Advanced malignancies involving bone

Transkript

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
19
Chapter 3. Zoledronic acid: clinical evidence for efficacy and safety
23
23
Multiple myeloma
25
breast cancer
27
lung cancer 31
renal cancer
33
prostate cancer
34
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 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.
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.
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).
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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.
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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
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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. J Clin Oncol 1998;16:593-602.
Bloomfield D. Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from
other cancers? An evidence-based review. J Clin Oncol 1998,16:1218-1225.
Broadus AE, Mangin M, Ikeda K et al. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N
Engl J Med 1988;319: 556-563.
Clarke NW, McClure J, George NJ. The effects of orchiectomy on skeletal metabolism in metastatic prostate cancer. Scand J Urol
Nephrol 1993;27:475-483.
Coleman RE. Skeletal complications of malignancy. Cancer 1997;80(suppl 8):1588-1594.
Coleman RE. Skeletal complications of malignancy. Cancer 1997;80(suppl 8):1588-1594.
Collinson MP, Tyrell CJ, Hutton C. Osteoporosis occurring in two patients receiving LHRH analogs for carcinoma of the prostate [letter].
Calcif Tissue Int 1994;54:327-328.
Cooper C, Schafheutle K, Dennison E, Kellingray S, Guyer P, Barker D. 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.
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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.
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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
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.
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).
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.
Body JJ, Diel IJ, Lichinitser MR et al: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and
bone metastases. Ann Oncol 2003;14:1399-1405.
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, Dumon JC. Treatment of tumour-induced hypercalcaemia with the bisphosphonate pamidronate: dose-response relationship and
influence of tumour type. Ann Oncol 1994;5:359-363 .
Body JJ, Lichinitser MR, Diehl IE et al. Double-blind placebo controlled trial of ibandronate in breast cancer metastatic to bone. Proc Am Soc
Clin Oncol 1999;18:575a.
Boyce BF, Adamson BB, Gallacher SJ et al. Mineralisation defects after pamidronate for Paget’s disease. Lancet 1994;343:1231-1232.
Coleman RE. Pamidronate disodium in the treatment and management of hypercalcaemia. Rev Contemp Pharmacother 1998;9:147-164.
Dearnaley DP, Sydes MR, on behalf of the MRC Pr05 Collaborators. Preliminary evidence that oral clodronate delays symptomatic progression
of bone metastases from prostate cancer: first results of the MRC Pr05 Trial [abstract]. Proc ASCO 2001;20:174a.
Gucalp R, Ritch P, Wiernik PH et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related
hypercalcemia. J Clin Oncol 1992;10:134-142.
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 Study Group. N Engl J Med 1996;335:1785-1791.
Janjan NA. Radiation for bone metastases: conventional techniques and the role of systemic radiopharmaceuticals. Cancer 1997;80(suppl
8):1628-1645.
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.
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. A randomized, double-blind comparison of risedronate and etidronate in the
treatment of Paget’s disease of bone. Am J Med 1999;106:513-520.
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.
Nussbaum SR, Younger J, Vandepol CJ et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of
malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993;95:297-304.
Pecherstorfer M, Herrmann Z, Body JJ et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the
treatment of hypercalcemia of malignancy. J Clin Oncol 1996;14:268-276.
Purohit OP, Radstone CR, Anthony C et al. A randomised double-blind comparison of intravenous pamidronate and clodronate in the
hypercalcaemia of malignancy. Br J Cancer 1995;72:1289-1293.
Ralston SH, Gallacher SJ, Dryburgh FJ et al. 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.
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).
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
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.
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

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