02) Zoledronic acid v pamidronate therapy

Rosen et al46 Patients with multiple myeloma or breast cancer with lytic lesions

Zoledronic acid (4 mg IV, every 3–4 weeks) or zoledronic acid (8 mg IV, every 3–4 weeks) or pamidronate (90 mg IV; every 3–4 weeks) for 24 months

Similar proportion of patients with at least one SRE;

2 SMR with zoledronic acid (1.04 events v 1.39 events per year;

P⫽ .084);

2 time to first SRE with zoledronic acid (380 days v 286 days,

P⫽ .538);

2 overall risk Denosumab v pamidronate therapy

Body et al19 Patients with multiple myeloma or breast cancer

Pamidronate (90 mg IV) v denosumab (0.1, 0.3, 1.0 or 3.0 mg/kg SC)

Sustained decrease in urinary and serum NTX in denosumab treated patients

Denosumab v zoledronic acid therapy

Henry et al47–49 Patients with solid tumors (excluding breast and prostate) or multiple myeloma

Denosumab (120 mg, SC, every 4 weeks) or zoledronic acid (4 mg IV, every 4 weeks)

1 time to first SRE (HR⫽ 0.83;

P⫽ .02);

1 pain relief (HR⫽ 0.85; P ⫽ .02); No change in OS

ACE-011 therapy

Abdulkardyrov et al50 Patients with stage II/III multiple myeloma and evidence of osteolytic bone disease

Placebo v ACE-011 (0.1, 0.3 and 0.5 mg/kg SC; up to 4 monthly)

1 in Hb in a dose-dependent manner;

33% v 75% of the patients had an increase in Hb ofⱖ1 g/dL; 17% v 45% show Hb response; 1 BALP; 2 pain

Abbreviations: SRE, skeletal-related event; SMR, skeletal morbidity rate; HR, hazard ratio; NTX, N-telopeptide levels; OS, overall survival; BALP, bone-specific alkaline phosphatase; Hb, hemoglobin; SC, subcutaneous; IV, intravenous.

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found that a survival advantage was derived by patients who had failed to respond to prior chemotherapy com-pared to those for which this was first-line chemother-apy (21 months v 14 months, P⫽ .041). It is unknown if a similar benefit could not be detected in the MRC clodronate study since all patients received first-line chemotherapy in that trial.43Overall, pamidronate was safe and well tolerated during the duration of treat-ment. These results suggest that the benefits of pam-idronate were predominantly restricted to reductions in skeletal complications. In contrast, Brincker et al reported no difference in skeletal morbidity in terms of bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions with oral pamidronate plus conventional intermittent mel-phalan/prednisolone in 300 patients with newly diag-nosed multiple myeloma45 (Table 3).19,41–50 Treatment with pamidronate also had no effect on patient sur-vival or hypercalcemia. However, pamidronate treat-ment appeared to have a palliative effect on severe pain (P ⫽ .02) and decreased reduction of body height (P ⫽ .02) compared to placebo. The overall negative result of the study was attributed to the low absorption of orally administered bisphosphonates in general.

Based on the encouraging results of a randomized phase II trial that showed similar antiresorptive effects compared to pamidronate, a phase III randomized trial was conducted to compare the long-term safety and efficacy of zoledronic acid (4 mg or 8 mg) with pam-idronate for 2 years in 1,648 patients with multiple myeloma or breast cancer with osteolytic lesions46,51 (Table 3). Zoledronic acid was similar to pamidronate in the reduction of the overall proportion of patients with at least one SRE other than HCM, (47% v 51%) and reduction of SMR (1.04 events per year v 1.39 events per year; P⫽ .084). Zoledronic acid was also compa-rable to pamidronate in the reduction of the time to first SRE in the multiple myeloma stratum (380 days v 286 days, P⫽ .538). The most common adverse events included bone pain, nausea, fatigue, pyrexia, and eme-sis and there was no difference in the renal safety profiles between the 4-mg zoledronic acid and pamidr-onate treatment groups. Based on these two random-ized trials, zoledronic acid is considered to be clearly noninferior to pamidronate in terms of long-term safety and skeletal effects.

Emerging Therapies in the Treatment of Bone Metastasis

In early-phase clinical studies, the investigational agent denosumab substantially diminished the levels of bone turnover markers in heavily pretreated patients with multiple myeloma.19,52 In a randomized trial, de-nosumab resulted in immediate and more sustained dose-dependent decrease in bone turnover markers

compared to pamidronate.19 Subsequently, a double-blind, phase III study compared denosumab with zoledronic acid among 1,776 bisphosphonate-naive pa-tients experiencing bone metastases from solid tumors (excluding breast and prostate cancers) or multiple myeloma47 (Table 3). In the initial report, denosumab was similar to zoledronic acid in terms of the median time to first on-study SRE (20.6 months v 16.3 months;

P⫽ .06), time to first-and-subsequent SRE (HR ⫽ 0.90; P ⫽ .14), and OS (HR ⫽ 0.95; P ⫽ .43). Subsequent

analysis demonstrated that time to first SRE or HCM was significantly longer with denosumab therapy compared to zoledronic acid (HR⫽ 0.83; P⫽.02) as well as the time to first radiation to bone (HR⫽ 0.78;

P⫽ .03).48 Patients that received denosumab also ex-perienced a significant delay in pain worsening com-pared to those that received zoledronic acid (median 169 days v 143 days for; HR⫽ 0.85; P ⫽ .02).49While these results are encouraging, longer follow-up results are needed to determine if these differences are durable.

A number of promising novel targeted agents with therapeutic potential in multiple myeloma bone dis-ease are being investigated in clinical trials, and are in early stages of clinical testing (Table 3). ACE-011 is a fully human soluble fusion protein that blocks activin A signaling, which is implicated in modulation of bone remodeling. Clinically, Ruckle et al showed that ACE-011 increased biomarkers of bone formation and con-comitantly decreased biomarkers of bone resorption in healthy volunteers.53 In addition, ACE-011 treatment resulted in a significant increase in hemoglobin, red blood cell levels, and bone mineral density.54 A ran-domized, placebo-controlled study in patients with multiple myeloma and evidence of bone disease demonstrated that addition of ACE-011 (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) to a regimen of melphalan/ prednisolone/thalidomide (MPT) resulted in a dose-dependent and significant increase in biomarkers of bone formation, improvement in pain reduction and bone metastases, and significant hematologic activity.50 BHQ880, a fully human DKK1 monoclonal anti-body, in combination with zoledronic acid increased bone mineral density by up to 6% in relapsed and/or refractory multiple myeloma.55

LUNG CANCER

Current clinical evidence with clodronate therapy in the treatment of bone metastasis from lung cancer is sparse and shows ambivalence in terms of analgesic effects. In an early small retrospective study in patients with non-small cell lung cancer (NSCLC), Caristi et al showed that clodronate in addition to radiation therapy decreased occurrence of pain worsening and increased complete pain relief compared with radiation therapy alone56 (Table 4).56 – 61 In contrast, Piga et al, in an assessment of clodronate therapy in 66 patients with

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bone metastases from poorly chemoresponsive tumors, such as NSCLC, bladder cancer, gastrointestinal can-cers, kidney cancer, and melanoma, showed no signif-icant difference in worsening of pain between control and clodronate therapy.57 However, analgesic require-ment appeared to be significantly higher in the placebo group (P⫽ .042). The primary drawback of both the studies was the sample size and the low number of pa-tients available for follow-up. More encouragingly, pam-idronate therapy has demonstrated significant improve-ment in OS compared to untreated patients (15.4 months

v2.1 months; P⬍.001), albeit in a retrospective analysis of 41 patients with bone metastases from NSCLC.58

In contrast, more robust clinical evidence exists for the role of zoledronic acid in reducing skeletal compli-cations in lung cancer. Rosen et al performed a ran-domized, placebo-controlled trial in 773 patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate), of which 378 patients had NSCLC. They reported that IV zoledronic acid significantly delayed the median time to first SRE (236 days v 155 days;

P⫽ .009) and decreased the annual incidence of SREs

(1.74 per year v 2.71 per year; P⫽ .012)59 (Table 4). Patients in the zoledronic acid treatment group also demonstrated a 31% reduction in the risk of developing a skeletal event (HR ⫽ 0.693; P ⫽ .003). Zoledronic acid was well tolerated over the course of the treat-ment and the most common adverse events, in all treatment groups, were bone pain and acute phase reactions of nausea, anemia and emesis.

Further, a retrospective analysis of patients with bone metastases from NSCLC demonstrated statistically significant improvement in OS with zoledronic acid in 507 patients with bone metastasis secondary to lung cancer or other solid tumors60(Table 4). Among patients with an SRE before study entry, zoledronic acid reduced the risk of SREs (P⫽ .009), reduced the mean skeletal morbidity rate (1.96 v 2.81 SREs per year; P ⫽ .030), and prolonged the median time to first SRE by nearly 4 months (215 days v 106 days for placebo; P ⫽ .011). In a retrospective exploratory analysis of 382 patients of this trial, Hirsh et al demonstrated significant correlations between

base-line NTX levels and clinical outcomes with

zoledronic acid.61 In both placebo-treated patients and zoledronic acid–treated patients, high baseline NTX significantly correlated with increased SRE risk. While high baseline NTX levels correlated with more than a twofold increased risk of bone lesion progres-sion (P ⫽ .039) and death (P ⫽ .001) compared to normal NTX levels in the placebo group, these cor-relations were not apparent in the zoledronic acid group. Importantly, zoledronic acid significantly de-creased the RR of death by 35% in patients with high baseline NTX (P ⫽ .024), underscoring the impor-tance of treating bone metastasis in patients with

high-risk disease. Recently, Zarogoulidis et al demon-strated that addition of zoledronic acid to docetaxel and carboplatin chemotherapy in 144 patients with stage IV lung cancer and evidence of bone metasta-ses led to significant prolongation of survival com-pared to those who received chemotherapy alone62 (Table 4). A positive correlation was also observed between the number of treatment cycles with zoledronic acid and patient survival (P ⬍.01) and time to progression (P ⬍.01).

SAFETY OF BONE-TARGETED THERAPY

Oral bisphosphonates are commonly associated with gastrointestinal adverse events such as epigastric pain and esophagitis.63IV bisphosphonates are often associ-ated with typical infusion-relassoci-ated side effects such as injection site reactions, flu-like syndromes, and some-times renal issues. The most commonly reported ad-verse events reported in the pivotal trial comparing zoledronic acid and pamidronate reported by Rosen et al were bone pain, nausea, fatigue, emesis, and fever.18 Renal complications with intravenous bisphosphonates are of some clinical concern. In the Rosen et al study, renal toxicities occurred at a frequency of about 10% and were not found to be different between zoledronic acid and pamidronate.18 In particular, change from baseline of serum creatinine of at least 2 times baseline value was 7.7% for patients treated with 4 mg zoledronic acid compared to 6.0% with pamidronate therapy. Due to these renal toxicity concerns, regular monitoring of renal function and dose adjustment ac-cording to creatinine clearance is advocated with zoledronic acid use. Recently, it was revealed that long-term bisphosphonate therapy might be associated with a rare incidence of osteonecrosis of the jaw (ONJ), with an estimated frequency of about 1%. Its incidence has been correlated with dental extraction procedures and corticosteroid therapy. The incidence of ONJ was sim-ilar between zoledronic acid and the investigational agent denosumab (1.4% v 2.0%).64 Although the inci-dence of adverse events (all grades) and serious adverse events was similar between the two treatment groups, Stopeck et al reported a lower rate of acute phase reactions with denosumab therapy compared to zoledronic acid (10.4 % v 27.3%).20 Taken together, while there might be some class effect toxicities with bone-tar-geted therapies that require vigilant monitoring and management, the benefits of bone-targeted therapy far outweigh any toxicities, particularly in light of the debilitating symptoms of skeletal disease that these patients would otherwise experience.

CURRENT TREATMENT GUIDELINES

According to the American Society of Clinical On-cology (ASCO), infusional bisphosphonates

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pamidr-onate 90 mg (delivered over 2 hours) or zoledronic acid (4 mg over 15 minutes every 3 to 4 weeks) are recommended for management of bone-related metas-tases in women with breast cancer who show evidence of bone destruction by plain radiography.65 However,

the presence or absence of bone pain is not considered a determinant of initiation of bisphosphonate therapy. In patients with bone metastasis from lung cancer, regardless of presence of symptoms, initiation of zoledronic acid and continuation of therapy as long as it is well Table 4. Clinical Trial Results of Bisphosphonate Therapy in Lung Cancer

Study Patients Treatment Results

Clodronate therapy

Caristi et al56 Patients with metastatic osteolysis from breast cancer and NSCLC who received RT

Clodronate for at least 3 days from the beginning of radiation therapy or no clodronate

2 pain worsening (33.3%

v 41.9%);

1 pain relief with

clodronate at end of RT (40.7% v 20.9%) and 4 – 6 weeks after therapy (70.3% v 53.7%)

Piga et al57 Patients with poorly responsive tumors such as NSCLC, bladder cancer, gastrointestinal cancers, kidney cancer, melanoma and metastatic carcinoma of unknown origin Placebo or clodronate (1,600 mg/d; oral; 1 year) No difference in pain palliation with clodronate; 2 analgesic requirement (P⫽ .042) Pamidronate therapy

Spizzo et al58 Patients with bone metastases from NSCLC

Pamidronate treatment (90 mg IV; every 4 weeks) or untreated 1 median OS (15.4 months v 2.1 months; P⬍.001). Zoledronic acid

Rosen et al59 Patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate)

Placebo or zoledronic acid (4 mg IV every 3 weeks for 21 months)

1 time to first SRE (236 days v 155 days; P⫽.009); 2 annual incidence of SREs (1.74 v 2.71 per year; P⫽ .012); 31% 2 in the risk of developing a skeletal event (HR⫽ 0.693; P ⫽ .003)

Hirsh et al61,62 Patients with bone metastases secondary to lung carcinoma

Placebo or zoledronic acid (4 mg IV every 3 weeks for 21 months)

2 risk of death in patients with high baseline NTX (P⫽ .024).

Zarogoulidis et al62

Patients with stage IV lung cancer with evidence of metastasis

Zoledronic acid (4 mg IV every 21 days) or no treatment in combination with docetaxel and carboplatin 1 survival (P⬍.01) and 1 time to progression (P⬍.01); No difference in pain palliation

Abbreviations: NSCLC, non-small cell lung cancer; SRE, skeletal-related event; HR, hazard ratio; NTX, N-telopeptide levels; OS, overall survival; RT, radiotherapy; IV, intravenous.

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tolerated is indicated in patients with an Eastern Coop-erative Oncology Group (ECOG) performance status ⱕ2.66 For palliative purposes, initiation of zoledronic acid is also suggested in patients with compromised performance status. In multiple myeloma, pamidronate and zoledronic acid are the current standard treatments for skeletal complications resulting from osteolytic bone disease.67 While guidelines recommend monthly treat-ment for up to 2 years, alternative dosing schedules are currently being evaluated, as are the benefits of treat-ment beyond 2 years.68

CONCLUSIONS

The natural history of bone metastases due to solid tumors or myeloma bone disease shows dismal prog-nosis. Skeletal complications due to bone metastasis are strong determinants of quality of life and survival in these patients. Based on solid evidence, treatment with bisphosphonates, particularly pamidronate and zoledronic acid, is deeply entrenched in the treatment paradigm of management of bone disease. In contrast to analgesics or radiation therapy, bone-targeted therapy is not only used with palliative intent but also in the prevention of future SREs. While patients with a history of SREs are more prone to developing subsequent SREs, zoledronic acid appeared to be effective in reducing skeletal mor-bidity regardless of prior SRE history. Looking forward, based on convincing evidence that profound survival benefits are achieved in patients with less advanced bone lesions, it is increasingly being speculated that initiation of bisphosphonate therapy early during the course of the disease might be an optimal management strategy. Several prospective studies are ongoing to evaluate the efficacy of bisphosphonates in delaying or preventing bone metastasis in many cancer types. Out-comes of these studies will provide further insights into the role of bone-targeted therapies in the management of bone metastases.

STATEMENT OF CONFLICT OF INTEREST

A. Lipton discloses the following potential conflicts of interest: Consulting fees: Amgen Inc; Cephalon, Inc; Novartis Pharmaceuticals Corporation; and Thar Phar-maceuticals. Speaker’s bureau: Amgen Inc, Genentech, and Novartis Pharmaceuticals Corporation. Contracted research: Monogram Biosciences, Oncogene Science/ Siemens HealthCare Diagnostics, Novartis Pharmaceu-ticals Corporation. Expert testimony: Novartis Pharma-ceutical Corporation.

Acknowledgment

The author wishes to thank Nathan Kelly, PhD, and Trudy Grenon Stoddert, ELS, for their assistance in preparing the manuscript for publication.

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