Advanced malignancies involving bone
Transkript
Advanced malignancies involving bone
Contents Foreword 2 Chapter 1. Skeletal-related events: clinical context 3 Hypercalcemia of malignancy 3 Multiple myeloma 8 Advanced malignancies involving bone 8 Metabolic bone disorders 10 Chapter 2. Skeletal-related events: management options 15 Hypercalcaemia of malignancy 15 Multiple myeloma 16 Advanced malignancies involving bone 18 Metabolic bone disorders 19 Chapter 3. Zoledronic acid: clinical evidence for efficacy and safety 23 Hypercalcemia of malignancy 23 Multiple myeloma 25 Advanced malignancies involving bone 26 breast cancer 27 lung cancer 31 renal cancer 33 prostate cancer 34 Metabolic bone disorders 37 Paget’s disease of bone 37 osteoporosis 38 rheumatoid arthritis 39 40 Chapter 4. Zoledronic acid: management issues 43 Pharmacological profile 43 Infusion protocol Additional potential applications of zoledronic acid 44 44 44 Conclusions 47 Duration of bisphosphonate therapy Managing bisphosphonate-related adverse events Foreword Zoledronic acid is a highly potent and well-tolerated intravenous bisphosphonate widely used for the management of hypercalcemia of malignancy, multiple myeloma, and advanced malignancies involving bone, including breast, prostate, lung, and other solid tumor metastases. Zoledronic is also licensed in numerous countries for the management Paget’s disease of bone and clinical trial data support the efficacy of this bisphosphonate in further metabolic bone diseases including postmenopausal osteoporosis and rheumatoid arthritis. In all patient groups, the benefits of zoledronic acid include reversal of bone loss, reduction in fracture rates, alleviation of pain, and improvements in quality of life. In pivotal trials, zoledronic acid demonstrates superiority over placebo and intravenous pamidronate in terms of efficacy, tolerability, and patient acceptability. This book appraises the clinical benefits of zoledronic acid across its wide range of clinical applications, based on the extensive published evidence base. Professor PierFranco Conte Department of Oncology and Hematology University of Modena and Reggio Emilia Modena, Italy Chapter 1. Skeletal-related events: clinical context Zoledronic acid has clinical applications in a range of conditions including hypercalcemia of malignancy, multiple myeloma, bone metastases, and metabolic disorders, which have in common underlying pathological processes. The clinical background to these skeletal-related events is the focus of this chapter. Hypercalcemia of malignancy Hypercalcemia of malignancy and primary hyperparathyroidism together account for more than 90% of all cases of hypercalcemia. For this reason, other possible causes of elevated serum calcium are usually not considered as potential diagnoses until malignancy and parathyroid disease are excluded (Table 1). Hypercalcemia of malignancy is a serious and unpleasant skeletal complication that can occur both in the presence and absence of metastases, and affects 10-20% of all cancer patients at some time during their disease, including 20-40% of patients with advanced disease (Mundy et al 1984; Vassilopoulou-Sellin et al 1993; Watters et al 1996). Patients with hypercalcemia of malignancy generally have a poor prognosis with a life expectancy of weeks to months. During that period, management is a challenge because of the unpleasant gastrointestinal and neurological symptoms. Pathophysiology Hypercalcemia of malignancy can be divided into two types with different pathogeneses: osteolytic and humoral. Osteolytic hypercalcemia results from direct destruction of bone by primary or metastatic tumor cells that release osteoclastic activating factors. These factors act locally to increase the activity of osteoclasts (bone-resorbing cells) without corresponding increases in the activity of osteoblasts (bone-forming cells). Humoral hypercalcemia is mediated by circulating factors including parathyroid hormone (PTH)-related protein (PTHrP) (Warrell 1997). PTHrP is similar in structure to PTH and acts to increase bone resorption while decreasing calcium excretion at the renal tubules (Broadus et al 1988; Horiuchi et al 1987; Suva et al 1987). Approximately 25% of patients with hypercalcemia of malignancy have elevated PTHrP levels. There are additional circulating growth factors involved in humoral hypercalcemia besides PTHrP, including transforming growth factor-alpha and -beta, interleukin-1 and -6, tumor necrosis factor -alpha and -beta, prostaglandins, cathepsins, and osteoprotegerin ligand (Figure 1). Further mediators that await identification may also be involved in the complex interactions that stimulate osteoclast activity. Table 1. Causes of hypercalcemia Malignancy Parathyroid disease Primary hyperparathyroidism Sporadic, familial, associated with multiple endocrine neoplasia I or II Tertiary hyperparathyroidism Associated with chronic renal failure or vitamin D deficiency Other endocrine disorders Hyperthyroidism Adrenal insufficiency Acromegaly Pheochromocytoma A intoxication (including analogs used to treat acne) Vitamin D-related Vitamin D intoxication Usually 25-hydroxyvitamin D2 in over-the-counter supplements Granulomatous disease sarcoidosis, berylliosis, tuberculosis Hodgkin’s lymphoma Medications Thiazide diuretics (usually mild) Lithium Milk-alkali syndrome (from calcium antacids) Vitamins Genetic disorders Familial hypocalciuric hypercalcemia: mutated calcium-sensing receptor Other Immobilization, with high bone turnover (e.g., Paget’s disease, bedridden child) Recovery phase of rhabdomyolysis Figure 1. Diagram of the molecular interactions between osteoclasts and tumor cells. TGF = transforming growth factor; TNF = tumor necrosis factor; EGF = epidermal growth factor; PGs = prostaglandins; OIF = osteoclast inhibitory factor; OAF = osteoclast activating factor Incidence The incidence of hypercalcemia of malignancy varies with the tumor type. It is most common in patients with multiple myeloma, where 30% to more than 80% of patients are affected (Watters et al 1996). Some 25-65% of patients with metastatic breast cancer also develop hypercalcemia of malignancy during their disease. By contrast, hypercalcemia of malignancy is rare in patients with prostate cancer. Some typical incidences are shown in Table 2. Table 2. Incidence of Hypercalcemia by Tumor Type Tumor Type Percentage of Patients Who Develop Hypercalcemia Lung 27.3 Breast 25.7 Head and neck 6.9 Unknown primary 4.7 Lymphoma/leukemia 4.3 Renal 4.3 Gastrointestinal 4.1 *Adapted from Lang-Kummer J: Hypercalcemia. In: Groenwald SL, Goodman M, Frogge MH, et al., eds.: Cancer Nursing: Principles and Practice. 4th ed. Sudbury, Mass: Jones and Bartlett Publishers, 1997, pp 684-701. There is little correlation between the occurrence of hypercalcemia of malignancy and the extent of metastatic bone disease (Grill et al 2000). Symptoms The symptoms of hypercalcemia of malignancy typically reflect the underlying cancer type as well as the duration of time over which the cancer develops, the history of cancer treatments, and the overall physical health of the patient including the presence of coexisting comorbidities. Symptoms do not correlate closely with serum calcium concentrations. Some patients develop symptoms when calcium is only slightly elevated, while others tolerate high calcium levels (> 13 mg/dL, 6.5 mEq/L or 3.24 mmol/L). The symptoms of hypercalcemia of malignancy are wide-ranging and can be difficult to diagnose without suspicion (Table 3) (Bajorunas 1990; Mahon 1989). Early recognition of symptoms is, however, vital since, if untreated, hypercalcemia of malignancy can progress rapidly to become life-threatening. Common symptoms include nausea, vomiting, alterations in mental state, constipation, malaise, lethargy, muscle weakness, polyuria, and headache that may progress to loss of consciousness and coma. Malaise and fatigue are reportedly the most common complaints at presentation (Ralston et al 1990). These symptoms can themselves contribute to a worsening in the patient’s condition. For example, nausea and vomiting can cause dehydration and increased calcium levels, while immobilization caused by weakness and lethargy may exacerbate calcium resorption from bone. Few patients experience all the symptoms that are associated with hypercalcemia, and some patients may experience none. In the absence of symptoms of hyercalcemia of malignancy, the symptoms or signs of the underlying malignancy may lead the patient to seek medical attention. Table 3. Symptoms of hypercalcemia of malignancy Renal Nephrolithiasis Nephrogenic diabetes insipidus Dehydration Polyurea Nephrocalcinosis Skeletal Bone pain Arthritis Osteoporosis Osteitis fibrosa cystica in hyperparathyroidism (subperiosteal resorption, bone cysts) Gastrointestinal Nausea, vomiting Anorexia, weight loss Constipation Abdominal pain Pancreatitis Peptic ulcer disease Neuromuscular Impaired concentration and memory Confusion, stupor, coma Lethargy and fatigue Muscle weakness Headache Corneal calcification (band keratopathy) Cardiovascular Hypertension Shortened QT interval on electrocardiogram Cardiac arrhythmias Vascular calcification Other Itching Keratitis, conjunctivitis Multiple myeloma Multiple myeloma is a progressive and incurable plasma cell cancer. Recent advances in therapy have, however, significantly helped lessen the severity of its effects. Pathophysiology Multiple myeloma is characterized by the proliferation of malignant plasma cells and the production of aberrant monoclonal immunoglobulins (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal K and A light chains). Plasma cell proliferation interferes with blood cell production in the marrow to cause leukopenia, anemia, and thrombocytopenia. The plasma cells may also produce soft tissue masses (plasmacytomas) and lytic lesions in the skeleton, causing weakness and bone pain. Immunoglobulin overproduction causes hyperviscosity, amyloidosis, and renal failure. The aberrant immunoglobulins may additionally impair humoral immunity, predisposing patients to infection. Multiple myeloma can also affect the kidneys in several ways, by direct tubular injury, amyloidosis, or involvement of a plasmacytoma, and the presence of renal impairment is associated with a particularly poor prognosis. Incidence An estimated 5-6 new cases of multiple myeloma occur per 100 000 persons per year. Patients with multiple myeloma experience an average of two skeletal events a year (Menssen et al 2002; Berenson et al 1998). Symptoms Multiple myeloma can be asymptomatic or it may display an array of symptoms including hypercalcemia, anemia, renal damage, and increased susceptibility to infection. Presenting symptoms typically involve bone pain, pathologic fractures due to osteoporosis, and weakness related to anemia. Bone pain is present in approximately 70% of patients at presentation and most usually involves the lumbar vertebrae. Spinal cord compression develops in 20% of patients and is one of the most severe adverse effects of myeloma, leading to back pain, weakness or paralysis in the legs, numbness, or dysesthesia in the lower extremities. Once established, these effects are rarely fully reversed. Advanced malignancies involving bone Metastases from solid cancers are the most common tumors that involve the skeleton. The clinical course of metastatic bone disease is typically long and patients may experience bone pain, fractures, hypercalcemia, and spinal cord compression over several years. These complications profoundly impair the patient’s quality of life and their severity can contribute eventually to the patient’s death, independent of the underlying malignancy. Pathophysiology Metastases involve bone through three main mechanisms: seeding via the circulation, direct extension, and retrograde venous flow. Once sited within the bone marrow cavity, tumor cells can secrete a variety of paracrine factors that stimulate bone cell activity (Figure 2). Figure 2. Interaction of tumor and bone cells within the bone microenvironment. Stimulation of osteoclast activity without accompanying increases in osteoblast function is of particular importance in many tumor types, including breast cancers; the result is osteolysis. Other tumor types stimulate osteoblast activity to deposit weakened bone (sclerosis). In yet other tumors, both osteolysis and sclerosis can be present simultaneously (mixed pattern). These changes in bone cell function characteristically alter levels of serum and urinary markers of bone metabolism that can be used to monitor disease progression and response to therapy. In addition to weakening the bone, patients with bone metastases frequently have reduced mobility, pain, and bone weakness. Together, these effects predispose patients to fractures, spinal cord compression, and bone marrow failure. Survival after the development of bone metastases ranges from 6–48 months, depending on the tumor type (Coleman 1997). Incidence The frequency of skeletal involvement varies with the tumor type. The tumors that most commonly involve bone are prostate, lung, bladder, stomach, rectum, and colon tumors in men and breast, uterus, colon, stomach, rectum, and bladder tumors in women. Approximately 80% of men with advanced prostate cancer, 70% of women with advanced breast cancer, and 30-65% of patients with metastatic lung cancer develop bone metastases (Coleman 1997; Coleman 1997; Bloomfield 1998; Carlin & Andriole 2000; Pentyala et al 2000). Skeletal events are experienced by approximately one half of patients with solid tumors that metastasize to bone (Theriault et al 1999; Lipton et al 1999). Women with breast carcinoma and bone metastases experience an average of four skeletal events, including two pathologic fractures, each year in the absence of effective therapy (Lipton et al 1999). Men with prostate cancer have a mean annual incidence of 1.5 events per year (Saad et al 2002), and this risk increases with the bone loss associated with orchiectomy or hormonal therapy (Townsend et al 1997; Collinson et al; 1994; Daniell 1997; Clarke et al 1993). Symptoms Skeletal symptoms include bone pain, fractures, neurologic impairment due to spinal cord compression, and signs of hypercalcemia. The development of bone pain in a patient known to have a primary tumor is highly suggestive of bone metastases. In general, bone pain intensity does not correlate directly with an increased fracture risk, but pain exacerbated by movement does appear to predict impending fracture. The probability of a fracture also increases with the duration of metastatic involvement. Fractures are therefore more common in patients with predominantly bone-only disease who otherwise have a relatively good prognosis. Common sites for metastases are the vertebrae, pelvis, proximal femur, ribs, proximal humerus, and skull. More than 90% of metastases fall within this distribution. Certain carcinomas may have a predilection for particular skeletal sites. For example, primary tumors arising in the pelvis tend to spread to the lumbosacral spine, while one-half of metastases in the hand originate from lung cancers. Bone metastases are frequently present at multiple sites by the time of diagnosis. Skeletal complications contribute importantly to the deterioration in quality of life and loss of independence of cancer patients; therefore, checking bone for metastatic disease is critical if a lesion is suspected. Metabolic bone disorders Paget’s disease of bone Paget’s disease of bone is a variably progressive disorder in which normal bone is replaced with disorganized bone that is prone to deformity and fracture. Pathophysiology Paget’s disease begins with the proliferation of abnormally large osteoclasts, which resorb bone up to 20 times the normal rate. This increased osteoclastic activity is followed by increased osteoblastic activity, which produces structurally disorganized bone (‘woven bone’) that is mechanically weaker and more susceptible to fracture. Lesions in Paget’s disease may be single or multiple and can involve any part of the skeleton, although they have a predilection for the spine, pelvis, femur, sacrum, and skull. In the final phase of Paget’s disease, cellular activity diminishes to leave sclerotic bone. Although the etiology of Paget’s disease remains unknown, both genetic and environmental (infectious) factors have been implicated, which may explain why some 40% of persons with Paget’s disease have a family history of the disease and why its geographical distribution worldwide is uneven. Up to 6-7% of the elderly population in Western Europe is affected by Paget’s disease (Cooper et al 1999). 10 Incidence The elderly are primarily affected. Within this age group, Paget’s disease is the second most common bone disorder after osteoporosis. Rates of Paget’s disease in the US are 2% of the population older than 60 years (Altman et al 2000). Symptoms Most patients with Paget’s disease (70-90%) are asymptomatic. The remainder may experience bone pain (the commonest symptom), osteoarthritis, bony deformity (commonly bowing of an extremity), fractures, excessive warmth from hypervascularity, and neurological complications, particularly hearing loss, from compression of neural tissues. Vertebral deformity can lead to spinal stenosis or cord compression. After onset, symptoms of the disease tend to worsen progressively. A diagnosis of Paget’s disease may be considered in an elderly person by the presence of bone pain, deformity, compression neuropathy, or other typical symptoms. In the absence of symptoms, Paget’s disease may be detected by an altered biochemical marker level, an x-ray abnormality, or hypercalcemia. Further evaluations can include x-rays and a technetium-labeled bone scan. Osteoporosis Osteoporosis is a systemic disease of the skelton characterized by low bone mass and deterioration in bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of disability, mortality, and economic burden worldwide, particularly in postmenopausal women and in the elderly of both genders. Approximately 50% of patients who have a hip fracture do not recover fully and experience a 20% increased risk of mortality in the next year (Cummings & Melton 2002). Pathophysiology After the third decade of life, the activities of osteoblastic and osteoclastic cells become uncoupled, with the result that bone resorption exceeds bone formation. The imbalance between resorption and formation is greatest in women following the climacteric. In the course of their lifetime, women lose 30-40% of their cortical bone and 50% of their trabecular bone, compared to losses of 15-20% and 25-30%, respectively, in men. Other risk factors for osteoporosis include a family history, Caucasian race, smoking, and use of certain medications (including chemotherapy). Incidence Osteoporosis is the commonest metabolic bone disease worldwide and women constitute 80% of all those affected. Osteoporosis is also the leading cause of fractures in the elderly, being associated with 80% of all fractures in people aged 50 years or older. 11 Symptoms There are no symptoms in the early stages of osteoporosis. Symptoms and signs occurring later may include fractures to the vertebrae, wrists, or hips (often the first indication of osteoporosis), low back or neck pain, and progressive loss of height with stooped posture. Rheumatoid arthritis Rheumatoid arthritis is a chronic inflammatory disease typically involving erosion and destruction of synovial membranes and articular structures of multiple joints simultaneously. The disease course can be short and limited or progressive, leading to severe joint deformities and disability. Pathophysiology The cause of rheumatoid arthritis remains unclear, but contributory factors include a genetic predisposition and infectious triggers. A complex autoimmune response involving CD4+ T cells and cytokines such as TNF-alpha and IL-1 is implicated, which produces inflammation, cell proliferation, and degeneration. Increased osteoblast activity is believed to be central to the development of bone damage, and is a rationale for investigation of bisphosphonate therapy in rheumatoid arthritis. Incidence The prevalence of rheumatoid arthritis is approximately 1% in the US, ranging from 0.5% to greater than 5% depending on ethnic variation. The disease can occur at any age but tends to peak in the fourth and fifth decades. The female-to-male ratio is approximately 3:1. Symptoms Rheumatoid arthritis has an insidious onset usually, although it can be abrupt. The diagnosis typically is made when four of seven qualifying criteria established by the American Rheumatism Association are met: • Morning stiffness lasting longer than 1 hour before improvement • Arthritis involving 3 or more joints • Arthritis of the hand, particularly involvement of the proximal interphalangeal, metacarpophalangeal, or wrist joints • Bilateral involvement of joint areas (ie, both wrists, symmetric PIP and MCP joints) • Positive serum rheumatoid factor (RF) • Rheumatoid nodules • Radiographic evidence of RA 12 References Altman RD, Bloch DA, Hochberg MC, Murphy WA. Prevalence of pelvic Paget’s disease of bone in the United States. J Bone Miner Res 2000;15:461-465. Bajorunas DR: Clinical manifestations of cancer-related hypercalcemia. Semin Oncol 1990;17 (2 Suppl 5):16-25. Berenson JR, Lichtenstein A, Porter L et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. 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The epidemiology of Paget’s disease in Britain: is the prevalence decreasing? J Bone Miner Res 1999;14:192-197. Cummings SR, Melton LJ III. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359:1761-1767. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997;157:439-444. Dodwell DJ. Malignant bone resorption: cellular and biochemical mechanisms. Ann Oncol 1992;3:257-267. Domchek SM, Younger J, Finkelstein DM et al. Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 2000;89:363-368. Grill V, Martin TJ. Hypercalcemia. In: Rubens RD, Mundy GR, eds. Cancer and the Skeleton. London: Martin Dunitz Ltd., 2000:7589. Horiuchi N, Caulfield MP, Fisher JE et al. Similarity of synthetic peptide from human tumor to parathyroid hormone in vivo and in vitro. Science 1987;238:1566-1568. Lipton A, Theriault RL, Hortobágyi 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 2000;88:1082-1090. Mahon SM: Signs and symptoms associated with malignancy-induced hypercalcemia. ������������������������������ Cancer Nurs 1989;12):153-160. Menssen HD, Sakalova A, Fontana A et al. ������������������������������������������������������������������������������������������� Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 2002;20:2353-2359. Mundy GR, Ibbotson KJ, D’Souza SM et al. The hypercalcemia of cancer: clinical implications and pathogenic mechanisms. N Engl J Med 1984;310:1718-1727. Ralston SH, Gallacher SJ, Patel U et al.: Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med 1990;112:499-504. Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458-1468. Suva LJ, Winslow GA, Wettenhall RE et al.: A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 1987;237:893-896. Theriault RL, Lipton A, Hortobágyi GN et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846-854. Townsend MF, Sanders WH, Northway RO, Graham SD Jr. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 1997;79:545-550. Vassilopoulou-Sellin R, Newman BM, Taylor SH et al. Incidence of hypercalcemia in patients with malignancy referred to a comprehensive cancer center. Cancer 1993;71:1309-1312. Warrell RP Jr: Metabolic emergencies. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds: Cancer: Principles and Practice of Oncology. 13 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997: 2486-93. Watters J, Gerrand G, Dodwell D. The management of malignant hypercalcaemia. Drugs 1996;52:837-848. Watters J, Gerrand G, Dodwell D. The management of malignant hypercalcaemia. Drugs 1996;52:837-848. Zekri J, Ahmed N, Coleman RE, Hancock BW The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 2001;19:379382. 14 Chapter 2. Skeletal-related events: management options To provide a context for the uses of bisphosphonates in current clinical practice, this chapter presents an overview of the management options in hypercalcemia of malignancy, malignant melanoma, metastases to bone, and metabolic bone diseases based on current clinical consensus derived from major reviews, guidelines, and formularies. Hypercalcaemia of malignancy Definitive treatment for hypercalcemia of malignancy is effective management of the underlying malignant disease, which will reduce the production of humoral factors, particularly PTHrP, that stimulate bone resorption and renal tubular calcium reabsorption. Effective new anticancer therapies have reduced the incidence of hypercalcemia of malignancy, and patients now typically develop hypercalcemia only in the later stages of advanced metastatic disease. The magnitude of hypercalcemia and the severity of symptoms is the basis for deciding whether to initiate hypocalcemic treatment. Immediate and aggressive treatment is required for patients with a corrected total serum calcium level >14 mg/dL (>7 mEq/L, 3.5 mmol/L). For patients with a serum calcium between 12 and14 mg/dL (6-7 mEq/L, 3.0-3.5 mmol/L), clinical manifestations guide therapy. For patients with mild hypercalcemia (serum calcium <12 mg/dL [<6 mEq/L, 3.0 mmol/L]), treatment is generally not indicated (Bilezikian 1992). Symptomatic treatment of hypercalcemia focuses initially on correcting dehydration and enhancing renal calcium excretion. Subsequently treatment is with agents that inhibit bone resorption. A response to treatment is indicated by reductions in serum calcium levels and in urinary calcium and hydroxyproline excretion and by resolution of symptoms. It has been suggested that polyuria, polydipsia, central nervous system symptoms, nausea, vomiting, and constipation are more likely to be managed successfully than anorexia, malaise, and fatigue. Pain control is achievable in patients who gain normocalcemia (Ralston et al 1990). Pharmacologic inhibition of bone resorption An intravenous bisphosphonate is the treatment of choice for managing hypercalcemia of malignancy following correction of dehydration. With this approach, 70-90% of patients will achieve normocalcemia, relief of symptoms, and an improved quality of life (Coleman 1999). Bisphosphonates may be divided into two distinct pharmacologic classes that have different mechanisms of action. Non-nitrogen-containing bisphosphonates (for example, etidronate, clodronate, and tiludronate) are metabolized intracellularly by osteoclasts to cytotoxic, nonhydrolyzable ATP analogs. Nitrogen-containing bisphosphonates (including alendronate, ibandronate, pamidronate disodium, risedronate, and zoledronic acid) inhibit prenylation 15 (Nussbaum et al 1993). Prenylation of guanosine triphosphatases is necessary for regulating a variety of intracellular processes in osteoclasts including morphology, function, and survival (Russell et al 1999)], and therefore inhibition of prenylation by bisphosphonates disrupts osteoclast activities and induces apoptosis (Benford et al 1999). Although oral bisphosphonates are effective in treating hypercalcemic episodes, they have limited efficacy compared with intravenous bisphosphonates (Major et al 2000; Body et al 1998). The use of oral formulations is further limited by a poor bioavailability that requires administration at high doses, which is associated with gastrointestinal toxicity including esophagitis. Among intravenous formulations, the nitrogen-containing bisphosphonates are more potent inhibitors of osteoclast-mediated bone resorption than non-nitrogen-containing bisphosphonates, with a lower tendency to toxic renal effects at effective doses (Purohit et al 1995; Ralston et al 1989; Warrell et al 1991; Nussbaum et al 1993; Pecherstorfer et al 1996). Prior to the introduction of zoledronic acid, the standard therapy for hypercalcemia of malignancy was intravenous pamidronate, which was effective in providing normocalcemia (Thiébaud et al 1986, 1988; Gucalp et al 1992; Body & Dumon 1994). Zoledronic acid is the most potent inhibitor of bone resorption identified to date and demonstrates superior efficacy to pamidronate in clinical trials (described in Chapter 3). Other therapeutics for hypercalcemia of malignancy Salmon calcitonin rapidly inhibits calcium and phosphorous resorption from bone and decreases renal calcium reabsorption, but its calcium-lowering effect persists for a few days only and tachyphylaxis is common. Combining calcitonin with bisphosphonates may offer a rapid onset of hypocalcemic response (Thiébaud et al 1990). Another agent with potential efficacy is plicamycin (mithramycin), which inhibits osteoclast RNA synthesis. Maximum response, however, does not occur until 48 hours after administration and rebound hypercalcemia usually follows multiple doses (Kennedy 1970). Repeated doses also predispose patients to adverse effects such as thrombocytopenia, increases in hepatic transaminases, nephrotoxicity, and hypophosphatemia. Gallium nitrate was developed as an antineoplastic agent but was found also to possess hypocalcemic activity. Gallium nitrate interferes with proton pumps in the osteoclast membrane, which impairs the ability of these cells to dissolve bone matrix. Disadvantages to its use include a continuous 5-day intravenous infusion schedule and a potential for nephrotoxicity (Warrell et al 1997). Multiple myeloma Deciding from among the range of potential treatments for myeloma may be a complex process. Treatment is tailored to the individual patient’s requirements including age and general health, stage of disease, the presence of complications, and outcomes from previous treatments Patients typically receive chemotherapy (e.g. bortezomib) to reduce the disease burden of multiple myeloma, often given in high-dose and combined with stem cell transplantation. Adjunctive therapy frequently includes radiation therapy to specific areas of pain or impending fracture. 16 Pharmacologic inhibition of osteoclastic bone resorption Bisphosphonates have an important role in the prevention of bony complications of multiple myeloma, including the management of hypercalcemia, fracture, and spinal cord compression. These agents are also able to promote bone healing. Based on trial evidence, the US Food and Drug Administration has approved the intravenous bisphosphonates, pamidronate and zoledronic acid, in multiple myeloma. Current treatment guidelines by the American Society of Clinical Oncology (ASCO) recommend using intravenous bisphosphonates at first radiographic evidence of osteopenia in patients with multiple myeloma (Table 1). As discussed in Chapter 3, there is now substantial evidence that zoledronic acid is clinically more effective than pamidronate, in addition to offering a superior administration regimen. Other therapies for multiple myeloma Erythropoietin may ameliorate the anemia that results from myeloma itself or the chemotherapy that is used to treat it, and is shown to improve quality of life. Patients with spinal cord compression may begin corticosteroid therapy immediately to reduce swelling. Surgical decompression may be appropriate, but laminectomy in this population is reported to have a high mortality rate (610%) and may not to be superior to radiation. Patients presenting with acute renal failure may benefit from plasmapheresis. Table 1. Selected ASCO recommendations for intravenous bisphosphonate use in multiple myeloma and bone metastases Lytic disease on plain radiographs • Intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended for multiple myeloma patients with lytic destruction of bone on plain radiographs Monitoring • In patients with pre-existing renal disease and a serum creatinine <265 μmol/L or <3.0 mg/ dL, no change is required in dosage, infusion time, or interval of pamidronate or zoledronic acid • Evaluation every 3 to 6 months is recommended for patients receiving chronic pamidronate or zoledronic acid therapy for albuminuria and azotemia. In patients experiencing unexplained albuminuria or azotemia, drug discontinuation is warranted until the renal problems resolve Duration of therapy • Once initiated, intravenous pamidronate or zoledronic acid is siggested to be continued until there is evidence of a substantial decline in the patient’s general performance status Myeloma patients with osteopenia based on normal plain radiograph or bone mineral density measurements • It is reasonable to start intravenous bisphosphonates in multiple myeloma with osteopenia but without radiographic evidence of lytic bone disease Pain control for bone involvement • Intravenous pamidronate or zoledronic acid is recommended for patients with pain due to osteolytic disease and as an adjunctive treatment for patients receiving radiation therapy, analgesics, or surgical intervention to stabilize fractures or impending fractures 17 Advanced malignancies involving bone Radiotherapy and systemic endocrine or cytotoxic therapy are the mainstays of definitive treatment for advanced cancers. Chemotherapeutic approaches currently being refined include the use of total androgen blockade in prostate cancer; unfortunately, as discussed later, androgen blockade is associated with reductions in bone mineral density. For the management of metastases, external beam radiotherapy provides palliation for localized bone pain, but is less effective in the presence of widespread bone pain or for patients whose pain recurs at previously irradiated sites. Strontium-89 shows efficacy in patients with prostate cancer (Lewington et al 1991). Because strontium-89 is taken up preferentially at sites of new bone formation, it may have greatest efficacy for sclerotic metastases, although it appears also to be effective in osteolytic bone metastases from breast cancer (Robinson et al 1993). More recently samarium-153, which is linked to the bisphosphonate ethylene diamine tetramethylene phosphonic acid, has been evaluated in prostate and breast cancer (Resche et al 1997). Samarium-153, like strontium-88, is preferentially taken up at sites of bone formation, where it emits alpha and gamma particles that provide imaging and therapeutic effects, respectively. Pharmacologic inhibition of osteoclastic bone resorption Bisphosphonates are an important treatment for reducing both the symptoms and complications of bone involvement and do so by restoring the rate of bone resorption to normal. Greatest experience to date of bisphosphonate use has been to treat bone pain due to metastases from advanced breast cancer. Controlled trials of pamidronate, clodronate, ibandronate, and zoledronic acid have all demonstrated significant pain relief in this indication (Body et al 1998, 1999; Berenson et al 1998). As with hypercalcemia of malignancy, intravenous infusion is necessary to obtain optimal effects. The efficacy of bisphosphonates in pain relief appears to be independent of the nature of the tumor or the radiographic appearance of metastases, and sclerotic lesions respond as well as lytic metastases. As there appears to be an association between metastatic bone pain and the rate of bone resorption, greatest benefit with bisphosphonates may be in those with most severe symptoms (Vinholes et al 1997). Large placebo-controlled studies have investigated pamidronate given monthly at a does of 90 mg by intravenous infusion in patients with advanced breast cancer and multiple myeloma who were also receiving systemic endocrine or cytotoxic therapy (Hortobagyi et al 1996; Janjan et al 1997; Berenson et al 1998). These trials showed that pamidronate significantly reduced skeletal morbidity in both conditions. Improvements morbidity began to appear after three months and were maintained throughout the two-year study period. In addition, the pamidronate-treated patients demonstrated a maintained quality of life and a reduction in pain and analgesic use compared to the placebo group. No significant overall effects on survival have been reported for pamidronate. More recently, large, well-designed trials comparing pamidronate and zoledronic acid have been performed. As described in detail in Chapter 3, these show that zoledronic acid is superior in efficacy with a more rapid onset of effect than pamidronate. 18 Bisphosphonates including clodronate, pamidronate, and more recently zoledronic acid have also been investigated for efficacy in the treatment of metastases from prostate cancer (Lipton et al 2001; Dearnaley et al 2001; Saad et al 2002). As discussed in detail in Chapter 3, the clinical trial database has been extended further by large trials of zoledronic acid in lung and other solid tumors (Rosden et al 2003). Prostate cancer – therapy-induced osteoporosis Men who receive androgen-deprivation therapy or orchiectomy for prostate cancer are at risk for reduced bone mass and an increased incidences of fractures (Townsend et al 1997). Smith et al (2001), for example, observed an 8.5% decrease in trabecular bone mineral density of the lumbar spine after one year of therapy with leuprolide (a gonadotropin releasing hormone [GnRH] agonist). Calcium and vitamin D supplementation are not adequate to prevent bone loss during GnRH agonist therapy. Other therapies that have been investigated include selective estrogen receptor modulators (e.g. raloxifene and toremifene), which effectively prevent loss of bone mineral density in postmenopausal women (Smith et al 2004). Another agent with potential is bicalutamide, which binds selectively to androgen receptors in target tissue, and is indicated in combination with a GnRH agonist to treat metastatic prostate cancer. Pharmacologic inhibition of treatment-related bone loss As may be predicted from the mode of action of bisphosphonates, these agents show efficacy in preventing treatment-related bone loss in patients with prostate cancer. Intermittent (3-monthly) administration of intravenous pamidronate or zoledronic acid prevents or even increases bone loss in men with prostate cancer treated by androgen-deprivation therapy or orchiectomy (Smith et al 2001; Ryan et al 2006). Ryan et al further observed that zoledronic acid increases bone mineral density even if initiated 6-12 months after initiation of androgen-deprivation therapy; further details of this trial are presented in Chapter 3. Metabolic bone disorders Paget’s disease The short-term objective in the treatment of Paget’s disease is alleviation of bone pain, and for this nonsteroidal anti-inflammatories and acetaminophen may be adequate. Longer term objectives are to prevent or minimize disease progression in patients at risk of complications. Although calcium and vitamin D supplementation may help reduce impaired bone mineralization, treatment with bisphosphonates should be considered as first-line therapy, with salmon calcitonin held as a second-line option if bisphosphonates are contraindicated. Bisphosphonate therapy is capable of normalizing biochemical markers of bone turnover and replacing woven bone with normal lamellar bone (Reid et al 1996). Bisphosphonates may also reduce bone pain (Miller et al 1999; Small et al 2003). Intravenous bisphosphonates are preferable over oral bisphosphonates because oral formulations require daily dosing for two to six months, with fasting before and after treatment and a need to remain upright for at least 30 minutes to reduce risk of upper gastrointestinal complications. Intravenous pamidronate is inconvenient because it is given by slow intravenous infusions each lasting a few hours over 19 multiple visits. Zoledronic acid offers the advantages of a more convenient administration schedule than pamidronate and a greater efficacy than oral risedronate, and to many authorities is considered the first-line medication (Reid et al 2005). Osteoporosis Numerous therapeutic options exist in the treatment of osteoporosis in postmenopausal women and the elderly. Hormone replacement therapy has been used for many years to increase serum estrogen levels and decrease the rate of bone resorption in postmenopausal osteoporosis, but recent controlled trials suggested that the harm of long-term hormone replacement may outweigh the benefits (Rossouw et al 2002). Selective estrogen-receptor modulators (SERMs), such as raloxifene, mimic the effects of estrogens in bone without stimulatory effects in other tissues, and demonstrate bone loss prevention and vertebral fracture rate reduction in women with postmenopausal osteoporosis. Toremifene is a newer SERM approved to treat advanced breast cancer and also being investigated to treat the osteoporosis associated with hormone therapy in prostate cancer. Bisphosphonates are now considered first-line agents for the prevention and treatment of osteoporosis, by offering consistent increases in bone mineral density and reduced rates of fracture. Oral bisphosphonates such as alendronate and risedronate reduce the risk of vertebral and non-vertebral fractures by 40-50%. Oral bisphosphonates, however, require to be taken daily on an empty stomach, which raises concerns of gastrointestinal intolerance and compliance. For this reason, intravenous bisphosphonates offer potential advantages. As shown by Reid et al, an annual infusion of zoledronic acid increases bone mineral density to a similar degree as daily administration of oral bisphosphonate (Chapter 3). Rheumatoid arthritis Many therapies are available for treating rheumatoid arthritis, including non-steroidal anti-inflammatories (NSAIDs), disease-modifying anti-rheumatologic drugs (DMARDs), immunosuppressants, biologic response modifiers, and corticosteroids. Traditionally, the treatment of rheumatoid arthritis has utilized a stepwise progression beginning with salicylates and NSAIDs and progressing to disease-modifying medications. NSAIDs (and COX-2 inhibitors, used with caution) are the cornerstone of therapy for mild, well-controlled disease, offering reductions in pain and inflammation and improvements in mobility and function. DMARDs such as methotrexate and sulfasalazine are used frequently as components of combination therapy regimens. Current recommendations suggest that for all but minor disease, DMARDs, biologic response modifiers, and combination therapy regimens are more effective if initiated early in the disease course, when destruction of synovial tissue and joints is beginning. Although the medications described above may be effective in many patients with rheumatoid arthritis, the prognosis of this disease is extremely variable and novel therapeutic approaches continue to be explored. As demonstrated in a recent proof of concept study, zoledronic acid therapy administered at 13-week intervals reduces the progression of erosions compared with placebo and warrants further investigation (Jarrett et al 2006) 20 References Adamson BB, Gallacher SJ, Byars J et al. Mineralisation defects with pamidronate therapy for Paget’s disease. Lancet 1993;342:1459-1460. American College of Rheumatology: Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002;46:328-346 Benford HL, Helfrich MH, Sebti S et al. Inhibition of protein geranylgeranylation by bisphosphonates and GGTI298 causes activation of caspase 3-like proteases in osteoclasts. Calcif Tissue Int 1999;64(suppl 1):S45. Berenson JR, Lichtenstein A, Porter L et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol 1998;16:593-602. Berenson JR, Lipton A, Rosen LS et al. Phase I clinical study of a new bisphosphonate, zoledronate (CGP-42446), in patients with osteolytic bone metastases. Blood 1998;88(suppl 1):586a. Bilezikian JP: Management of acute hypercalcemia. N Engl J Med 1992;326:1196-1203. Body JJ, Bartl R, Burckhardt P et al. Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol 1998;16:3890-3899. 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Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum 2006;54:1410-1414. Kennedy BJ: Metabolic and toxic effects of mithramycin during tumor therapy. Am J Med 1970;49:494-503. Lewington VJ, McEwan AJ, Ackery DM et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991;27:954-958. Lipton A, Small E, Saad F et al. The new bisphosphonate, ZometaTM (zoledronic acid) decreases skeletal complications in both lytic and blastic lesions: a comparison to pamidronate [abstract 34]. Cancer Invest 2001;20:45-47. Major PP, Lipton A, Berenson J et al. Oral bisphosphonates: a review of clinical use in patients with bone metastases. Cancer 2000;88:6-14. Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. 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Treatment of severe hypercalcaemia with mithramycin and aminohydroxypropylidene bisphosphonate. Lancet 1988;2:277. Ralston SH, Gallacher SJ, Patel U et al. Comparison of three intravenous bisphosphonates in cancer-associated hypercalcemia. Lancet 1989;2:1180-1182. Ralston SH, Gallacher SJ, Patel U et al. Cancer-associated hypercalcemia: morbidity and mortality. Clinical experience in 126 treated patients. 21 Ann Intern Med 1990;112:499-504. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653. Reid IR, Miller P, Lyles K et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 2005;353:898908. Reid IR, Nicholson GC, Weinstein RS et al. Biochemical and radiologic improvement in Paget’s disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med 1996;101:341-348. Resche I, Chatal JF, Pecking A et al. A dose-controlled study of 153Sm-Ethylenedia minetetramethylenephosphate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 1997;33:1583-1591. Robinson RG, Preston DF, Baxter KG et al. Clinical experience with strontium-89 in prostatic and breast cancer patients. Semin Oncol 1993;20(suppl 2):44-48. 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 2003;21:3150-3157. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333. Russell RG, Rogers MJ, Frith JC et al. The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res 1999;14(suppl 2):53–65. Ryan CW, Huo D, Demers LM, Beer TM, Lacerna LV. Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer. J Urol 2006;176:972-978. Saad F, Gleason DM, Murray R et al. Zoledronic acid reduces skeletal complications in patients with hormone-refractory prostate carcinoma metastatic to bone: a randomized, placebo-controlled trial. J Natl Cancer Inst 2002;94:1458-1468. Small EJ, Smith MR, Seaman JJ et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003;21:4277-4284 Smith MR, Fallon MA, Lee H, Finkelstein JS.Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 2004;89:3841-3846. Smith MR, McGovern FJ, Zietman AL et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:948-955. Thiébaud D, Jacquet AF, Burckhardt P. Fast and effective treatment of malignant hypercalcemia. Combination of suppositories of calcitonin and a single infusion of 3-amino 1-hydroxypropylidene-1-bisphosphonate. Arch Intern Med 1990;150: 2125-2128. Thiébaud D, Jaeger P, Jacquet AF et al. A single-day treatment of tumor-induced hypercalcemia by intravenous amino-hydroxypropylidene bisphosphonate. J Bone Miner Res 1986;1:555-562. Thiébaud D, Jaeger P, Jacquet AF et al. Dose-response in the treatment of hypercalcemia of malignancy by a single infusion of the bisphosphonate AHPrBP. J Clin Oncol 1988;6:762-768. Townsend MF, Sanders WH, Northway RO, Graham SD Jr. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 1997;79:545-550. Vinholes JJ, Purohit OP, Abbey ME et al. Relationships between biochemical and symptomatic response in a double-blind trial of pamidronate for metastatic bone disease. Ann Oncol 1997;8:1243-1250. Warrell Jr RP, Murphy WK, Schulman P et al. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 1991;9:1467-1475. Warrell RP Jr. Metabolic emergencies. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997: 2486-93. 22 Chapter 3. Zoledronic acid: clinical evidence for efficacy and safety Zoledronic acid is a new-generation bisphosphonate and the most potent inhibitor of bone resorption in its class. Zoledronic acid is licensed in many countries for the following indications: 1. Hypercalcemia of malignancy 2. Multiple myeloma 3. Bone metastases or bone pain presumed due to bone metastases from breast cancer, lung cancer, prostate cancer, and other solid tumor types 4. Prophylaxis of bone loss secondary to androgen deprivation therapy in prostate cancer 5. Paget’s disease of bone Zoledronic acid is also an experimental therapy for osteoporosis, rheumatoid arthritis, and other indications. The extensive clinical data that support these applications of zoledronic acid will be described in detail in this chapter. Hypercalcemia of malignancy Zoledronic acid was approved by the US Food and Drug Administration in 2001 for the treatment of hypercalcemia of malignancy based on pivotal clinical studies that directly compared zoledronic acid with pamidronate administered intravenously. In patients with moderate to severe hypercalcemia of malignancy, zoledronic acid demonstrated a significantly higher response rate than pamidronate with the benefit of a more rapid infusion time (15 minutes, versus 2 hours for pamidronate). Given the superior efficacy, more convenient administration schedule, and comparable safety profile of zoledronic acid compared with pamidronate, zoledronic acid may become the treatment of choice for hypercalcemia of malignancy. Efficacy data Early clinical trials including a dose-ranging study in patients with hypercalcemia of malignancy (Body et al 1999; Berenson et al 2001) established that zoledronic acid was effective in reducing serum calcium levels with a duration of normocalcemia exceeding 21 days and was safe and well tolerated. The superior efficacy of zoledronic acid (4 or 8 mg, by single daily intravenous injection) compared with pamidronate (90 mg) was demonstrated in a pooled analysis of two large, randomized, 23 phase III trials based in the US/Canada and Europe/Australia, respectively, in 287 patients with moderate to severe hypercalcemia of malignancy (i.e. baseline corrected serum calcium 3.0 mmol/l [12.0 mg/dl l]) (Major et al 2001). These trials represented the largest comparative investigations of bisphosphonate therapy ever conducted in patients with hypercalcemia of malignancy. Pamidronate was chosen as comparator because of its widespread use in patients with osteolytic lesions from multiple myeloma or metastatic breast cancer. Zoledronic acid was administered via a 5-minute infusion and pamidronate via a 2-hour infusion. Patients who relapsed or were refractory to initial treatment with zoledronic acid or pamidronate were eligible for treatment with zoledronic acid at 8 mg in a second phase of the trial. Patients were followed for 56 days or until serum calcium levels were 2.9 mmol/l. Complete response was defined as a corrected serum calcium level <2.7 mmol/l by day 10. The complete response rate was significantly higher for zoledronic acid (88.4% for 4 mg and 86.7% for 8 mg) than for pamidronate (69.7%) (Figure 1). Patients treated with zoledronic acid also achieved a more rapid normalization of serum calcium than those treated with pamidronate (Figure 2) and experienced a longer median duration of response than those in the pamidronate group. The 4 mg dose of zoledronic acid was nearly as effective as the 8 mg dose, with no significant differences. Figure 1. Proportion of patients achieving a complete response by treatment group. Figure 2. Mean CSC levels at baseline and days 4, 7, and 10 for patients treated with zoledronic acid, 4 mg (filled circles) or 8 mg (filled squares), or pamidronate disodium, 90 mg (filled triangles). Per-protocol entrance criteria (mean CSC 3.0 mmol/l [12.0 mg/dl], solid line) and normalization value (mean CSC 2.7 mmol/l [10.8 mg/dl], dashed line) are indicated. In the 69 patients who relapsed or were refractory to therapy in the first phase of the trial, retreatment with 8 mg zoledronic acid achieved a complete response in 36 (52%) patients by day 10. This response rate represents a clinically meaningful effect in a population who exhibited diminished serum calcium responsiveness to earlier bisphosphonate therapy (Nussbaum et al 1993; Thiébaud et al 1990). Zoledronic acid was equally effective regardless of the patients’ gender, age, tumor type, presence of bone metastases, or serum PTHrP level. In contrast, pamidronate was less effective in patients with humoral-type hypercalcemia of malignancy (61% complete response rate) than in patients with the osteolytic form (80%) (Major et al 2001). Zoledronic acid was safe and well 24 tolerated at both 4 mg and 8 mg doses (Major et al 2001). The outcomes of these pivotal provided the basis for concluding that zoledronic acid is superior to pamidronate for the treatment of hypercalcemia of malignancy. The benefits of zoledronic acid that were demonstrated in these trials based in North America, Europe, and Australia were confirmed in an open-label trial from Japan (Kawada et al 2005). Patients (n=27) with hypercalcemia of malignancy, defined as a corrected serum calcium level 12.0 mg/dl, were treated with a single dose of zoledronic acid, 4 mg, by 15-minute infusion. The mean corrected serum calcium level decreased from 14.5 to 9.6 mg/dl by day 10. Complete response, defined as a decrease of corrected serum calcium 10.8 mg/dl by day 10, was achieved in 84% of patients (similar to Major et al 2001). The median time to relapse was 23 days and, interestingly, was shorter in patients with high PTHrP levels than in patients with low levels. Clinical symptoms associated with hypercalcemia of malignancy, including depressed level of consciousness, anorexia, nausea, vomiting, fatigue and mouth dryness, improved as the corrected serum calcium level was decreased. The most frequently observed adverse event was fever ( 38°C). No serious adverse events associated with renal toxicity were reported. Based on these results, zoledronic acid was concluded to be as effective and well tolerated for hypercalcemia of malignancy in Japanese patients as in other patient poulations investigated. Infusion time benefits The observation of increases in serum creatinine in some patients receiving a 5-minute infusion of zoledronic acid, comparable with those following a 2-hour infusion of pamidronate (90 mg) (Berenson et al 2001), caused the recommended infusion rate for zoledronic acid to be increased from 5 to 15 minutes in patients who require repeated administration. After extension of the infusion rate to 15 mintues, increases in serum creatinine levels are similar to placebo in patients with metastatic bone disease (Saad et al 2002). The 15-minute infusion time for zoledronic acid (compared with 2 hours for pamidronate) offers significant advantages. Gammon and Le (2003) observed that the shorter administration time of zoledronic acid compared to pamidronate offers the opportunity to treat more patients with existing clinical staff and improves the quality of patients’ lives by shortening their time in clinic. In conclusion, these pivotal trials in patients with moderate to severe hypercalcemia of malignancy have demonstrated that zoledronic acid is significantly superior to pamidronate. Incidences of adverse events were similar between zoledronic acid and pamidronate. The superior efficacy and convenience of zoledronic acid suggest that zoledronic acid may represent the therapy of choice for the treatment of hypercalcemia of malignancy. Multiple myeloma The US Food and Drug Administration in 2002 approved an expanded indication for zoledronic acid for the treatment of patients with bone metastases that include multiple myeloma. Treatment guidelines by the American Society of Clinical Oncology recommend use of intravenous bisphosphonates including zoledronic acid at first radiographic evidence of osteopenia in patients with multiple myeloma to significantly reduce the occurrence and delay the 25 onset of skeletal complications (Berenson et al 2002). The trial evidence reviewed below shows that zoledronic acid is at least comparable in efficacy to pamidronate in multiple myeloma. Zoledronic acid was compared to pamidronate in a phase II study of 280 patients with lytic bone metastases from multiple myeloma (n=108) or breast cancer (n=172) (Berenson et al 2001). Patients were randomized to nine monthly infusions of 0.4 mg, 2 mg, or 4 mg zoledronic acid via a 5-minute infusion or to 90 mg of pamidronate as a 2-hour infusion. The primary end point was identification of the dose of zoledronic acid that reduced the need for radiation to less than 30% of treated patients. Zoledronic acid at 2 mg and 4 mg reduced the need for radiation to 18% and 21% of patients, respectively. A larger, international, multicenter, double-blind, randomized trial compared 4 or 8 mg doses of zoledronic acid to 90 mg pamidronate every 3 to 4 weeks for 12 months in 1648 patients with stage III multiple myeloma (n=510) or breast cancer (n=1138) who had lytic disease (Rosen et al 2001). The infusion time for zoledronic acid was 15 minutes compared to 2 hours for pamidronate. The primary endpoint was the proportion of patients with at least one skeletalrelated event, defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone at 13 months (after 12 months of treatment and 1 month of follow-up). In the zoledronic acid 4 mg arm, 44% of patients had at least one skeletal-related event compared with 46% in the pamidronate arm, which confirmed the non-inferiority of zoledronic acid compared to pamidronate. In addition, zoledronic acid significantly reduced the need for radiotherapy compared with pamidronate (15% versus 20%). Further details of this trial are described in the Breast Cancer section, below. Rosen and colleagues (2003) reported a longer-term (25-month) safety and efficacy study comparing zoledronic acid with pamidronate in these patients with multiple myeloma or breast carcinoma. Patients received zoledronic acid 4 mg or 8 mg (reduced to 4 mg) or 90 mg pamidronate every 3-4 weeks for 24 months. After 25 months, zoledronic acid reduced the overall proportion of patients with a skeletal-related event and reduced the skeletal morbidity rate similarly to pamidronate. However, compared with pamidronate, zoledronic acid significantly reduced the overall risk of skeletal complications (including hypercalcemia of malignancy) by an additional 16% (P=0.030). Zoledronic acid and pamidronate were equally well tolerated. These long-term follow-up data confirm that zoledronic acid has at least similar efficacy to pamidronate in patients with multiple myeloma. Additional trials offer support for these large investigations. For example, a single-center study of nine patients which compared ������������������������������������������������������������� zoledronic acid and pamidronate ����������������������������� in multiple myeloma patients substantiated that zoledronic ��������������������������������������������������������������������������� acid offers equivalent efficacy and safety to pamidronate at 12 months when administered by the same regimens and using similar assessments as described above (Kraj et al 2002). Advanced malignancies involving bone Three pivotal studies evaluated the efficacy and safety of zoledronic acid in patients with cancer bone metastases. These studies included an investigation of patients with breast cancer or multiple myeloma using pamidronate as active control (described above) and two placebo- 26 controlled investigations in patients with solid tumors and prostate cancer. Study durations were 13, 9, and 15 months, respectively. In each study, the primary analysis was a comparison of the proportions of patients with at least one skeletal-related event, defined as a pathologic fracture, spinal cord compression, need for radiotherapy to bone, or surgery to bone. Based on the results of these randomized, phase III clinical trials that enrolled in total more than 3000 patients, zoledronic acid (4 mg by 15-minute infusion) has received multinational regulatory approval for the treatment of bone metastases secondary to all solid tumor types as well as bone lesions from multiple myeloma. Unlike pamidronate, zoledronic acid has been shown to reduce skeletal morbidity in patients with both osteolytic and osteoblastic bone lesions. Zoledronic acid can be safely administered via 15-minute infusion, compared with the minimum recommended infusion time of 2 hours for pamidronate. On the basis of these benefits, zoledronic acid is emerging as the new standard of care for managing skeletal morbidity in patients with advanced cancers involving bone. For patients with breast cancer, guidelines from the American Society of Clinical Oncology recommend that bisphosphonate therapy should be initiated at first radiographic evidence of bone destruction or an abnormal bone scan with localized pain (Hillner et al 2000). Patients who are receiving bisphosphonate therapy should continue to do so throughout the course of their disease for as long as it is tolerated. No guidelines have been developed for patients with solid tumors other than breast cancer, but treatment with zoledronic acid at first diagnosis of metastatic bone disease may be a reasonable approach based on phase III trials of zoledronic acid in prostate cancer, lung cancer, or other solid tumors, as described below. Zoledronic acid remains the only bisphosphonate that is proven effective in the treatment of bone metastases in patients with advanced prostate cancer and other solid tumors. An additional benefit of therapy with zoledronic acid is pain relief (Vogel et al 2004). A recent open-label study investigated zoledronic acid 4 mg intravenously over 15 minutes every 3-4 weeks as treatment for bone metastases in patients with multiple myeloma, breast cancer, or prostate cancer. The majority of patients (65%) had received other bisphosphonate therapy previously (pamidronate in 95%). Of the 613 patients investigated, 461 (75%) reported pain at baseline. At every visit, these patients experienced statistically significant decreases in mean pain score compared with baseline. While overall quality of life measures remained stable during the study, individual score items including mean physical well-being and emotional well-being improved significantly. Zoledronic acid was generally well tolerated, with 77% of patients completing all six infusions. The authors concluded that, with appropriate monitoring, cancer patients with bone metastases achieve clinical benefits from zoledronic acid therapy, including those who previously received alternative intravenous bisphosphonate treatment. Breast cancer The benefits of bisphosphonate therapy in breast cancer patients include correction of hypercalcemia, relief of pain, and reduction in skeletal-related events. The potent effects of zoledronic acid in treating hypercalcemia of malignancy are reported above. For metastatic bone pain, at least 50% of the patients obtain a clinically relevant analgesic effect from bisphosphonate therapy. The frequency of skeletal-related events is reduced by 30-40% on 27 prolonged administration, and intravenous bisphosphonates are now recognized as the preferred treatment for prevention of skeletal complications. The American Society of Clinical Oncology guidelines for patients with breast cancer recommend therapy with zoledronic acid or pamidronate for prevention of skeletal complications in patients with radiologic evidence of bone lesions (Hillner et al 2004). Pamidronate was the early standard of care in these patients. Subsequently, comparative trials have demonstrated the non-inferiority and, in longer-term investigations, the superiority of zoledronic acid relative to pamidronate in patients with breast cancer. Efficacy data In a large non-inferiority trial, Rosen et al (2001) randomly assigned 1648 patients with either stage III multiple myeloma or advanced breast cancer and at least one bone lesion to treatment with 4 or 8 mg of zoledronic acid via 15-minute intravenous infusion or 90 mg of pamidronate via 2-hour intravenous infusion every 3-4 weeks for 12 months. The primary efficacy endpoint was the proportion of patients experiencing at least one skeletal-related event over 13 months. The proportion of patients with at least one skeletal-related event was similar in all treatment groups (including 44% of patients who received 4 mg zoledronic acid versus 46% of patients who received pamidronate). The median time to first skeletal-related event was approximately one year in each treatment group. The skeletal morbidity rate was slightly lower in patients treated with zoledronic acid than in those receiving pamidronate, and zoledronic acid (4 mg) significantly decreased the incidence of radiation therapy to bone, both overall and in the subset of patients who were receiving hormonal therapy. Pain scores decreased in all treatment groups. Zoledronic acid (4 mg) and pamidronate were equally well tolerated. The most common adverse events in these groups were bone pain, nausea, fatigue, and fever. Fewer than 5% of serious adverse events were related to the study drug. The incidence of renal impairment among patients treated with 4 mg of zoledronic acid via 15-minute infusion was similar to that in patients treated with pamidronate. In conclusion, zoledronic acid (4 mg) via 15-minute intravenous infusion was as effective and well tolerated as 90 mg of pamidronate in the treatment of osteolytic and mixed bone metastases/ lesions in patients with advanced breast cancer or multiple myeloma. A subanalysis that concentrated on patients who had breast carcinoma with at least one osteolytic lesion at study entry (n=528) showed that the proportion with a skeletal-related event was lower in the 4 mg zoledronic acid group than the pamidronate group (48% versus 58%, P=0.058) (Rosen et al 2004). In addition, the time to first skeletal-related event was significantly longer in the 4 mg zoledronic acid group than the pamidronate group (median 310 versus 174 days; P=0.013). Moreover, multiple-event analysis demonstrated significant further reductions in the risk of developing skeletal-related events for zoledronic acid compared with pamidronate (30% in the osteolytic subset [P=0.010] and 20% for all patients with breast cancer [P=0.037]). These data indicate that 4 mg zoledronic acid was more effective than 90 mg pamidronate in reducing skeletal complications in patients with breast carcinoma with at least one osteolytic lesion. The same authors compared the longer-term safety and efficacy of zoledronic acid and pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma (Rosen et al 2003). After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with a skeletal-related event and reduced the skeletal morbidity rate 28 similarly to pamidronate. Compared with pamidronate, however, zoledronic acid reduced the overall risk of developing skeletal complications (with inclusion of hypercalcemia of malignancy) by an additional 16% (P=0.030). In patients with breast carcinoma, 4 mg zoledronic acid was significantly more effective than pamidronate, reducing the risk of skeletal-related events by an additional 20% (P=0.025). Zoledronic acid (4 mg) and pamidronate were equally well tolerated. These long-term follow-up data demonstrate that zoledronic acid is more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and is of similar efficacy in patients with multiple myeloma. More recently, a 12-month, multicenter, randomized, placebo-controlled study in Japanese women with metastatic bone disease secondary to breast cancer (n=228) demonstrated that zoledronic acid was significantly more effective than placebo in decreasing the incidence of skeletal-related events. The trial was placebo controlled because no bisphosphonate had been approved in Japan for treating patients with bone metastases. Zoledronic acid or placebo were administered via 15-minute infusions every 4 weeks for one year. The skeletal-related event rate was 0.63 events/year in the zoledronic acid group versus 1.10 events/year in the placebo group (rate ratio, 0.57; P=0.016). The skeletal-related event rate ratio at one year (excluding hypercalcemia of malignancy) was 0.61 (P=0.027), showing that zoledronic acid reduced the rate of skeletal-related events by 39% compared with placebo. The percentage of patients with at least one skeletal-related event (excluding hypercalcemia of malignancy) was reduced 20% by zoledronic acid (29.8% versus 49.6%; P=0.003). In addition, zoledronic acid consistently reduced the incidence of all types of skeletal-related events (Figure 3). Fig 3. Proportion of patients with each type of skeletal-related event (SRE). Comp, compression; HCM, hypercalcemia of malignancy. (*), excluding HCM. Zoledronic acid significantly delayed the time to first skeletal-related event (median not reached versus 364 days; P=0.007). Zoledronic acid also consistently reduced Brief Pain Inventory (BPI) composite scores from baseline and compared with placebo throughout the study (Figure 4). Fig 4. Mean change from baseline Brief Pain Inventory (BPI) composite pain scores by treatment group and time on study. (*), P < .05. 29 Zoledronic acid was well tolerated and most adverse events were mild to moderate in severity. Similar to other bisphosphonate studies, the most frequent adverse events suspected to be study drug-related were pyrexia, nausea, and fatigue. There was no evidence of decreased renal function among patients treated with zoledronic acid compared with placebo. The authors comment that the magnitude of the therapeutic benefit after one year was striking. Zoledronic acid produced an absolute 20% and a relative 40% reduction in the percentage of patients with at least one skeletal-related event compared with placebo. In comparison, earlier pamidronate trials that enrolled similar patients demonstrated an absolute 10-13% reduction and a relative 18-23% reduction in the percentage of patients with a skeletal-related event after one year (Theriault et al 1999; Hortobagyi et al 1996). This is consistent with the findings of the randomized trial by Rosen et al (2004), which showed that zoledronic acid is superior to pamidronate, particularly among patients with predominantly osteolytic lesions. Cartenì and colleagues (2006) described a recent open-label study of the efficacy and safety of zoledronic acid in breast cancer patients with newly diagnosed ( 6 weeks) bone metastases. Zoledronic acid (4 mg) was administered via a 15-minute infusion every 3 or 4 weeks for 12 infusions. Skeletal-related events were defined as pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone, and hypercalcemia of malignancy. Among 312 patients enrolled, 30% experienced at least one skeletal-related event during the 12-month study and 22% experienced only one skeletal-related event (Figure 5). Figure 5. Percentage of patients who experienced a skeletal-related event by frequency (intent-to-treat population). The most common skeletal-related event was radiation to bone (22%), followed by pathologic non-vertebral fractures (4.8%). The median time to first skeletal-related event was not reached. Of 237 evaluable patients, 138 (58%) experienced a decrease in pain score, 19% no change from baseline, and 23% an increase in pain. In quality of life analysis, total FACT-G indicated no change in overall score and improvements in the physical well-being, emotional well-being, and functional well-being subscales. Zoledronic acid was well tolerated. Adverse events were generally mild to moderate in severity and were consistent with the known safety profile of intravenous bisphosphonates. The most frequently reported adverse events, regardless of relationship to study drug, were pyrexia (22%) and bone pain (10%). Of the patients who reported pyrexia, 85% had only a single episode following the first infusion. Serum creatinine levels did not increase significantly from baseline. In conclusion, breast cancer patients with newly diagnosed bone metastases who were treated with zoledronic acid experienced a low incidence of skeletal-related events compared with 30 patients who received placebo, and pain was decreased from baseline. This study confirms both the efficacy and safety of zoledronic acid in the treatment of patients with bone metastases from advanced breast cancer. The more recent trials (such as that by Cartenì et al, above) have frequently included formal quality of life (QoL) assessments. A detailed study by Weinfurt et al (2004) measured healthrelated QoL in patients with metastatic breast cancer who were treated with zoledronic acid or pamidronate. As may be predicted, patients with a history of skeletal-related events began the study with significantly lower QoL scores. Patients receiving zoledronic acid or pamidronate over the course of the 12-month study reported improvements in QoL including areas of physical, functional, and emotional well-being. Both pain and analgesic use decreased from baseline. These results suggest that by, effectively preventing skeletal-related events, QoL is likely to improve. Clemons and colleagues (2006) evaluated whether additional benefits would be gained from use of zoledronic acid (4 mg) in metastatic breast cancer patients who suffered progressive metastases or skeletal-related events despite prior therapy with pamidronate or clodronate. Thirty-one women completed the 8-week study. By week 8, patients experienced significant improvement in pain control (P<0.001) with a downward trend in a bone turnover marker (urinary N-telopeptide) (P=0.008). This is the first study to demonstrate that patients with progressive bone metastases or skeletal-related events can obtain clinically relevant palliative benefits by a switch from clodronate or pamidronate to zoledronic acid. If confirmed in randomized trials, this finding would have major implications for the use of bisphosphonates in both metastatic and adjuvant settings. Lung cancer Skeletal-related events complicate the clinical course for many patients with lung cancer and other solid tumors, despite improvements in primary therapy. Compared to investigations of skeletal complications associated with breast cancer, studies of bisphosphonates in patients with other solid tumors have been more limited. Against this background, trials of zoledronic acid in patients with lung and other solid tumors offer evidence of significant clinical benefit. Rosen et al (2003) assessed the efficacy and safety of zoledronic acid in 773 patients with bone metastases secondary to solid tumors other than breast or prostate cancer in a multicenter, randomized, placebo-controlled, nine-month trial. Approximately 50% of patients had nonsmall cell lung cancer (NSCLC), 8% small-cell lung cancer, and 10% renal cell carcinoma. Two thirds of the patients had experienced a skeletal-related event before study entry. Patients were randomly assigned to receive zoledronic acid (4 or 8 mg) or placebo every 3 weeks for 9 months, with concomitant antineoplastic therapy. The 8 mg dose was reduced to 4 mg (8/4 mg group) during the trial because of concerns over decreased renal tolerability at the higher dose level. The primary efficacy assessment was the proportion of patients with at least one skeletalrelated event, defined as pathologic fracture, spinal cord compression, radiation therapy to bone, and surgery to bone. The proportion of patients with a skeletal-related event was reduced in both zoledronic acid groups compared with placebo (38% for 4 mg and 35% for 8/4 mg zoledronic acid versus 44% for placebo; P=0.127 and P=0.023, respectively). In the analysis of all skeletal events (including 31 hypercalcemia of malignancy), 4 mg zoledronic acid significantly reduced the proportion of patients with an event compared with placebo (38% versus 47%; P=0.039). Additionally, 4 mg zoledronic acid significantly increased the time to first event (median 230 versus 163 days for placebo; P=0.023) (Figure 6) and significantly reduced the risk of developing skeletal events (hazard ratio 0.732; P=0.017). Fig 6. Kaplan-Meier estimates of time to first skeletal-related event (not including hypercalcemia of malignancy). The skeletal morbidity rate (the number of events per year; including hypercalcemia) was significantly lower among patients treated with 4 mg zoledronic acid (mean ± SD 2.24 ± 9.12; P=0.017) compared with placebo (2.73 ± 5.29). The mean BPI composite pain score increased slightly from baseline to month 9 in all treatment groups. However, the mean composite pain score decreased in patients in the 4 mg zoledronic acid group who had pain at baseline. There were no statistically significant differences between zoledronic acid and placebo with respect to any global quality of life outcomes. All markers of bone metabolism decreased from baseline to study end in patients treated with zoledronic acid. Zoledronic acid was well tolerated. The proportion of patients experiencing nausea, vomiting, and dyspnea was higher in the 4 mg zoledronic acid group than the placebo group, whereas more patients experienced bone pain in the placebo group. The proportion of patients with decreased renal function (based on change in serum creatinine) was not significantly different between the 4 mg zoledronic acid and placebo groups. In conclusion, zoledronic acid at the recommended dose of 4 mg via a 15-minute infusion every 3 weeks produced a consistent reduction in skeletal morbidity compared with placebo in patients with lung cancer and other solid tumors. The authors point out that zoledronic acid is the first bisphosphonate shown to reduce skeletal complications in patients with bone metastases from solid tumors other than breast and prostate cancer. Rosen et al (2004) subsequently reported on the efficacy and safety of zoledronic acid therapy administered over 21 months in these patients. At endpoint, fewer patients treated with zoledronic acid developed at least one skeletal-related event compared with patients treated with placebo (39% with 4mg dose [P=0.127] and 36% with 8/4 mg dose [P=0.023], compared with 46% treated with placebo). Furthermore, 4 mg zoledronic acid significantly delayed the median time to first skeletal-related event (236 days versus 155 days with placebo; P=0.009) and significantly reduced the annual incidence of skeletal-related events (1.74 versus 2.71 per year; P=0.012). 32 The 4 mg dose of zoledronic acid reduced the risk of developing a skeletal event by 31% (hazard ratio 0.693; P=0.003). Zoledronic acid was well tolerated on long-term use; the most commonly reported adverse events in all treatment groups included bone pain and transient, acute-phase reactions of nausea, anemia, and emesis. To the authors’ knowledge, zoledronic acid is the first bisphosphonate to demonstrate longer-term safety and efficacy in this patient population. A retrospective exploratory analysis of these patients concentrated on the influence of a history of skeletal complications on the response to zoledronic acid. Before study entry, 347 (69%) of 503 patients evaluable for efficacy experienced one or more skeletal-related events. These patients had a higher risk of developing a skeletal-related event during the study than patients with no prior event (odds ratio 1.41). For patients with a skeletal-related event before study entry, zoledronic acid when compared with placebo reduced the risk of further events by 31% (P=0.009), reduced the mean skeletal morbidity rate (1.96 versus 2.81 events per year; P=0.030), and prolonged the median time to first event (215 days versus 106 days; P=0.011). In patients with no skeletal-related event before study entry, zoledronic acid reduced the risk of events by 23% (P=0.308), reduced the mean skeletal morbidity rate (1.34 versus 2.53 events per year; P=0.332), and prolonged the median time to first event by 2.5 months (P=0.534). This exploratory analysis indicates that zoledronic acid reduces skeletal morbidity regardless of the history of skeletal-related events. Renal cancer A subset analysis of the solid tumor trial by Rosen et al (reported above) was performed to investigate the efficacy of zoledronic acid in renal cell carcinoma patients (Lipton et al 2003). Among the 74 renal carcinoma patients in the trial, there was a high incidence of skeletalrelated events and heavy burden of disease from bone metastases at baseline compared with the overall trial population, reflecting the aggressive nature of bone metastases from renal cell carcinoma. Significantly fewer patients treated with 4 mg zoledronic acid had a skeletal-related event compared with placebo (37% versus 74%, P=0.015). (This compares with event rates of 44% for placebo in the overall trial population.) Zoledronic acid significantly prolonged the time to first skeletal-related event (median not reached at 9 months versus 72 days for placebo; P=0.006) (Figure 7). Fig.7. Kaplan-Meier estimates of time to first skeletal-related event in patients with bone metastases from renal cell carcinoma during a 9-month trial of zoledronic acid. Data presented are for the 4-mg zoledronic acid and placebo groups. The number of evaluable patients in each group is listed for each of the time points. NR, not reached; SRE, Skeletal-related event. 33 Zoledronic acid also significantly reduced the annual incidence of skeletal-related events by 21% (mean 2.68 versus 3.38 events per year for placebo, P=0.014) and significantly reduced the risk of developing a skeletal-related event by 61% compared with placebo (risk ratio 0.394, P=0.008). Median time to progression of bone lesions was significantly extended with zoledronic acid treatment (P=0.014). The authors comment that, because of the clinically aggressive nature of bone lesions in renal cell carcinoma, these patients have the potential to receive substantial benefit from treatment with zoledronic acid. Zoledronic acid was well tolerated and the adverse event profile of zoledronic acid was similar to that of placebo. Adverse events occurring more frequently in patients receiving zoledronic acid included nausea, fatigue, pyrexia, rigors, and lower-limb edema. Consistent with the reported analgesic effects of zoledronic acid, more patients in the placebo group reported bone pain (63% versus 52% with 4 mg zoledronic acid). Renal function was closely monitored and the profile of renal-related adverse events was similar in the 4 mg zoledronic acid and placebo groups. Therefore, 4 mg of zoledronic acid appears not to be associated with any significant elevated risk of decreased renal function in patients with renal cell carcinoma. A total of 13 renal cell carcinoma patients were enrolled in the 21-month extension phase of the trial (Lipton et al 2004). Results from the extension phase confirmed the nine-month study. Median times to first event (median 424 versus 72 days; P=0.007) and to bone lesion progression (median 589 versus 89 days; P=0.014) were significantly prolonged in the 4 mg zoledronic acid group compared with placebo. A non-significant trend to improved survival was also observed for patients treated with zoledronic acid (median 347 versus 216 days; P=0.104). The safety data were consistent with the nine-month core analysis. The efficacy results may suggest possible antitumor effects for zoledronic acid, which are being further investigated. Zoledronic acid is the first bisphosphonate to provide the clinically meaningful benefits of significantly reduced skeletal morbidity and significantly prolonged time to bone lesion progression in patients with bone metastases from renal cell carcinoma. Prostate cancer The effect of zoledronic acid on skeletal complications in patients with hormone-refractory prostate cancer and a history of bone metastases was investigated by Saad et al (2002). Patients were randomly assigned to double-blind treatment with intravenous zoledronic acid at 4 mg (n=214) or 8 mg (subsequently reduced to 4 mg; 8/4) (n=221), or placebo (n=208) every 3 weeks for 15 months. Proportions of patients with skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed in this well-designed trial. The rate of skeletal-related events was higher in patients who received placebo (44.2%) than in those who received zoledronic acid at 4 mg (33.2%; –11.0% difference, 95% confidence interval [CI] –20.3% to –1.8%; P=0.021) or at 8/4 mg (38.5%; –5.8% difference, 95% CI = –15.1% to 3.6%; P=0.222). Compared with patients who received placebo, significantly fewer patients who received zoledronic acid 4 mg experienced a fracture (22.1% versus 13.1%, P=0.015) and any 34 skeletal-related event other than fracture (34.6% versus 25.7%, P=0.048). Median time to first skeletal-related event was 321 days for patients who received placebo and was not reached for patients who received zoledronic acid 4 mg (P=0.011) (Figure 8). Fig. 8. Kaplan–Meier estimates of event rates for time to the first on-study skeletal-related event for all intent-to-treat patients with metastatic prostate cancer randomly assigned to receive zoledronic acid at 4 mg, zoledronic acid at 8/4 mg, or placebo. The number of patients at risk at each time point is shown in the table below the graph. At the last study evaluation (450 days), P value (two-sided) from Cox regression = .011 for zoledronic acid at 4 mg versus placebo and P = .491 for zoledronic acid at 8/4 mg versus placebo. Urinary markers of bone resorption (N-telopeptide-, pyridinoline-, and deoxypyridinolineto-creatinine ratios) were significantly decreased in patients who received zoledronic acid compared with placebo. Serum bone alkaline phosphatase, as a measure of bone formation activity, increased significantly more in patients who received placebo than in patients who received zoledronic acid at 4 mg (33.7%, 95% CI = 21.1% to 56.3%, P=0.001). Levels of serum PTH increased significantly more in patients who received zoledronic acid 4 mg than in patients who received placebo (17.1%, 95% CI = 3.3% to 27.5%, P=0.001). The median survival time was 464 days for patients who received placebo and 546 days for patients who received zoledronic acid at 4 mg (P=0.091). There were no significant differences between patients who received zoledronic acid and those who received placebo regarding percent change from baseline in serum prostate specific antigen (PSA), indicating that zoledronic acid had no apparent effect on the secretion or clearance of PSA. Pain and analgesic use scores increased more in patients who received placebo than in patients who received zoledronic acid. Disease progression, performance status, and quality-of-life scores did not differ between the groups. Zoledronic acid 4 mg given as a 15-minute infusion was well tolerated. Fatigue, anemia, myalgia, fever, and lower limb edema occurred in more patients in the zoledronic acid groups than in the placebo group. Renal function deterioration occurred in 15.2% of patients who received zoledronic acid at 4 mg compared to 11.5% who received placebo. The study had a low completion rate, with about one third of patients completing the planned 15 months of study treatment. The authors comment that this is not surprising given the median time to disease progression of 84 days for each treatment group and the median survival of approximately 15 months in the placebo group. In conclusion, all major study outcomes concerning skeletal-related events were superior for patients who received zoledronic acid 4 mg than for patients who received placebo. Zoledronic acid 4 mg was concluded to reduce skeletal-related events in prostate cancer patients with bone metastases. In an analysis of 122 patients who completed 24 months on the study, fewer patients in the 35 zoledronic acid 4 mg group than in the placebo group had at least one skeletal-related event (38% versus 49%, difference –11.0%, 95% CI –20.2% to –1.3%; P=0.028), and the annual incidence of events was 0.77 versus 1.47 (P= 0.005). The median time to first skeletal-related event was 488 days for the zoledronic acid 4 mg group versus 321 days for placebo (P=0.009). Compared with placebo, zoledronic acid 4 mg reduced the ongoing risk of skeletal-related event by 36% (risk ratio 0.64, 95% CI = 0.485 to 0.845; P=0.002). Long-term treatment with 4 mg of zoledronic acid was therefore concluded to provide sustained clinical benefits for men with metastatic hormone-refractory prostate cancer. The optimal duration of zoledronic acid therapy is not known and therefore, similar to the treatment guidelines for breast cancer, it may be reasonable to treat patients with zoledronic acid for as long as it is tolerated or until the patient experiences a substantial decline in performance status. A subanalysis of this trial was also performed to assess clinically meaningful changes in pain using the BPI over 60 weeks (Weinfurt et al 2006). For all 11 pain assessments, patients receiving zoledronic acid (n=76) reported more favorable, clinically meaningful changes in pain scores than patients receiving placebo (n=62). Overall, patients receiving zoledronic acid had a 33% chance of a favorable pain response, compared with 25% for patients receiving placebo (P=0.04; 95% CI 0.5% to 15.6%). Zoledronic acid was therefore more likely than placebo to be associated with clinically meaningful reductions in pain. In conclusion, zoledronic acid may help to avert the pain experienced by patients with progressing metastatic disease secondary to prostate cancer. Applications in androgen deprivation therapy Androgen deprivation as primary tumor therapy reduces bone mineral density and increases the risk of fracture in patients with prostate cancer. Even in the absence of metastases to bone, therefore, zoledronic acid may be expected to offer benefits for skeletal integrity in these patients. Ryan et al (2006) evaluated the effects of zoledronic acid on bone mineral density and biochemical markers of bone turnover in 120 patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less. Patients were randomized to receive 4 mg zoledronic acid or placebo intravenously every 3 months for one year, with stratification according to androgen deprivation therapy duration (less than 6 months versus 6-12 months). Compared with placebo, zoledronic acid increased bone mineral density at one year at the femoral neck, total hip, and lumbar spine by 3.6% (P=0.0004), 3.8% (P<0.0001) and 6.7% (P<0.0001), respectively. The benefits of zoledronic acid on bone mineral density were independent of androgen deprivation therapy duration. Additionally, bone specific alkaline phosphatase and N-telopeptide levels decreased from baseline in the zoledronic acid group (P<0.0001) but increased in the placebo group. In conclusion, zoledronic acid increased bone mineral density and suppressed markers of bone turnover in patients with prostate cancer without bone metastases. Saad and colleagues (2006) have commented recently that a treatment algorithm developed at the 3rd International Consultation on Prostate Cancer had recommended use of zoledronic acid for the prevention of skeletal complications in patients with bone metastases from prostate cancer, regardless of hormone status, and for the prevention of treatment-induced bone loss in patients without evidence of bone metastases. According to this algorithm, zoledronic acid should be considered for the prevention of skeletal morbidity in patients with prostate cancer throughout their treatment continuum. 36 Metabolic bone disorders Paget’s disease of bone Two randomized, double-blind, active-controlled trials compared a single 15-minute infusion of 5 mg zoledronic acid with 60 days of oral risedronate (30 mg per day) in 357 men and women with radiologically confirmed Paget’s disease of bone. The primary efficacy endpoint was the rate of therapeutic response at six months, defined as normalization or at least a 75% reduction in alkaline phosphatase levels. In the pooled results, serum alkaline phosphatase levels were more rapidly and markedly reduced in the zoledronic acid group than in the risedronate group (Figure 9A). Rates of therapeutic response were consistently higher in the zoledronic acid group than in the risedronate group from 10 days onward, attaining rates of 96.0% and 74.3%, respectively, at six months (P<0.001) (Figure 9B). Alkaline phosphatase levels normalized in 88.6% and 57.9% of patients, respectively (P<0.001) (Figure 9C). Fig. 9. Median change from baseline (percent) values for urinary N-telopeptide-to-creatinine ratio (A), serum bone alkaline phosphatase (B), and serum parathyroid hormone (C), all measures of bone metabolism, in patients with metastatic prostate cancer enrolled in a randomized, placebo-controlled phase III trial of zoledronic acid. Error bars show 95% confidence intervals for median percent change at 3 months, 9 months, and at the end of the study. At the last visit, all P values (two-sided) from Cochran–Mantel–Haenszel test with modified ridit score = .001 for the difference between each zoledronic acid group and placebo, with the exception that P = .003 for the difference in serum bone alkaline phosphatase between zoledronic acid at 8/4 mg and placebo. Zoledronic acid was associated with a shorter median time to first therapeutic response than risedronate (64 versus 89 days, P<0.001). The higher rates of response in the zoledronic acid group were independent of patient age, sex, baseline alkaline phosphatase level, and presence or absence of previous therapy for Paget’s disease. Serum levels of the N-terminal propeptide of type I collagen, a specific index of osteoblast activity, showed a pattern similar to alkaline phosphatase but the response tended to be greater. Bone resorption, assessed by serum levels of C-telopeptide and the ratio of urinary C-telopeptide to creatinine, showed greater reductions with zoledronic acid than risedronate at all times. Quality of life, measured by the physical-component score of the Medical Outcomes Study 36item Short-Form General Health Survey, increased significantly from baseline at both three and 37 six months in the zoledronic acid group and differed significantly from the risedronate group at three months. Pain scores improved in both groups. During post-trial follow-up (median 190 days), 21 of 82 patients (25.6%) in the risedronate group suffered a loss of therapeutic response, compared with one of 113 patients (0.9%) in the zoledronic acid group (P<0.001). The numbers of patients with adverse events (146 in the zoledronic acid group and 133 in the risedronate group) and serious adverse events (9 and 11, respectively) were similar in the two groups. The mean serum creatinine level decreased slightly but significantly by day 10 in the zoledronic acid group compared with the risedronate group. At subsequent visits, serum creatinine values were similar and did not differ significantly. A single infusion of 5 mg zoledronic acid over a 15-minute period is concluded to produce a more rapid, complete, and sustained response than daily treatment with risedronate in patients with Paget’s disease. No other currently used agent has been demonstrated to yield significant improvements in quality-of-life measures in randomized, controlled trials. The greater convenience for the patient from the zoledronic acid regimen is an additional benefit of importance for patients with Paget’s disease. On the basis of these data, zoledronic acid received European marketing authorization for the treatment of Paget’s disease of the bone. Osteoporosis Oral bisphosphonates are widely used agents in the treatment of osteoporosis, but they require daily administration on an empty stomach, which is associated with gastrointestinal intolerance in addition to the poor bioavailability from this route of administration. The global rate of noncompliance with long-term oral bisphosphonate therapy for osteoporosis has been reported to be above 50%. An alternative route of delivery, by intravenous administration, has not been as extensively studied, but trials of zoledronic acid offer promising outcomes. Reid et al (2002) examined the effects of intravenous zoledronic acid on bone resorption in 351 postmenopausal women with low bone mineral density in a randomized, double-blind, placebocontrolled trial. Patients received zoledronic acid at 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. A fifth group received zoledronic acid 4 mg as a single annual dose and a sixth group received two doses of 2 mg each, six months apart. Bone mineral density of the lumbar spine increased 4.3–5.1% in all zoledronic acid groups compared to placebo (P<0.001). Femoral neck BMD increased 3.1-3.5% in zoledronic acid groups compared to placebo (P<0.001), while distal radius BMD (0.8 to 1.6%) and total body BMD (0.9 to 1.3%) were also significantly elevated in all but one zoledronic acid treatment group. Biochemical markers of bone resorption were comparably suppressed in all zoledronic acid groups compared to placebo, reaching a nadir at 1 month (median decreases of 65-83% in serum C-telopeptide and 50-69% in urinary N-telopeptide:creatinine ratio) which was sustained at 12 months. Biochemical markers of bone formation, including serum osteocalcin and bonespecific alkaline phosphatase, showed suppression persisting at 12 months for all zoledronic acid doses (P<0.001). In general, zoledronic acid was well-tolerated, with the most common adverse effects of decreased calcium concentrations, myalgia, and pyrexia. Mean serum calcium concentrations 38 declined by approximately 0.08 mmol/L between baseline and one month in the zoledronic acid groups (P<0.05 for all comparisons). From 3 months onwards, calcium concentrations were similar between zoledronic acid and placebo groups. Treatment-related dropout rates were not significantly different between the groups. These results indicate that an annual infusion of zoledronic acid can produce an increase in bone mineral density similar to that of the daily administration of oral bisphosphonates. An annual infusion of zoledronic acid may be an effective treatment for postmenopausal osteoporosis and may represent an attractive option with the potential to increase patient compliance and possibly minimize the risk of adverse effects compared to oral bisphosphonate therapy. Supportive data were presented recently at the 2006 American Society for Bone and Mineral Research conference. The Health Outcomes and Reduced Incidence with Zoledronic acid Once yearly (HORIZON) Pivotal Fracture Trial (n=7736) evaluated the potential of yearly infusion of zoledronic acid 5 mg to decrease risk of fracture in postmenopausal women with osteoporosis. Interim analysis encompassing 99% of data from the study showed that patients taking zoledronic acid experienced a 70% risk reduction in new spine fractures (P<0.0001) and a 40% risk reduction in hip fractures (P=0.0032) over 3 years compared to placebo. This met the study’s two primary endpoints. The most common side effects included fever, muscle pain, flu-like symptoms, and bone pain. Rheumatoid arthritis Based on the results of a recent proof of concept study, zoledronic acid shows promise as a treatment in early rheumatoid arthritis. Jarrett and colleagues (2006) assessed whether zoledronic acid could achieve a 50% or greater reduction in the development of new erosions in 39 patients with early rheumatoid arthritis and clinical synovitis of the hand or wrist. Patients were randomized to receive infusions of either zoledronic acid (5 mg) or placebo at baseline and at week 13, and both groups additionally received methotrexate (MTX) 7.5-20 mg/week. At week 26, the mean change in hand and wrist erosions assessed at magnetic resonance imaging (MRI) was 61% lower in the zoledronic acid than the placebo group (0.9 versus 2.3; P=0.176). The mean increase in number of hand and wrist bones with erosions was 0.3 for zoledronic acid compared with 1.4 for placebo (P=0.029). The proportion of patients with new MRI-visualized bone edema was numerically lower in the zoledronic acid group compared with placebo (33% versus 58%; P=0.121). The safety profile of zoledronic acid was similar to that of placebo. The results of this study suggest that zoledronic acid therapy proves structural benefit to bone in patients with rheumatoid arthritis. 39 Additional potential applications of zoledronic acid Transplant-related bone loss Clinically important bone loss that is associated with fractures occurs within 3 to 6 months of liver transplantation. A 12-month, randomized, double-blind, placebo-controlled trial of 62 adults undergoing liver transplantation for chronic liver disease investigated the effect of zoledronic acid 4 mg (n = 32) or saline (n = 30) infused within 7 days of transplantation and at months 1, 3, 6, and 9 (Crawford et al 2006). All patients additionally received calcium carbonate and ergocalciferol supplementation. The primary outcome was bone mineral density measured by dual x-ray absorptiometry. Differences in bone loss at 3 months after transplantation favored zoledronic acid over placebo. Group differences, after adjusting for baseline weight and serum PTH level, were 4.0% (95% CI 1.1% to 7.0%) at the lumbar spine, 4.7% (1.9% to 7.6%) at the femoral neck, and 3.8% (1.7% to 6.0%) at the total hip. At 12 months, group differences were 1.1% (-2.1% to 4.4%), 2.7% (0.0% to 5.4%), and 2.4% (0.1% to 4.7%), respectively. The authors concluded that treatment with zoledronic acid can prevent bone loss within the first year after liver transplantation. Thalassemia-induced osteoporosis Voskaridou and colleagues (2006) evaluated the effect of zoledronic acid in patients with thalassemia-induced osteoporosis. Sixty-six patients were randomized to receive 4 mg zoledronic acid intravenously every 6 months (23 patients; group A) or every 3 months (21 patients; group B) or to receive placebo every 3 months (22 patients; group C) for one 1 year. Bone mineral density of the lumbar spine, femoral neck and wrist was measured before and at 12 months after treatment. Patients in group A showed no change in bone mineral density at any site at 12 months, but experienced reductions in bone pain, bone-specific alkaline phosphatase, osteocalcin, and osteoprotegerin. Patients in group B showed a significant increase in lumbar spine bone mineral density, accompanied by reductions in bone pain, C-telopeptide, bone-specific alkaline phosphatase, C-telopeptide, and osteocalcin. Patients in group C showed no alteration in bone mineral density at any site and no improvement in bone pain, while they experienced an increase in markers of bone resorption. Zoledronic acid at a dose of 4 mg intravenously every 3 months appears to be an effective treatment for increasing bone mineral density and reducing bone resorption in thalassemiainduced osteoporosis. 40 References Berenson JR, Hillner BE, Kyle RA et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20:3719-3736. Berenson JR, Rosen LS, Howell A et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases: a double-blind, randomized dose-response study. Cancer 2001;91:1191-1200. Berenson JR, Vescio RA, Rosen LS et al. A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases. Clin Cancer Res 2001;7:478-485. Body JJ, Lortholary A, Romieu G et al. A dose-finding study of zoledronate in hypercalcemic cancer patients. J Bone Miner Res 1999;14:1557-1561. Cartenì G, Bordonaro R, Giotta F et al. Efficacy and safety of zoledronic acid in patients with breast cancer metastatic to bone: a multicenter clinical trial. The Oncologist 2006;11:841-848. Clemons MJ, Dranitsaris G, Ooi WS et al. Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy. J Clin Oncol 2006 Sep 25; [Epublication ahead of print] Crawford BA, Kam C, Pavlovic J et al. Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2006;144:239-248. Gammon DC, Le HT. Zoledronic acid vs pamidronate for the prevention of hypercalcemia of malignancy or bone metastases in hospital outpatients: Time analysis and economic implications Hosp Pharm 2003; 38:1148-1150. Hillner BE, Ingle JN, Berenson JR et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 2000;18:1378-1391. Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042-4057. Hirsh V, Tchekmedyian NS, Rosen LS, Zheng M, Hei YJ. Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications. Clin Lung Cancer 2004;6:170-174. Hortobagyi GN, Theriault RL, Porter L et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases: Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996;335:1785-1791 Jarrett SJ, Conaghan PG, Sloan VS et al. Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum. 2006;54:1410-1414. Kenji K, Hironobu M, Keniichi O et al. A multicenter and open label clinical trial of zoledronic acid 4 mg in patients with hypercalcemia of malignancy. Jpn J Clin Oncol 2005;35:28-33. Kohno N, Aogi K, Minami H et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005;23:3314-3321 Kraj M, Poglod R, Maj S, Pawlikowski J, Sokolowska U, Szczepanik J. Comparative evaluation of safety and efficacy of pamidronate and zoledronic acid in multiple myeloma patients (single center experience). Acta Pol Pharm. 2002;59:478-482. Lipton A, Colombo-Berra A, Bukowski RM et al. Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid. Proceedings of the First International Conference. Clinl Cancer Res 2004;10:6397S-6403S. 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 2000;88:1082-1090. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962-969. Major P, Lortholary A, Hon J et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558-567. Nussbaum SR, Warrell Jr RP, Rude R et al. Dose-response study of alendronate sodium for the treatment of cancer-associated hypercalcemia. J Clin Oncol 1993;11:1618-1623. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377-387. 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 2003;98:1735-1744. 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 41 Tumors Study Group. J Clin Oncol 2003;21:3150-3157. Rosen LS, Gordon D, Tchekmedyian NS et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 2004;100:2613-2621. Rosen LS, Gordon DH, Dugan W Jr et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36-43. Ross JR, Saunders Y, Edmonds PM et al. A systematic review of the role of bisphosphonates in metastatic disease. Health Technol Assess 2004;8:1-176. Ryan CW, Huo D, Demers LM, Beer TM, Lacerna LV. Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer. J Urol 2006;176:972-978. Saad F, Gleason DM, Murray R et al; for the Zoledronic Acid Prostate Cancer Study Group. Randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458-1468. Saad F, Gleason DM, Murray R et al; for the Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879882. Saad F, McKiernan J, Eastham J. Rationale for zoledronic acid therapy in men with hormone-sensitive prostate cancer with or without bone metastasis. Urol Oncol 2006;24:4-12. Smith MR, Eastham J, Gleason DM et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003;169:2008-2012. Theriault RL, Lipton A, Hortobagyi GN et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial: Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846-854. Thiébaud D, Jaeger P, Burckhardt P. Response to retreatment of malignant hypercalcemia with the bisphosphonate AHPrBP (APD): respective role of kidney and bone. J Bone Miner Res 1990;5:221-226. Vogel CL, Yanagihara RH, Wood AJ et al. Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist 2004;9:687-695. Voskaridou E, Anagnostopoulos A, Konstantopoulos K et al. Zoledronic acid for the treatment of osteoporosis in patients with βthalassemia: results from a single-center, randomized, placebo-controlled trial. Haematologica 2006;91:1193-1202. Weinfurt KP, Anstrom KJ, Castel LD, Schulman KA, Saad F. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 2006;17:986-989. Weinfurt KP, Castel LD, Li Y et al. Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Med Care 2004;42:164-175. 42 Chapter 4. Zoledronic acid: management issues Chapter 4 describes characteristics of zoledronic acid that are relevant to clinical management including information on its pharmacological profile, infusion profile, and aspects of adverse event management applicable to all agents in the class. Zoledronic acid is an antihypercalcemic and bone resorption inhibitor that is administered parenterally. Approved indications vary by country, but include treatment for hypercalcemia of malignancy, multiple myeloma, bone metastases from solid tumors in conjunction with standard antineoplastic therapy, including breast carcinoma, prostate carcinoma (those that progress after treatment with at least one hormonal therapy), other solid tumors, and Paget’s disease. Zoledronic acid also demonstrates efficacy for preventing bone loss in men taking androgendeprivation therapy for prostate carcinoma, in postmenopausal women with osteoporosis, and in patients with early rheumatoid arthritis. For the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases, adults typically receive 4 mg in solution injected into a vein in not less than 15 minutes. Pharmacological profile Chemistry The active ingredient of zoledronic acid is (1-hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate. The molecular formula is C5H10N2O7P2·H2O and the molecular weight 290.11. Zoledronic acid is an odorless, white crystalline material. It is soluble at alkaline pH and sparingly soluble in water. The drug is supplied as a sterile, lyophilized powder intended for reconstitution before infusion. The recommended storage temperature is 25°C. Absorption The area under the plasma concentration versus time curve (AUC) for zoledronic acid is dose proportional from 2 to 16 mg. Accumulation over repeated cycles is low. Patients with mild and moderate renal impairment show an increased AUC of 15% and 43%, respectively, although no significant relationship between zoledronic acid exposure (AUC) and adverse events has been established. The use of zoledronic acid in patients with severe renal failure is not recommended. Protein binding Protein binding is approximately 22 % and is independent of concentration. 43 Elimination The excretion of zoledronic acid is primarily renal, at a clearance rate of 3.7 ± 2.0 liters per hour. The remainder is bound to bone and is slowly released back into systemic circulation, giving rise to a 146 hour terminal half-life. Dose-finding studies Doses selected for clinical trials were based on changes in bone resorption markers and evidence of efficacy. In studies of patients with cancer bone metastases, markers were consistently suppressed for at least 4 weeks at doses 4 mg. In patients with multiple myeloma or breast cancer bone metastases who received zoledronic acid at 0.4, 2, or 4 mg, there was a significant difference in skeletal-related event rate between the 0.4 and 4 mg groups. On the basis of these studies, zoledronic acid doses of 4 and 8 mg were selected for Phase III evaluation. In later trials the 4 mg dose has been most frequently investigated. Infusion protocol The protocol for administering zoledronic acid has been standardized as infusion by a peripheral intravenous line over no less than 15 minutes. All intravenous bisphosphonates have the potential to increase serum creatinine levels, and patients with serum creatinine 3.0 mg/dl were excluded from phase III zoledronic acid trials, so patients should have serum creatinine levels <3.0 mg/dl (<4.5 mg/dl in patients with hypercalcemia of malignancy) in order to receive zoledronic acid treatment. Patients should be encouraged to drink two glasses of water before receiving their bisphosphonate infusion. The patient’s vital signs and the infusion site should be monitored periodically during infusion and after infusion is completed. Duration of bisphosphonate therapy There are limited data on the optimal duration of zoledronic acid therapy. Current guidelines for patients with bone metastases from breast cancer suggest that, once initiated, bisphosphonate therapy should be continued for as long as it is well tolerated or until there is a significant decrease in the performance status (Hillner et al 2003). There are no consensus guidelines for the duration of bisphosphonate therapy in patients with prostate cancer, but recommendations from a multidisciplinary panel suggest that bisphosphonate treatment should be ongoing after bone metastases are diagnosed (Carroll et al 2003). This is supported by reports that the efficacy of zoledronic acid does not decrease during long-term use. In patients with bone metastases from solid tumors other than breast or prostate cancer, no formal recommendations have been published. However, zoledronic acid has demonstrated significant benefits in this setting in patients who have experienced prior skeletal-related events, so treatment should not be discontinued on the basis of skeletal-related event history (Hirsh et al 2004). Managing bisphosphonate-related adverse events The safety profile of zoledronic acid has been well established, based on randomized controlled trials and extensive clinical experience. In general, intravenous administration of zoledronic acid is well tolerated with a predictable and manageable side effect profile. The monitoring 44 guidelines and treatment interruption criteria detailed in the prescribing information are the same for zoledronic acid and pamidronate. The most common adverse events associated with administration of intravenous bisphosphonates are self-limiting flu-like symptoms related to an acute-phase reaction. These symptoms typically develop within 24 hours after the first infusion, and symptoms generally persist for 48 hours (Zojer et al 1999). Acute-phase reactions usually diminish or disappear following the second or third infusion. A less common adverse event is decreased renal function, which may occur after the administration of any intravenous bisphosphonate. Approximately 10% of patients treated with zoledronic acid (4 mg via 15 minute infusion) develop renal function deterioration, defined as an increase of 0.5 mg/dl in patients with normal baseline serum creatinine or an increase of 1.0 mg/dl in patients with baseline serum creatinine 1.4 mg/dl, which is similar to the frequency reported for 90 mg pamidronate via 2-hour infusion. It is believed that underlying disease-related factors may contribute to the incidence of renal impairment in patients with multiple myeloma or advanced cancer (Corso et al 2002). Renal monitoring guidelines have been established to minimize the risk of renal deterioration during intravenous bisphosphonate therapy (Berenson et al 2002; Hillnes et al 2000). Serum creatinine should be measured within 7 to 10 days of the first infusion and measured before administration of each subsequent dose (Hillner et al 2003). Infusion of bisphosphonate should be withheld in any patient whose serum creatinine level has increased by 50% above baseline, in patients with normal baseline serum creatinine whose levels increased by 0.5 mg/dl, and in patients with abnormal baseline serum creatinine whose levels have increased by 1.0 mg/dl. Infusion can be resumed after serum creatinine has returned to within 10% of baseline. A complication occurring in less than 2% of patients in phase III clinical trials of intravenous bisphosphonates is ocular inflammation. For patients who develop ocular symptoms, prompt ophthalmologic evaluation will determine the safety of subsequent bisphosphonate therapy. Recently, retrospective case studies have reported an association between long-term bisphosphonate therapy and osteonecrosis of the jaws. The incidence of osteonecrosis appears to be rare, occurring in <1 in 10 000 patients. The risk of developing osteonecrosis at any site is four times higher in cancer patients than in the normal population due to multiple risk factors, including chemotherapy or radiation therapy. Trauma, infection, and a history of dental procedures contribute to an elevated risk (Tarassoff & Csermak 2003). Physicians should assess the dental status of patients before administration of bisphosphonate therapy and monitor patients for oral hygiene and the occurrence of jaw osteonecrosis. Attention to proper administration, dose, and schedule are crucial to minimize the incidence and severity of the adverse events of intravenous bisphosphonates including zoledronic acid. 45 References 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 2003;26:661-671. Berenson JR, Hillner BE, Kyle RA et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20:3719-3736. Body JJ, Diel IJ, Lichinitzer M et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133-1137. Body JJ. Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 2001;28(suppl 11):49–53. Bounameaux HM, Schifferli J, Montani JP et al. Renal failure associated with intravenous diphosphonates. Lancet 1983;1:471. Carroll PR, Altwein J, Brawley O et al. Management of disseminated prostate cancer. In: Denis L, Bartsch G, Khoury S et al. eds. Prostate Cancer: 3rd International Consultation on Prostate Cancer—Paris. Paris: Health Publications, 2003:249-284. Coleman RE, Purohit OP, Black C et al. Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease. Ann Oncol 1999;10:311-316. Coleman RE. Bisphosphonates: clinical experience. The Oncologist 2004;9(suppl 4):14-27. Conte PF, Guarneri V. Safety of Intravenous and Oral Bisphosphonates and Compliance With Dosing Regimens. The Oncologist 2004; Suppl 4:28–37. Corso A, Zappasodi P, Lazzarino M. Urinary proteins and renal dysfunction in patients with multiple myeloma. Biomed Pharmacother 2002;56:139-143. Eastham JA. Bisphosphonates and prostate cancer: maintaining bone integrity and quality of life. Am J Urol Rev 2004;2(suppl 2):5– 8. Ezra A, Golomb G. Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption. Adv Drug Deliv Rev 2000;42:17-195. Green JR, Müller K, Jaeggi KA. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994;9:745-751 Hillner BE, Ingle JN, Berenson JR et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 2000;18:1378-1391. Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042-4057. Hirsh V, Tchekmedyian NS, Rosen L et al. Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on prior history of skeletal complications. Proc Am Soc Clin Oncol 2004;23:669. Paterson AHG, Powles TJ, Kanis JA et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59-65. Powles T, Paterson S, Kanis JA et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–3224. Saad F. The role of intravenous bisphosphonates in the management of prostate cancer: treatment guidelines. Am J Urol Rev 2004;2(suppl 2):9-15. Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer patients. J Oral Maxillofac Surg 2003;61:12381239. Wozniak AJ. Lung cancer: principles and practice. Management of bone metastases in lung cancer. Updates 2004;4:1-12. Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 1999;21:389406. 46 Conclusions This monograph has reviewed the evidence base for zoledronic acid in a range of indications, in each of which significant clinical need exists. In hypercalcemia of malignancy, zoledronic acid is a potent and well-tolerated therapy with efficacy at least equivalent to the previous gold standard, intravenous pamidronate, and with the additional advantage of a more rapid (15-minute) infusion schedule. Zoledronic acid is the first bisphosphonate to demonstrate significant and long-lasting benefit for reducing skeletal complications in patients with multiple myeloma and a variety of solid tumors, including breast, prostate cancer, lung cancer, and renal cancers. Uniquely, osteolytic, osteoblastic, and mixed bone lesions all improve with zoledronic acid therapy. Treatment with zoledronic acid prevents or delays debilitating skeletal complications, slows the deterioration in quality of life, and shows potential antitumor efficacy in these patients. In metabolic bone disease, zoledronic acid is widely licensed for the treatment of Paget’s disease of bone and has efficacy in osteoporosis of different causes as well as rheumatoid arthritis. Long-term treatment with zoledronic acid has been shown to be safe and well tolerated in clinical practice. Adherence to renal monitoring contributes effectively to renal safety. The consistent efficacy demonstrated for zoledronic acid in large, well-designed trials and in clinical practice suggests that this medication may become first-choice therapy across the range of indications discussed in this publication. 47