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Bisphosphonates in the treatment of skeletal metastases
Bisphosphonates in the Treatment of Skeletal Metastases PierFranco Contea and Robert Colemanb Metastatic bone disease puts an enormous burden on patients and health care resources. Disruption of normal bone homeostasis by bone metastases leads to troublesome skeletal complications, such as bone pain, pathologic fractures, hypercalcemia of malignancy, and spinal cord compression. Bisphosphonates are an effective treatment for skeletal complications. These agents act primarily by initiating biochemical processes that ultimately result in apoptosis of osteoclasts, but they also have a number of other antitumor functions (eg, inhibition of angiogenesis). At present, the most widely used bisphosphonates are oral clodronate and intravenous pamidronate and zoledronic acid. Although these agents are effective in reducing skeletal complications, they are associated with varying safety and convenience issues. More recently, the availability of ibandronate as intravenous and oral formulations represents a new alternative for the treatment of metastatic bone disease. Further studies are necessary to establish the comparative benefits of bisphosphonates in metastatic bone disease. Semin Oncol 31:59-63 © 2004 Elsevier Inc. All rights reserved.
M
etastatic bone disease is a common and distressing complication of various cancers, particularly breast cancer, multiple myeloma, and prostate cancer (Table 1).1 The onset of metastatic bone disease is devastating for patients because it indicates that their cancer is incurable with significant morbidity. Approximately 65% to 75% of patients with metastatic breast cancer develop skeletal metastases, surviving for about 2.5 years.2,3 Bone metastases arise when primary tumor cells metastasize to active hematopoietic bone marrow tissue in skeletal areas with high proportions of trabecular bone, such as the skull, spine, pelvis, femur, and humerus, causing bone lesions. In healthy individuals, normal bone remodeling is maintained by balanced interactions between osteoclasts, which mediate bone resorption, and osteoblasts, which promote new bone formation. Skeletal metastases interfere with normal bone homeostasis by expressing growth factors and cytokines that accelerate osteoclast activity, resulting in bone resorption and the release of factors that interact with the tumor cells, further stimulating osteoclasts. Consequently, bone metabolism is extensively mod-
aDepartment
of Oncology and Haematology, The University of Modena and Reggio Emilia, Modena, Italy. bYorkshire Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, UK. Address reprint requests to PierFranco Conte, MD, Department of Oncology & Hematology University Hospital, Via del Pozzo 71, 41100 Modena, Italy.
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.07.024
ified, compromising skeletal integrity and leading to clinical sequelae.
Complications of Metastatic Bone Disease Most patients with metastatic bone disease have severe bone pain and debility, and are eventually confined to bed, as well as suffering other problems.2,4 Bone pain is frequently the first sign of metastatic disease and approximately 80% of all breast cancer patients will have one episode of bone pain that requires treatment.2 A major cause of prolonged disability is pathologic fracture (eg, rib fracture and vertebral collapse), which is the second most common complication of bone metastases, occurring in 10% to 20% of patients. Approximately 10% to 15% of patients develop hypercalcemia of malignancy, where elevated serum calcium levels from bone destruction can lead to gastrointestinal, renal, and central nervous system dysfunction. Spinal cord compression occurs in up to 5% of patients with metastatic bone disease. The burden of metastatic bone disease is enormous. Impaired mobility, poor functional capacity, and dependence on family and care givers have a detrimental impact on patients’ quality of life. Based on the placebo arm of clinical trials, patients with breast cancer experience three to four skeletal events per year,5,6 and patients who experience a skeletal event are more likely to develop subsequent skeletal 59
P. Conte and R. Coleman
60 Table 1 The Incidence of Metastatic Bone Disease1 Primary Tumor Type
Incidence (%)
Myeloma Breast Prostate Thyroid Bladder Lung Renal Melanoma
70-95 65-75 65-75 60 40 30-40 20-25 14-45
complications.7 Unsurprisingly, the economic consequences of metastatic bone disease are substantial. In a retrospective analysis of breast cancer patients with bone metastases, the cost of treating skeletal complications was approximately $52,000 greater in patients with skeletal-related events than in patients without these events.8 Therefore, any treatment must meet the primary goals of preventing or delaying complications of bone metastases to restore normal levels of patient functioning, and helping to reduce the disease burden on health care providers.
Therapeutic Options Current therapeutic options for metastatic bone disease include radiotherapy, surgery, analgesics, and bisphosphonates (Table 2).9,10 Chemotherapy, radiotherapy, hormone therapy, and monoclonal antibodies treat the primary tumor and metastases. Radiotherapy can also treat painful metastatic lesions and prevent or treat fractures in at-risk patients. However, it cannot correct anatomic abnormalities such as fracture or retropulsion of bone into the spinal canal, so surgery is sometimes needed to treat, or indeed prevent, pathologic fractures. Analgesics (mainly opioids) are prescribed for bone pain, and antiresorptive therapy with bisphosphonates prevents skeletal events and helps treat bone pain.
Bisphosphonates in Metastatic Bone Disease Bisphosphonates are pyrophosphate analogues with the common structural element of a phosphorus-carbon-phosphorus bond, which is essential for binding to the bone surface where the drug exerts its therapeutic effect.2,11,12 Each bisphosphonate has a different side chain attached to the
central carbon atom, which influences its antiresorptive properties and ability to bind to bone (Fig 1). Side chains containing a primary nitrogen atom (eg, pamidronate) are more potent than the non-nitrogen bisphosphonates (eg, clodronate). Potency is further enhanced by modification of the primary amine to form a tertiary amine (eg, ibandronate), which is sometimes part of a ring structure (eg, zoledronic acid).12 The antiresorptive actions of bisphosphonates are mediated by several different mechanisms.13,14 The nitrogen-containing aminobisphosphonates (eg, pamidronate, zoledronic acid, ibandronate) inhibit farnesyl diphosphate synthase in the mevalonate pathway, thus blocking the prenylation of small signaling proteins required for cell function and survival (eg, Ras, Rho).15-18 A second group of bisphosphonates resembles pyrophosphate (eg, clodronate) and inhibits adenosine triphosphate-dependent intracellular enzymes.19 Ultimately, these actions lead to potent inhibition of osteoclastmediated bone resorption. The drugs concentrate in newly mineralizing bone in the cavity underneath the resorbing osteoclast. After release from the bone surface, the bisphosphonates are internalized by the osteoclast, and a cascade of biochemical processes leads to osteoclast apoptosis (Fig 2).20 This appears to be a fundamentally important mechanism for bisphosphonates, but preclinical and clinical studies show that they may also have direct antitumor activity.12
Treatment Choice in Bisphosphonate Therapy The most widely used bisphosphonate options for metastatic bone disease are clodronate, pamidronate, and zoledronic acid. Clodronate Clodronate, an older-generation oral bisphosphonate has been around for about 30 years. In a double-blind, placebocontrolled trial of 173 patients with breast cancer and bone metastases, clodronate 1,600 mg/day significantly reduced the incidence of all skeletal events, including vertebral fractures, and the total number of hypercalcemic episodes, with a nonsignificant trend for reducing bone pain.21 Additional benefits of clodronate include the ability to reduce the occurrence of skeletal metastases.22-25 Although oral clodronate is a more convenient and flexible alternative to intravenous (IV) formulations, especially for long-term therapy, recent trials have shown that the efficacy
Table 2 Treatment Strategies for Metastatic Bone Disease Strategy
Usage
Chemotherapy and hormone therapy, monoclonal antibodies Radiotherapy
Treat primary tumor and metastases Treat primary tumor, treat painful metastatic lesions and prevent/treat fractures in at-risk patients Prevent/treat pathologic fractures Bone-pain management Prevent skeletal events, help treat bone pain
Surgery Analgesics (opioids) Antiresorptive therapy (bisphosphonates)
Bisphosphonates in skeletal metastases
61
Figure 1 The structure of bisphosphonates.
of clodronate is somewhat lower than that of the IV bisphosphonates.26,27 In a comparative study, 56% of patients treated with IV pamidronate achieved a symptomatic response (defined using a combination of pain scores and analgesic consumption) compared with 22% of patients on clodronate.27 The poor gastrointestinal tolerability, large tablet size, and frequent dosing with clodronate may also limit acceptability for patients, jeopardizing therapeutic outcomes.19,25,26,28 Pamidronate Extensive clinical experience in breast cancer patients has been obtained with IV pamidronate, the first aminobisphosphonate approved for tumor osteolysis. Two large phase III trials involving 754 women with stage IV breast cancer and osteolytic bone metastases showed that adding pamidronate to standard therapy reduced the number of patients with any skeletal complication (53% v 68%; P ⬍ .001), including pathologic fractures, the need for radiotherapy and surgery,
spinal cord compression, and hypercalcemia.5,6,29,30 Median times to first skeletal complication (12.7 v 7.0 months; P ⬍ .001) and new pathologic fracture (25.2 v12.8 months; P ⬍ .001) were also significantly increased with pamidronate compared with placebo. Although pain and analgesia scores increased in both groups, there was significantly less deterioration in the pamidronate group (P ⬍ .001). As mentioned, IV pamidronate has shown better effectiveness than oral clodronate.25,31 In a randomized, 2-year study, IV pamidronate achieved better pain reduction than oral clodronate (30% v 15%).31 Nevertheless, pamidronate has not shown significant efficacy benefits in other solid tumors such as prostate cancer.32 It is also inconvenient to administer (a 2-hour monthly infusion), and causes renal toxicity on rare occasions and flu-like acute reactions in up to one third of patients after the first infusion.33 An oral formulation of pamidronate was investigated but there was no further research,
Figure 2 Mechanism of action of bisphosphonates. PCP, phosphorous-carbon-phosphorous bond.20
P. Conte and R. Coleman
62 possibly because of the frequent and sometimes severe gastrointestinal side effects reported.2 Zoledronic Acid Recent evidence has shown advantages for zoledronic acid over pamidronate in metastatic bone disease. In a phase III, 13-month trial, zoledronic acid 4 mg was at least as effective as pamidronate 90 mg in preventing or delaying the occurrence of skeletal complications in patients with breast cancer or multiple myeloma.34 A 12-month extension to the trial confirmed the long-term benefits of zoledronic acid.35 Using multiple-event analysis, Rosen et al showed that zoledronic acid reduced the risk of developing skeletal complications by 20% more than pamidronate. Clinical trials suggest that zoledronic acid is effective in a variety of additional tumor types. In a 15-month phase III trial of 643 men with prostate cancer, zoledronic acid significantly reduced the proportion of patients with a skeletal event (33%; P ⫽ .021), delayed the onset of the first skeletal event (median not reached v 321 days; P ⫽ .011) and had a significantly greater impact on pain at 3 and 9 months, compared with placebo.36 Zoledronic acid also reduced skeletal morbidity in patients with bone metastases secondary to lung cancer and other solid tumors.37,38 As well as apparent efficacy advantages over pamidronate, zoledronic acid is more convenient, with a rapid 15-minute infusion. However, there are occasional reports of nephrotoxicity. Increases (⬎0.5 mg/dL) in serum creatinine levels were reported in 8% to 9% of patients receiving zoledronic acid or pamidronate at some time during the course of the phase III comparative trial.34 However, there were no differences in serum creatinine between zoledronic acid- and pamidronate-treated patients. Renal function monitoring is recommended in patients receiving pamidronate or zoledronic acid, and use is restricted in patients with severe renal impairment. Caution is advised in patients with renal deterioration or when other nephrotoxic drugs are prescribed. Although administration is more convenient than for pamidronate, IV infusion of zoledronic acid still requires regular hospital visits lasting more than 1 hour.39 This makes significant demands on hospital resources and impacts on patients’ lifestyle.
Conclusion Although current bisphosphonates can effectively treat and prevent some skeletal events, their clinical usefulness is limited by tolerability and convenience issues. More recently, increased risk of osteonecrosis of the jaws has been observed in patients treated with certain bisphosphonates.40,41 However, further research is needed to establish the exact relationship between bisphosphonate use and development of osteonecrosis.41 A clinical need remains for a treatment with superior efficacy and tolerability, and easier administration and flexibility. The ideal bisphosphonate would give better prevention of skeletal events than current options, effective relief of metastatic bone pain, fewer side effects, an improved renal safety
profile (with no need for renal monitoring), and the flexibility of either IV or oral administration. Ibandronate is a new bisphosphonate recently approved in the European Union for the treatment of skeletal complications in patients with bone metastases and breast cancer. In separate, placebo-controlled, phase III trials, IV and oral formulations of ibandronate reduced the frequency of skeletal events and provided a sustained reduction in metastatic bone pain.42,43 Ibandronate was generally well tolerated; encouragingly, the renal safety profiles of ibandronate and placebo were similar.42,43 The availability of IV and oral dosing may provide patients with a spectrum of bisphosphonate care from initial IV treatment through to long-term at-home oral maintenance therapy. Therefore, ibandronate represents an alternative to existing bisphosphonates for improved patient management. Further studies are necessary to establish the comparative benefits of bisphosphonates in metastatic bone disease. In addition, the optimal duration of bisphosphonate therapy should be determined. Although the American Society of Clinical Oncology guidelines recommend that bisphosphonate therapy is continued until “evidence of substantial decline in a patient’s general performance status,”44 there are few data to support this recommendation.
References 1. Coleman RE: Metastatic bone disease: Clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165-176, 2001 2. Diel IJ, Solomayer E-F, Bastert G: Treatment of metastatic bone disease in breast cancer: Bisphosphonates. Clin Breast Cancer 1:43-51, 2000 3. Domchek SM, Younger J, Finkelstein DM, et al: Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 89:363-368, 2000 4. Fulfaro F, Casuccio A, Ticozzi C, et al: The role of bisphosphonates in the treatment of painful metastatic bone disease: A review of phase III trials. Pain 78:157-169, 1998 5. 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. J Clin Oncol 17:846-854, 1999 6. Lipton A, Theriault RL, Hortobagyi GN, et al: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials. Cancer 88:10821090, 2000 7. Lacerna L, Hohneker J: Zoledronic acid for the treatment of bone metastases in patients with breast cancer and other solid tumors. Semin Oncol 30:150-160, 2003 (suppl 16) 8. Delea T, McKiernan J, Liss M, et al: Impact of skeletal complications on total medical care costs in breast cancer patients with bone metastases. Bone 34:S86, 2004 (suppl 1) 9. Coleman RE: Management of bone metastases. Oncologist 5:463-470, 2000 10. Janjan N: Bone metastases: Approaches to management. Semin Oncol 28:28-34, 2001 (suppl 11) 11. Guise TA, Chirgwin JM: Role of bisphosphonates in prostate cancer bone metastases. Semin Oncol 30:717-723, 2003 12. Neville-Webbe HL, Holen I, Coleman RE: The anti-tumour activity of bisphosphonates. Cancer Treat Rev 28:305-319, 2002 13. Fleisch H: Bisphosphonates: Mechanism of action. Endocr Rev 19:80100, 1998 14. Francis M, Russell RG, Fleisch H: Diphosphonates inhibit formation of calcium phosphate crystals in-vitro and pathological calcification invivo. Science 165:1264-1266, 1969 15. Russell RG, Rogers MJ, Frith JC, et al: The pharmacology of bisphos-
Bisphosphonates in skeletal metastases
16.
17.
18. 19.
20. 21.
22.
23.
24.
25.
26. 27.
28.
29.
30.
phonates and new insights into their mechanisms of action. J Bone Miner Res 14:53-65, 1999 (suppl 2) Luckman SP, Hughes DE, Coxon FP, et al: Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent posttranslational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13:581-589, 1998 Coxon FP, Helfrich MH, Van’t Hof R, et al: Protein geranylgeranylation is required for osteoclast formation, function and survival: Inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 15:1467-1476, 2000 Rogers MJ, Frith JC, Luckman SP, et al: Molecular mechanisms of action of bisphosphonates. Bone 24:73s-79s, 1999 (suppl 5) Ross JR, Saunders Y, Edmonds PM, et al: Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 327: 469, 2003 Russell RG, Rogers MJ: Bisphosphonates: From the laboratory to the clinic and back again. Bone 25:97-106, 1999 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 11:59-65, 1993 Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357-363, 1998 Diel IJ, Solomayer EF, Gollan C: Bisphosphonates in the reduction of metastases in breast cancer–Extended follow-up results [abstract 314]. Proc Am Soc Clin Oncol 19:82a, 2000 Saarto T, Blomqvist C, Virkkunen P, et al: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in nodepositive breast cancer patients: 5-Year results of a randomized controlled trial. J Clin Oncol 19:10-17, 2001 Powles T, Paterson S, Kanis JA, et al: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219-3224, 2002 Pavlakis N, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 1:CD003474, 2002 Jagdev SP, Purohit P, Heatley S, et al: Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 12: 1433-1438, 2001 Atula S, Powles T, Paterson A, et al: Extended safety profile of oral clodronate after long-term use in primary breast cancer patients. Drug Saf 26:661-671, 2003 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 335:1785-1791, 1996 Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16:20382044, 1998
63 31. Diel IJ, Marschner N, Kindler M, et al: Continual oral versus intravenous interval therapy with bisphosphonates in patients with breast cancer and bone metastases [abstract 488]. Proc Am Soc Clin Oncol 18:128a, 1999 32. 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 21:4277-4284, 2003 33. Body JJ: Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 28:49-53, 2001 (suppl 11) 34. 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, doubleblind, comparative trial. Cancer 7:377-387, 2001 35. Rosen LS, Gordon D, Kaminski M, et al: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 98:1735-1744, 2003 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 94:1458-1468, 2002 37. 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–the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150-3157, 2003 38. Lipton A, ZhEngl 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 98:962-969, 2003 39. DesHarnais Castel L, Bajwa K, Markle JP, et al: A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease. Support Care Cancer 9:545-551, 2001 40. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115-1157, 2003 41. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527-534, 2004 42. 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 14:1399-1405, 2003 43. 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 90:1133-1137, 2004 44. Hillner BE, Ingle JN, Chlebowski RT: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003
M
etastatic bone disease is a common and distressing complication of various cancers, particularly breast cancer, multiple myeloma, and prostate cancer (Table 1).1 The onset of metastatic bone disease is devastating for patients because it indicates that their cancer is incurable with significant morbidity. Approximately 65% to 75% of patients with metastatic breast cancer develop skeletal metastases, surviving for about 2.5 years.2,3 Bone metastases arise when primary tumor cells metastasize to active hematopoietic bone marrow tissue in skeletal areas with high proportions of trabecular bone, such as the skull, spine, pelvis, femur, and humerus, causing bone lesions. In healthy individuals, normal bone remodeling is maintained by balanced interactions between osteoclasts, which mediate bone resorption, and osteoblasts, which promote new bone formation. Skeletal metastases interfere with normal bone homeostasis by expressing growth factors and cytokines that accelerate osteoclast activity, resulting in bone resorption and the release of factors that interact with the tumor cells, further stimulating osteoclasts. Consequently, bone metabolism is extensively mod-
aDepartment
of Oncology and Haematology, The University of Modena and Reggio Emilia, Modena, Italy. bYorkshire Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, UK. Address reprint requests to PierFranco Conte, MD, Department of Oncology & Hematology University Hospital, Via del Pozzo 71, 41100 Modena, Italy.
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.07.024
ified, compromising skeletal integrity and leading to clinical sequelae.
Complications of Metastatic Bone Disease Most patients with metastatic bone disease have severe bone pain and debility, and are eventually confined to bed, as well as suffering other problems.2,4 Bone pain is frequently the first sign of metastatic disease and approximately 80% of all breast cancer patients will have one episode of bone pain that requires treatment.2 A major cause of prolonged disability is pathologic fracture (eg, rib fracture and vertebral collapse), which is the second most common complication of bone metastases, occurring in 10% to 20% of patients. Approximately 10% to 15% of patients develop hypercalcemia of malignancy, where elevated serum calcium levels from bone destruction can lead to gastrointestinal, renal, and central nervous system dysfunction. Spinal cord compression occurs in up to 5% of patients with metastatic bone disease. The burden of metastatic bone disease is enormous. Impaired mobility, poor functional capacity, and dependence on family and care givers have a detrimental impact on patients’ quality of life. Based on the placebo arm of clinical trials, patients with breast cancer experience three to four skeletal events per year,5,6 and patients who experience a skeletal event are more likely to develop subsequent skeletal 59
P. Conte and R. Coleman
60 Table 1 The Incidence of Metastatic Bone Disease1 Primary Tumor Type
Incidence (%)
Myeloma Breast Prostate Thyroid Bladder Lung Renal Melanoma
70-95 65-75 65-75 60 40 30-40 20-25 14-45
complications.7 Unsurprisingly, the economic consequences of metastatic bone disease are substantial. In a retrospective analysis of breast cancer patients with bone metastases, the cost of treating skeletal complications was approximately $52,000 greater in patients with skeletal-related events than in patients without these events.8 Therefore, any treatment must meet the primary goals of preventing or delaying complications of bone metastases to restore normal levels of patient functioning, and helping to reduce the disease burden on health care providers.
Therapeutic Options Current therapeutic options for metastatic bone disease include radiotherapy, surgery, analgesics, and bisphosphonates (Table 2).9,10 Chemotherapy, radiotherapy, hormone therapy, and monoclonal antibodies treat the primary tumor and metastases. Radiotherapy can also treat painful metastatic lesions and prevent or treat fractures in at-risk patients. However, it cannot correct anatomic abnormalities such as fracture or retropulsion of bone into the spinal canal, so surgery is sometimes needed to treat, or indeed prevent, pathologic fractures. Analgesics (mainly opioids) are prescribed for bone pain, and antiresorptive therapy with bisphosphonates prevents skeletal events and helps treat bone pain.
Bisphosphonates in Metastatic Bone Disease Bisphosphonates are pyrophosphate analogues with the common structural element of a phosphorus-carbon-phosphorus bond, which is essential for binding to the bone surface where the drug exerts its therapeutic effect.2,11,12 Each bisphosphonate has a different side chain attached to the
central carbon atom, which influences its antiresorptive properties and ability to bind to bone (Fig 1). Side chains containing a primary nitrogen atom (eg, pamidronate) are more potent than the non-nitrogen bisphosphonates (eg, clodronate). Potency is further enhanced by modification of the primary amine to form a tertiary amine (eg, ibandronate), which is sometimes part of a ring structure (eg, zoledronic acid).12 The antiresorptive actions of bisphosphonates are mediated by several different mechanisms.13,14 The nitrogen-containing aminobisphosphonates (eg, pamidronate, zoledronic acid, ibandronate) inhibit farnesyl diphosphate synthase in the mevalonate pathway, thus blocking the prenylation of small signaling proteins required for cell function and survival (eg, Ras, Rho).15-18 A second group of bisphosphonates resembles pyrophosphate (eg, clodronate) and inhibits adenosine triphosphate-dependent intracellular enzymes.19 Ultimately, these actions lead to potent inhibition of osteoclastmediated bone resorption. The drugs concentrate in newly mineralizing bone in the cavity underneath the resorbing osteoclast. After release from the bone surface, the bisphosphonates are internalized by the osteoclast, and a cascade of biochemical processes leads to osteoclast apoptosis (Fig 2).20 This appears to be a fundamentally important mechanism for bisphosphonates, but preclinical and clinical studies show that they may also have direct antitumor activity.12
Treatment Choice in Bisphosphonate Therapy The most widely used bisphosphonate options for metastatic bone disease are clodronate, pamidronate, and zoledronic acid. Clodronate Clodronate, an older-generation oral bisphosphonate has been around for about 30 years. In a double-blind, placebocontrolled trial of 173 patients with breast cancer and bone metastases, clodronate 1,600 mg/day significantly reduced the incidence of all skeletal events, including vertebral fractures, and the total number of hypercalcemic episodes, with a nonsignificant trend for reducing bone pain.21 Additional benefits of clodronate include the ability to reduce the occurrence of skeletal metastases.22-25 Although oral clodronate is a more convenient and flexible alternative to intravenous (IV) formulations, especially for long-term therapy, recent trials have shown that the efficacy
Table 2 Treatment Strategies for Metastatic Bone Disease Strategy
Usage
Chemotherapy and hormone therapy, monoclonal antibodies Radiotherapy
Treat primary tumor and metastases Treat primary tumor, treat painful metastatic lesions and prevent/treat fractures in at-risk patients Prevent/treat pathologic fractures Bone-pain management Prevent skeletal events, help treat bone pain
Surgery Analgesics (opioids) Antiresorptive therapy (bisphosphonates)
Bisphosphonates in skeletal metastases
61
Figure 1 The structure of bisphosphonates.
of clodronate is somewhat lower than that of the IV bisphosphonates.26,27 In a comparative study, 56% of patients treated with IV pamidronate achieved a symptomatic response (defined using a combination of pain scores and analgesic consumption) compared with 22% of patients on clodronate.27 The poor gastrointestinal tolerability, large tablet size, and frequent dosing with clodronate may also limit acceptability for patients, jeopardizing therapeutic outcomes.19,25,26,28 Pamidronate Extensive clinical experience in breast cancer patients has been obtained with IV pamidronate, the first aminobisphosphonate approved for tumor osteolysis. Two large phase III trials involving 754 women with stage IV breast cancer and osteolytic bone metastases showed that adding pamidronate to standard therapy reduced the number of patients with any skeletal complication (53% v 68%; P ⬍ .001), including pathologic fractures, the need for radiotherapy and surgery,
spinal cord compression, and hypercalcemia.5,6,29,30 Median times to first skeletal complication (12.7 v 7.0 months; P ⬍ .001) and new pathologic fracture (25.2 v12.8 months; P ⬍ .001) were also significantly increased with pamidronate compared with placebo. Although pain and analgesia scores increased in both groups, there was significantly less deterioration in the pamidronate group (P ⬍ .001). As mentioned, IV pamidronate has shown better effectiveness than oral clodronate.25,31 In a randomized, 2-year study, IV pamidronate achieved better pain reduction than oral clodronate (30% v 15%).31 Nevertheless, pamidronate has not shown significant efficacy benefits in other solid tumors such as prostate cancer.32 It is also inconvenient to administer (a 2-hour monthly infusion), and causes renal toxicity on rare occasions and flu-like acute reactions in up to one third of patients after the first infusion.33 An oral formulation of pamidronate was investigated but there was no further research,
Figure 2 Mechanism of action of bisphosphonates. PCP, phosphorous-carbon-phosphorous bond.20
P. Conte and R. Coleman
62 possibly because of the frequent and sometimes severe gastrointestinal side effects reported.2 Zoledronic Acid Recent evidence has shown advantages for zoledronic acid over pamidronate in metastatic bone disease. In a phase III, 13-month trial, zoledronic acid 4 mg was at least as effective as pamidronate 90 mg in preventing or delaying the occurrence of skeletal complications in patients with breast cancer or multiple myeloma.34 A 12-month extension to the trial confirmed the long-term benefits of zoledronic acid.35 Using multiple-event analysis, Rosen et al showed that zoledronic acid reduced the risk of developing skeletal complications by 20% more than pamidronate. Clinical trials suggest that zoledronic acid is effective in a variety of additional tumor types. In a 15-month phase III trial of 643 men with prostate cancer, zoledronic acid significantly reduced the proportion of patients with a skeletal event (33%; P ⫽ .021), delayed the onset of the first skeletal event (median not reached v 321 days; P ⫽ .011) and had a significantly greater impact on pain at 3 and 9 months, compared with placebo.36 Zoledronic acid also reduced skeletal morbidity in patients with bone metastases secondary to lung cancer and other solid tumors.37,38 As well as apparent efficacy advantages over pamidronate, zoledronic acid is more convenient, with a rapid 15-minute infusion. However, there are occasional reports of nephrotoxicity. Increases (⬎0.5 mg/dL) in serum creatinine levels were reported in 8% to 9% of patients receiving zoledronic acid or pamidronate at some time during the course of the phase III comparative trial.34 However, there were no differences in serum creatinine between zoledronic acid- and pamidronate-treated patients. Renal function monitoring is recommended in patients receiving pamidronate or zoledronic acid, and use is restricted in patients with severe renal impairment. Caution is advised in patients with renal deterioration or when other nephrotoxic drugs are prescribed. Although administration is more convenient than for pamidronate, IV infusion of zoledronic acid still requires regular hospital visits lasting more than 1 hour.39 This makes significant demands on hospital resources and impacts on patients’ lifestyle.
Conclusion Although current bisphosphonates can effectively treat and prevent some skeletal events, their clinical usefulness is limited by tolerability and convenience issues. More recently, increased risk of osteonecrosis of the jaws has been observed in patients treated with certain bisphosphonates.40,41 However, further research is needed to establish the exact relationship between bisphosphonate use and development of osteonecrosis.41 A clinical need remains for a treatment with superior efficacy and tolerability, and easier administration and flexibility. The ideal bisphosphonate would give better prevention of skeletal events than current options, effective relief of metastatic bone pain, fewer side effects, an improved renal safety
profile (with no need for renal monitoring), and the flexibility of either IV or oral administration. Ibandronate is a new bisphosphonate recently approved in the European Union for the treatment of skeletal complications in patients with bone metastases and breast cancer. In separate, placebo-controlled, phase III trials, IV and oral formulations of ibandronate reduced the frequency of skeletal events and provided a sustained reduction in metastatic bone pain.42,43 Ibandronate was generally well tolerated; encouragingly, the renal safety profiles of ibandronate and placebo were similar.42,43 The availability of IV and oral dosing may provide patients with a spectrum of bisphosphonate care from initial IV treatment through to long-term at-home oral maintenance therapy. Therefore, ibandronate represents an alternative to existing bisphosphonates for improved patient management. Further studies are necessary to establish the comparative benefits of bisphosphonates in metastatic bone disease. In addition, the optimal duration of bisphosphonate therapy should be determined. Although the American Society of Clinical Oncology guidelines recommend that bisphosphonate therapy is continued until “evidence of substantial decline in a patient’s general performance status,”44 there are few data to support this recommendation.
References 1. Coleman RE: Metastatic bone disease: Clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165-176, 2001 2. Diel IJ, Solomayer E-F, Bastert G: Treatment of metastatic bone disease in breast cancer: Bisphosphonates. Clin Breast Cancer 1:43-51, 2000 3. Domchek SM, Younger J, Finkelstein DM, et al: Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 89:363-368, 2000 4. Fulfaro F, Casuccio A, Ticozzi C, et al: The role of bisphosphonates in the treatment of painful metastatic bone disease: A review of phase III trials. Pain 78:157-169, 1998 5. 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. J Clin Oncol 17:846-854, 1999 6. Lipton A, Theriault RL, Hortobagyi GN, et al: Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials. Cancer 88:10821090, 2000 7. Lacerna L, Hohneker J: Zoledronic acid for the treatment of bone metastases in patients with breast cancer and other solid tumors. Semin Oncol 30:150-160, 2003 (suppl 16) 8. Delea T, McKiernan J, Liss M, et al: Impact of skeletal complications on total medical care costs in breast cancer patients with bone metastases. Bone 34:S86, 2004 (suppl 1) 9. Coleman RE: Management of bone metastases. Oncologist 5:463-470, 2000 10. Janjan N: Bone metastases: Approaches to management. Semin Oncol 28:28-34, 2001 (suppl 11) 11. Guise TA, Chirgwin JM: Role of bisphosphonates in prostate cancer bone metastases. Semin Oncol 30:717-723, 2003 12. Neville-Webbe HL, Holen I, Coleman RE: The anti-tumour activity of bisphosphonates. Cancer Treat Rev 28:305-319, 2002 13. Fleisch H: Bisphosphonates: Mechanism of action. Endocr Rev 19:80100, 1998 14. Francis M, Russell RG, Fleisch H: Diphosphonates inhibit formation of calcium phosphate crystals in-vitro and pathological calcification invivo. Science 165:1264-1266, 1969 15. Russell RG, Rogers MJ, Frith JC, et al: The pharmacology of bisphos-
Bisphosphonates in skeletal metastases
16.
17.
18. 19.
20. 21.
22.
23.
24.
25.
26. 27.
28.
29.
30.
phonates and new insights into their mechanisms of action. J Bone Miner Res 14:53-65, 1999 (suppl 2) Luckman SP, Hughes DE, Coxon FP, et al: Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent posttranslational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13:581-589, 1998 Coxon FP, Helfrich MH, Van’t Hof R, et al: Protein geranylgeranylation is required for osteoclast formation, function and survival: Inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 15:1467-1476, 2000 Rogers MJ, Frith JC, Luckman SP, et al: Molecular mechanisms of action of bisphosphonates. Bone 24:73s-79s, 1999 (suppl 5) Ross JR, Saunders Y, Edmonds PM, et al: Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 327: 469, 2003 Russell RG, Rogers MJ: Bisphosphonates: From the laboratory to the clinic and back again. Bone 25:97-106, 1999 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 11:59-65, 1993 Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357-363, 1998 Diel IJ, Solomayer EF, Gollan C: Bisphosphonates in the reduction of metastases in breast cancer–Extended follow-up results [abstract 314]. Proc Am Soc Clin Oncol 19:82a, 2000 Saarto T, Blomqvist C, Virkkunen P, et al: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in nodepositive breast cancer patients: 5-Year results of a randomized controlled trial. J Clin Oncol 19:10-17, 2001 Powles T, Paterson S, Kanis JA, et al: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20:3219-3224, 2002 Pavlakis N, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 1:CD003474, 2002 Jagdev SP, Purohit P, Heatley S, et al: Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 12: 1433-1438, 2001 Atula S, Powles T, Paterson A, et al: Extended safety profile of oral clodronate after long-term use in primary breast cancer patients. Drug Saf 26:661-671, 2003 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 335:1785-1791, 1996 Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16:20382044, 1998
63 31. Diel IJ, Marschner N, Kindler M, et al: Continual oral versus intravenous interval therapy with bisphosphonates in patients with breast cancer and bone metastases [abstract 488]. Proc Am Soc Clin Oncol 18:128a, 1999 32. 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 21:4277-4284, 2003 33. Body JJ: Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 28:49-53, 2001 (suppl 11) 34. 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, doubleblind, comparative trial. Cancer 7:377-387, 2001 35. Rosen LS, Gordon D, Kaminski M, et al: Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 98:1735-1744, 2003 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 94:1458-1468, 2002 37. 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–the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150-3157, 2003 38. Lipton A, ZhEngl 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 98:962-969, 2003 39. DesHarnais Castel L, Bajwa K, Markle JP, et al: A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease. Support Care Cancer 9:545-551, 2001 40. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 61:1115-1157, 2003 41. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg 62:527-534, 2004 42. 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 14:1399-1405, 2003 43. 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 90:1133-1137, 2004 44. Hillner BE, Ingle JN, Chlebowski RT: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003