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BOND 03-002

Produced by Gardiner-Caldwell U.S. Five Paragon Drive, Montvale, NJ 07645-1742, USA. Copyright © 2003 Gardiner-Caldwell U.S. All rights reserved.

Product Monograph
Hypercalcemia of Malignancy


1. Executive summary 2. Disease overview: hypercalcemia of malignancy
2.1 Definition 2.2 Pathology and presentation 2.3 Epidemiology 2.4 Prevalence by tumor type 2.5 Etiology and physiologic fundamentals 2.6 Symptoms and clinical manifestations 2.7 Therapeutic management of hypercalcemia 2.8 Role of bisphosphonates

3 4 4 4 4 5 5 6 6 7 8 8 8 9 9 10 12 13 14 14 14 15 16 18 18 20 20 20 21

3. Bondronat®: product description
3.1 Chemical structure 3.2 Mechanism of therapeutic effect 3.3 Preclinical pharmacology 3.4 i.v. administration 3.5 Pharmacokinetics 3.6 Clinical pharmacology studies in populations of special interest 3.7 Drug interactions

4. Clinical efficacy and safety: experience in hypercalcemia of malignancy
4.1 Introduction 4.2 Pilot study (Study MF 4104) 4.3 Dose-finding study (0.6mg–2mg) by single i.v. infusion (Study MF 4223) 4.4 Dose-response study in cancer-associated hypercalcemia (Study MF 4302) 4.5 Safety of a single dose infusion of Bondronat 2mg or 4mg i.v. (Study MF 4442) 4.6 Comparison with pamidronate (Study MF 4490)

5. Clinical use of Bondronat®
5.1 Indications 5.2 Dosage and administration 5.3 Use in special patient populations


5 Introduction of oral Bondronat in the treatment of metastatic bone disease 22 22 22 23 24 24 25 25 25 26 26 26 27 7.6.1 Introduction 6.5 Rapid infusion 8.4 Studies in other indications 7. in patients with opioid-resistant pain 7.3 Bondronat in patients with prostate cancer and painful metastatic bone disease 6. References 2 .4 Short infusion time 6.v. Ongoing research with Bondronat® 7. Bondronat® in metastatic bone disease 6.1 Introduction 7.2 Bondronat in patients with breast cancer and metastatic bone disease 6.2 Bondronat i.3 Preclinical studies of the antitumor effect of Bondronat 7.

It provides a brief overview of the epidemiology. Shorter administration times are expected to be beneficial to healthcare providers and patients by improving dosing convenience and reducing associated nursing care costs.2 ● Bondronat is well tolerated: – no product-related renal toxicity2 – overall incidence of adverse events (AEs) is similar to placebo – few patients experience injection site reactions. rapidly reduces elevated serum calcium levels1 – more than 75% of patients achieved normocalcemia with Bondronat 4mg1. Further data on the use of Bondronat 50mg oral and 6mg i. ● Bondronat is effective for the treatment of hypercalcemia of malignancy: – Bondronat i.v.v. Finally. in metastatic bone disease will be available in early 2004. pharmacology and pharmacokinetics of Bondronat are also reviewed and the results of clinical trials with Bondronat in hypercalcemia of malignancy are presented. Bondronat in patients with hypercalcemia of malignancy.v. etiology and current approaches to management of hypercalcemia of malignancy. Executive summary This monograph focuses on the treatment of hypercalcemia of malignancy with Bondronat. infusion over 2 hours.2 – normocalcemia is maintained for a mean of 14 days compared with pamidronate (4 days). 3 .v. ● This monograph focuses on the use of i.1 ● Bondronat is given by i.1. The chemistry. recent studies suggest that a bolus injection (2mg dose)3 or 30-minute infusion (4mg dose)4 are well tolerated. diagnosis. the monograph focuses on administration of Bondronat and briefly looks at the ongoing clinical development of Bondronat in other indications.

Most laboratories define normal serum calcium as 2.5). sex (increased risk in women) and malignancy duration.3mg/dL). Most often there is widespread bone destruction due to metastases in patients with hypercalcemia of malignancy.12 The development of hypercalcemia is usually an indicator of poor prognosis and short life expectancy.57 <2. moderate.8–3.5–10. Stage Normal Mild Moderate Severe Serum calcium (mmol/L) 2. The degree of severity of hypercalcemia is commonly divided into three categories: mild. Hypercalcemia is the most common life-threatening complication in patients with cancer.5. 2. Hypercalcemia of malignancy is defined as elevated serum calcium in patients with cancer either with or without metastatic bone disease.11. the majority have a malignancy. Hypercalcemia can be life-threatening. Risk factors for hypercalcemia of malignancy include tumor site (e. further elevating serum calcium levels (see section 2.7 Hypercalcemia is therefore defined as serum calcium levels above the normal upper range. which releases calcium.1–2.10 In patients with hypercalcemia there is increased bone resorption. lung and breast).5–10.3 Serum calcium (mg/dL) 8.12–2. or complications of hypercalcemia such as hypercalcemic nephropathy. .3 Epidemiology Up to 40% of all patients with cancer will develop hypercalcemia . as calcium levels increase.6.3 >3. .g.1 Definition Hypercalcemia can be life-threatening .2. In hospitalized patients who develop hypercalcemia. irregular heartbeats may develop and may lead to cardiac arrest.2 Pathology and presentation Hypercalcemia can occur in patients with or without bone metastases. Disease overview: hypercalcemia of malignancy 2.5 Note that approximately 40% of serum calcium is bound to albumin and this should be corrected for in the determination of serum calcium levels. and severe (Table1). .3 <12 12–14 >14 2.57mmol/L (8. Impaired renal clearance of circulating calcium also occurs.9 Table 1. 4 . Up to 40% of all patients with cancer will develop hypercalcemia at some time during the course of their disease and overall approximately 10% of patients will develop severe hypercalcemia.8 2.8. . Severity of hypercalcemia of malignancy. associated with increased renal tubular resorption of calcium. resulting in elevation of serum calcium levels.

Table 2. Bone is a unique tissue that is affected by cancer since it is a tissue that is normally continuously undergoing remodeling. It is most common in patients with breast cancer.g. parathyroid hormone [PTH]. calcitonin and calcitrol [or 1. PTH-related peptide [PTHrP]) and local growth factors that are released by bone (e. . kidney and intestine to disrupt calcium homeostasis 2.2. Humoral factors secreted by tumors which act on bone.5.g.2 Abnormalities of calcium and bone homeostasis in patients with cancer Hypercalcemia in cancer patients may be associated with three different pathologic mechanisms or a combination of more than one of these mechanisms:14 1. insulin-like growth factor I [IGF-I] and IGF-II). transforming growth factor-beta [TGF-β].4 Prevalence by tumor type Hypercalcemia occurs more frequently in patients with certain types of tumor.25-(OH)2D3]. the pathogenesis of hypercalcemia is linked to regulation of bone metabolism as well as calcium metabolism.5. the pathogenesis of hypercalcemia is linked to regulation of bone metabolism as well as calcium metabolism. In healthy individuals. This process of remodeling is regulated by both systemic hormones (e.5 Etiology and physiologic fundamentals 2. In many cases the mechanism is likely to be a combination of the first two mechanisms listed above14 since they are closely related and the same factors could . tumor necrosis factor [TNF]. Coexisting primary hyperparathyroidism.1 Normal calcium and bone homeostasis Most of the calcium in the body is found in the bones. and is mediated by osteoclasts (involved in resorption) and osteoblasts (involved in new bone formation). lymphoma) Head and neck Renal Prostate Unknown primary Other Frequency (%) 35 25 14 6 3 3 7 7 2. squamous cell lung cancer and multiple myeloma (Table 2). resorption of bone and formation of new bone occurs continuously. Local factors secreted by bone metastases acting directly on the osteoclasts 3.13 Tumor site Lung Breast Hematologic malignancies (myeloma. Most common causes of hypercalcemia in malignant disease. 5 . Therefore. . 2. interleukin-6 [IL-6].

vomiting. electrocardiogram changes Weight loss. leading to hypercalcemia. stabilize the metabolic state and treat the symptoms associated with hypercalcemia of malignancy.3 Local osteolytic hypercalcemia This mechanism may predominate in patients with extensive metastases and is mediated by local factors produced by the bone metastases or by inflammatory cells. Hypercalcemia occurs when the normal process of bone resorption and bone formation is uncoupled and bone resorption predominates.14 Table 3. Therapeutic management of hypercalcemia In managing hypercalcemia of malignancy.5.6 Symptoms and clinical manifestations Patients with mild or moderately elevated serum calcium levels may have few or no symptoms. Body system Gastrointestinal CNS Renal Cardiovascular Other Symptoms Anorexia. However. it is important to treat the underlying tumor since factors released by tumor cells and metastases can cause the hypercalcemia. pyrexia 2. lethargy. corneal calcification. polyuria and polydipsia (in early/mild stages). The extent and type of symptoms parallels the severity of hypercalcemia9 and also the rate at which serum calcium levels increase (Table 3). stupor.5. In contrast.act both as humoral and local mediators.7. Symptoms of hypercalcemia according to body system. dehydration. some authors consider that altered humoral regulation of calcium is the most common mechanism occurring in up to 80% of cases of hypercalcemia15. coma Impaired renal function. Hypercalcemic symptoms may be non-specific and accompanied by an increased pain threshold. nausea. in metastatic prostate cancer the lesions are predominantly osteoblastic resulting in increased bone formation and.17 Local inflammatory factors are osteolytic and stimulate osteoclasts to resorb and destroy bone. oligosuria. including: 6 . thus releasing calcium. hypercalcemia is less common in these patients. uremia (in later stages) Cardiac arrest. 2. 2. 2.4 Humoral hypercalcemia This mechanism may predominate in most patients who have less severe hypercalcemia. Further action is also required to normalize calcium levels. therefore. constipation. muscle weakness Mental confusion.16 with local osteolytic hypercalcemia occurring in up to 30% of cases.

Successful treatment of hypercalcemia of malignancy: ● ● ● ● ● reduces morbidity improves quality of life increases mental and physical wellbeing shortens hospitalization prolongs the life of the patient. whereas patients with severe hypercalcemia require immediate and aggressive intervention (Table 4). . moderate and severe hypercalcemia. furosemide (frusemide) ● Anticalcemic therapies – bisphosphonates e.11 The approach to treatment of hypercalcemia depends on the severity and duration of the disease. decreasing serum calcium levels.20 In general. mobilization. Bondronat 2. . Therapeutic measures for patients with mild.11 Therapy to manage symptoms and to stabilize metabolic status is sufficient for symptomatic patients with mild hypercalcemia of malignancy. Moderate (3–3. the standard treatment for controlling hypercalcemia of malignancy. diet).8 Role of bisphosphonates Bisphosphonates are well established as the standard treatment for controlling hypercalcemia of malignancy.8 Between 70 and 90% of patients achieve normocalcemia with i. bisphosphonates are administered in conjunction with rehydration and loop diuretics.● ● ● ● ● rehydration therapy improvement of renal calcium excretion prevention of calcium uptake from the intestine reduction of bone resorption supportive measures (e.5mmol/L or >14mg/dL) hypercalcemia ● Rehydration ● Correct renal calcium clearance once rehydrated – loop diuretics e. 7 .v. and the patient’s clinical condition.5mmol/L or 12–14mg/dL ) Mild hypercalcemia (<3mmol/L or <12mg/dL ) ● Rehydration ● Stabilize the metabolic state ● Supportive measures for: – nausea and vomiting – mobilization – febrile episodes to severe (>3. most typically in patients with moderate to severe hypercalcemia. These agents inhibit bone resorption by modulating osteoclast activity and recruitment. Symptoms generally dictate the level of treatment for patients with moderate hypercalcemia.g.21 Bisphosphonates are .g.18 Table 4.g.19 Bisphosphonates may also inhibit tumor development. bisphosphonate treatment ameliorating symptoms and improving their quality of life.

. This is attributed to the ability of Bondronat to act on osteoclasts (the cells involved in bone resorption) and tumor cells by: ● reducing osteoclast number and function22.22. Bondronat regulates osteoclast action by inducing osteoclast apoptosis.3. . leading to a decrease in serum phosphate levels due to decreased renal tubular resorption.23 ● reducing tumor growth by apoptosis24 ● reducing tumor adhesion to bone.23 Bondronat regulates osteoclast action by inducing osteoclast apoptosis. Bondronat®: product description 3. Bondronat reduces the excessive destruction and resorption of bone. Chemical structure of ibandronate (Bondronat). Primarily. It is this latter side chain that makes Bondronat one of the most potent inhibitors of osteoclastic activity in clinical use. 8 . causing calcium efflux to decrease. The reduction in calcium causes PTH levels to increase. When taken up by osteoclasts.1 Chemical structure Bondronat [is] one of the most potent inhibitors of osteoclastic activity .24 As a result of these actions. OH OH 3. Bondronat instigates osteoclast apoptosis by inhibiting farnesyl pyrophosphate synthetase in the mevalonate metabolic pathway and the prenylation of proteins.2 Mechanism of therapeutic effect Bondronat reduces serum calcium in patients with hypercalcemia of malignancy.23 CH3 O OH N H 3C P O– Na+ H2O P O OH Figure 1. Bondronat preferentially binds to resorption surfaces of bone. probably due to the high calcium concentrations. and methyl and pentyl substituents at the nitrogen atom at R’’ (Figure 1). Ibandronate (Bondronat) is a third-generation bisphosphonate with a hydroxyl group at the R’ position.

therefore. peripheral nervous system.3. infusion. . Bondronat prevents bone resorption to a similar extent as other bisphosphonates (Figure 2). In this model Bondronat both prevented this deterioration and increased bone mineral density.3.3 Preclinical pharmacology Bondronat has been evaluated in animal models of tumor-induced hypercalcemia.27 3.v.4 Relative potency of bisphosphonates In preclinical studies. aldendronate. administration of Bondronat quickly and effectively reduces hypercalcemia. 50.27 toxicity or infusion site reactions have been reported with Bondronat bolus injection or i.4 i.3.v.v. . respectively). 10-. This supports Bondronat administration at doses lower than those of most other bisphosphonates allowing more practical oral dosing and shorter intravenous administration times. 3. respiratory system or gastrointestinal system. 9 . cardiovascular system. Unlike some other bisphosphonates.26 3. administration Hypercalcemia is frequently a medical emergency.25 3. In these patients i.and 500-fold. serum calcium levels must be rapidly reduced. Preclinical models show that Bondronat: ● ● ● ● dose-dependently inhibits the development of hypercalcemia reduces serum calcium for 2 weeks after a single dose i. administration is equivalent to subcutaneous administration Bondronat is more potent than risedronate.v.1 Model of bone destruction Tumor cells were inoculated into the marrow of the femur to destroy the bone and reduce the strength of the bone.3. pamidronate and clodronate (2-.v. Bondronat prevents the development of these changes associated with the tumor.3 Preclinical safety The effect of Bondronat on other organ systems has been evaluated and it is shown not to have any effect on the CNS. but at considerably lower doses both in vitro and in vivo in animal models. . no clinically significant renal toxicity or infusion site reactions have been reported with Bondronat bolus injection or i.2 Model of bone destruction in aged rats Hypercalcemia and hypercalcuria are accompanied by an increase in markers of bone resorption and histomorphometric deterioration of bone structure and mass.3. infusion. no clinically significant renal 3.

8 10.104 Relative potency in vitro IC50 Zoledronate 103 Bondronat Risedronate 102 Clodronate 101 Dimethyl-APD Alendronate Pamidronate Neridronate 100 10 Figure 2.4 384±41.v. administration of Bondronat 6mg to healthy volunteers (Study BP16145).v. Pharmacokinetic parameters after i.2±24.3 Mean±SD AUC∞ = area under the curve extrapolated to infinity Cmax = maximum plasma concentration t1/2 = half life CL = clearance rate Vz = volume of distribution CLr = renal clearance fe = fraction excreted 10 .0 160±26.8±4.30 Infusion time Parameter† AUC∞ (h•ng/mL) Cmax (ng/mL) t1/2(h) CL (mL/min) Vz (L) CLr (mL/min) fe (% dose) † 60 minutes (n=19) 787±128 308±44.7 70.1 88. administration in healthy volunteers (Table 5).7 141±32.3±10.27.0 52.28 Table 5.1 130±18.6±1.1±2.6 78.3 118±17. 0 Etidronate 101 102 103 104 Relative potency in vivo (rat) ED50 105 3.3 12.3 139±16.6±14.4 51. Relative potencies of Bondronat and other bisphosphonates.84 15 minutes (n=18) 643±104 397±94.3±2.0 53.6±7.30 30 minutes (n=20) 730±84.5 Pharmacokinetics The pharmacokinetics of Bondronat have been studied extensively following i.9±11.5 10.6 147±42.

with small amounts having been recovered in the spleen. particularly at sites of bone resorption. the volume of distribution (Vz).2 3. In contrast. A shorter infusion time of Bondronat 6mg in healthy individuals over 15 minutes. administration (dose range 0.2 Metabolism Bondronat is not metabolized in humans or animals. the t1/2 of bisphosphonates is long (months to years depending on the rate of bone turnover).3 Elimination The kidneys excrete almost 50–60% of circulating Bondronat into the urine by glomerular filtration and a specialized secretary pathway. and therefore declines in patients with intrinsic renal disease when renal function is impaired. renal clearance (CLr). in comparison to 30 and 60 minutes. Renal clearance is directly related to creatinine clearance. Non-renal clearance can also decrease with reduced renal function and has been shown to vary more than renal clearance in patients with metastatic breast cancer. The plasma half-life of Bondronat is relatively short due to rapid uptake in the bone.30 uptake is expected to be proportionally higher in cancellous bone.5. half life (t1/2). The remaining portion of the drug is primarily bound to the skeleton and released at a rate that is proportional to the rate of bone turnover. 11 . Serum concentrations are proportional to dose and fall rapidly in a multi-exponential manner. but without changing the AE profile (Table 5). primarily in the bone (40–50% of the circulating dose). As the surface to volume ratio of cancellous bone is 10-fold greater than that of cortical bone. 85% of Bondronat is protein bound at therapeutic concentrations. The incidence of renal adverse events was similar with the shorter infusion time (indicated by unchanged serum creatinine. Bondronat principally binds to calcium binding sites. without adverse renal effects.29 Preclinical studies have shown that Bondronat is widely distributed throughout the body. and fraction excreted (fe) were similar. . liver and kidney. Bondronat can be administered at a lower dose than many other bisphosphonates (due to its greater potency). whereas 2mg or 4mg Bondronat is given depending on the baseline calcium level.27 In healthy individuals. As expected. 3. circulating Bondronat has a renal clearance of approximately 60–100mL/min. the dose of pamidronate used to restore normocalcemia ranges from 30 to 90mg.5. Bondronat can be infused quickly as a bolus injection or 15-minute infusion . creatinine clearance and markers of tubular or glomerular damage).27 At the bone surface. the infusion rate affects the pharmacokinetic profile of Bondronat.1 Distribution In human plasma. with half of the absorbed oral dose being found in the urine within 24 hours.29 3. Please see prescribing information for dosing recommendations. For example. Within the skeleton.5–6mg). No affinity for cytochrome P450 isoenzyme specific substrates is expressed by Bondronat at clinically relevant concentrations.v. .5. increased the maximum plasma concentration (Cmax) and clearance rate (CL) and reduced the area under the curve extrapolated to infinity (AUC∞).The pharmacokinetics of Bondronat are linear after i.

Approximately 37% of the administered dose is removed during a 4-hour hemodialysis (Study MF 7168).27 12 .3.6. 3. race.6 Clinical pharmacology studies in populations of special interest In addition to studies in healthy volunteers described above.2 Patients with renal impairment The effect of renal impairment on the pharmacokinetics of Bondronat has been investigated (Study MF 7148).6.v. Bondronat were well tolerated in a study of 14 subjects with normal renal function and in 20 patients with varying degrees of renal impairment. Bondronat can be dialyzed.27 140 120 100 CLr (mL/min) 80 60 40 20 0 Figure 3. the effect of gender. Relationship between Bondronat renal clearance (CLr) and creatinine clearance (CLcr) (Study MF 7148).1 Gender and race The bioavailability and pharmacokinetic profile of Bondronat is similar in both men and women.27 In subjects with end-stage renal disease. A linear relationship was observed between Bondronat renal clearance and creatinine clearance (Figure 3).3.27 3. Dose adjustment Dose adjustment is unnecessary for patients with mild to moderate renal impairment (creatinine clearance >30mL/min) as Bondronat exposure increases less than 1-fold.27 No clinically relevant interethnic differences were detected between Asian and Caucasian subjects.29 CLcr <30 CLcr 40–70 CLcr >90 r2=0. Both oral and i.6.771 0 20 40 60 80 100 120 140 CLcr (mL/min) 3. renal impairment and metastatic bone disease on the pharmacokinetic profile of Bondronat has been studied.

4 Patients with hepatic impairment Bondronat has not been investigated in patients with hepatic impairment. 13 .6. 3. .27 These included: – H2 antagonists (ranitidine) – hormone replacement therapy (estrogen) – tamoxifen – melphalan/prednisolone. therefore it is advised that Bondronat is only given if the benefits outweigh the risks. as the liver has no significant role in the metabolism of Bondronat. . dose adjustment should not be necessary in patients with hepatic impairment. ● Drug interaction studies have been performed with reference drugs which may be administered in conjunction with Bondronat and no meaningful interactions were observed. However. .There is limited experience with Bondronat in patients with hypercalcemia of malignancy and severe renal impairment (serum creatinine 5mg/dL or >442µmol/L). clinically significant pharmacokinetic drug interactions [with Bondronat] have not been shown and are considered unlikely. clinically significant pharmacokinetic drug interactions have not been shown and are considered unlikely: ● In-vitro studies indicate that drug–drug interactions through biotransformation by cytochrome P450 are unlikely as Bondronat is not metabolized by the liver. 3.7 Drug interactions Due to the lack of metabolism and renal route of elimination of Bondronat.

) was investigated in an open. multicenter pilot study to investigate the efficacy and tolerance of a single i.0mg i. MF 4490 II 72 Single infusion of of Bondronat 2mg or 4mg i. multicenter dose-finding study to evaluate efficacy and safety of a single infusion of Bondronat Open. multicenter phase I pilot study involving 36 patients with tumor-induced hypercalcemia.v. 60mg or 90mg i. hypercalcemia of malignancy 4.v or of pamidronate 15mg.v. 1. Studies with Bondronat i.2mg steps i.v.v. 60mg and 90mg) Dose regimen (mg) Single infusion of 0.2–2. multicenter study to describe the safety of a single administration of Bondronat Multicenter. The efficacy and safety of Bondronat has been studied in clinical trials involving more than 500 patients with hypercalcemia of malignancy (Table 6). 30mg.0mg in 0. 14 . open.v.1mg or 2mg i.6mg. in the treatment of hypercalcemia of malignancy. Table 6.1 Introduction This section focuses on clinical trials investigating the efficacy and safety of Bondronat in the treatment of hypercalcemia of malignancy. 30mg. MF 4442 IV 124 Single infusion of 2mg or 4mg i. dose of Bondronat Open.v.2 Pilot study (Study MF 4104) The efficacy and tolerability of a single infusion of Bondronat (0.v. randomized. 4. multicenter dose-finding study to evaluate efficacy and safety of a single infusion of Bondronat Double-blind. No. in steps of 0. 4mg or 6mg i.2–2. MF 4302 II 147 Single infusion of 2mg. single dose. controlled study over 4 weeks on the efficacy and safety of Bondronat (2mg and 4mg) versus pamidronate (15mg.2mg MF 4223 II 174 Single infusion of 0. These studies show that Bondronat can be used to effectively reduce serum calcium levels in patients with hypercalcemia of malignancy whilst maintaining a good tolerability profile.Clinical efficacy and safety: experience in 4. of Study MF 4104 Phase I patients 36 Design Open.v. randomized. randomized.

6mg.6mg/dL).6mg 1.31 Response rates of 44%.29 4.8mg/dL). was evaluated in a phase II.1mg and 2mg.27 4.6mg. There was an equal distribution of non-serious AEs between the groups.31 Patients were considered to have responded when they became normocalcemic. respectively.3 Dose-finding study (0.65mmol/L/10. 1.1mg and 2mg.2 Tolerability None of the adverse events (AEs) reported were dose dependent. 80 * Patients normalized (%) 60 40 20 0 0.1 Efficacy Bondronat dose-dependently reduced serum calcium (Figure 4).1 Bondronat dose (mg) 2 Figure 4.3.8mg. 4. The median time-to-relapse of hypercalcemia was 11 days.2 Safety There were 195 AEs of which 99 were considered serious and 96 non-serious.6mg–2mg) by single i.3. Malignancy progression was the most common AE.6mg. 1. open.1mg and 2mg groups.v.1mg or 2mg i. randomized.6mg.2. multicenter study involving 174 patients with cancer. Response rates of 44%. and serum calcium levels >2. 1. respectively. 1.31 4. 17 days and 12 days for the 0.2. The response to Bondronat negatively correlated with the initial serum calcium level.4. 52% and 67% were achieved for patients receiving Bondronat 0.7mmol/L (>10. More serious AEs 15 .v.1 Efficacy The minimum dose required to achieve normocalcemia was 0. 52% and 67% were achieved for patients receiving Bondronat 0. respectively. and the duration of response ranged from 0 to 23 days.6 *p=0. Bondronat normalizes serum calcium levels in a dose-dependent manner. over 2 hours). infusion (Study MF 4223) The efficacy and safety of a single infusion of Bondronat (0.028 vs 0. the time to the first normal value ranged from 1 to 7 days. Among all patients who achieved normocalcemia (≤2.

131 patients were eligible for evaluation. Only three serious AEs and 16 non-serious AEs were considered to be related to treatment with Bondronat (Table 7). dose-finding study involving 147 patients with cancer-associated hypercalcemia resistant to rehydration alone. multicenter. with 50% of patients in the 2mg group achieving serum calcium levels below 2. Among patients who received Bondronat 2mg there were 133 AEs reported compared with 117 AEs among patients on 4mg and 104 AEs on 6mg.1 Bondronat therefore. regardless of dose. this enabled further dose escalation studies to be performed. this enabled further dose escalation studies to be performed. Bondronat did not adversely affect renal function. Table 7. Some patients maintained normocalcemia for up to 36 days (Figure 5). 4.v.5% in the 6mg group (Figure 6).1mg than those receiving 0.4.2 Safety There was no significant difference between the three treatment groups in the number or type of recorded AEs. was evaluated in a phase II. No injection site reactions were reported.4 Dose-response study in cancer-associated hypercalcemia (Study MF 4302) The efficacy and safety of Bondronat (2mg.05).8mg/dL) compared with 75.1 4.Because the overall incidence of AEs was low.1 Efficacy Serum calcium levels decreased from Day 2 with Bondronat. double-blind.6% in the 4mg group and 77. The Bondronat 4mg and 6mg doses were significantly more effective than the 2mg dose in correcting hypercalcemia (p<0.31 Because the overall incidence of AEs was low. showed a dose-dependent effect up to 4mg. reaching a nadir by Day 5.0mg.1 Bondronat showed a dose-dependent effect up to 4mg. Three factors influenced the response to Bondronat: ● the dose of Bondronat – higher doses were more effective ● the severity of the presenting hypercalcemia – severe hypercalcemia was associated with a lower complete response rate ● the type of tumor – patients with breast and hematological tumors responded better than other types of tumor.6mg or 2.6% of patients.7mmol/L (10.31 Serious Fever (n=1) Nausea (n=1) Thrombocytopenia (n=1) Non-serious Fever (n=10) Asymptomatic hypocalcemia (n=4) Esophagitis (n=1) Increased liver enzymes (n=1) 4.1 Of these patients. 4mg and 6mg) i. were observed in patients receiving Bondronat 1. 16 .4. Serious and non-serious AEs possibly related to Bondronat treatment.1 The incidence of AEs with Bondronat was not dose-dependent. regardless of dose.1 Fever was observed in 21. randomized.

1 This was considered to be ‘possibly related’ to Bondronat in 12. 17 . significant difference between 2mg vs 4mg and 6mg group upper limit of normal for adjusted calcium (2.80 Serum calcium (mmol/L) 3.7mmol/L or <10.80 2.05 vs 2mg Bondronat 4 Bondronat dose (mg) 6 Figure 6. 1997).01.20 3.1 *p<0.1 Hypocalcemia was reported in two patients receiving Bondronat 4mg and four patients receiving Bondronat 6mg.60 2.7mmol/L) 80 * * Patients normalized (%) 60 40 20 0 2 *p≤0. (Reproduced from Ralston et al.05. (Reproduced from Ralston et al.40 0 * ** † 2mg 4mg 6mg ** † ** ** † ** ** ** ** ** 0 1 2 3 4 5 6 7 Days after infusion 10 14 21 28 Figure 5.60 3. **p<0.9% of cases. Effect of Bondronat infusion on serum calcium levels by time. 1997). but was not dose dependent.40 3.00 2. No renal events were reported.8mg/dL) according to Bondronat dose. Patients (%) achieving normocalcemia (<2.3.05. significant change from Day 0 † p<0.

05.27 4.0%).4. A total of 43 patients with serum calcium levels between >2.4%) and of pamidronate was 60mg (50.6.4mg/dL]) and pamidronate (–0. Serum calcium levels were normalized in 85. In the per protocol population.5 Safety of a single dose infusion of Bondronat 2mg or 4mg i. Overall 76.0mg (78. randomized trial involving 72 patients with hypercalcemia of malignancy (albumin-corrected serum calcium >2. respectively.5–4.5.41mmol/L [–1. Bondronat was significantly more effective than pamidronate for patients who had high baseline serum calcium levels (p<0.7mmol/L (>10.03).6 Comparison with pamidronate (Study MF 4490) The efficacy and safety of Bondronat was compared with pamidronate in a phase II. respectively.4% and 74. open-label. Bondronat was significantly more effective than pamidronate for patients who had high baseline serum calcium levels.8% receiving pamidronate responded to treatment.2 4. stratified. Patients received either a single infusion of Bondronat (2mg or 4mg) i.9%).0mmol/L (≥12mg/dL) were given Bondronat 4mg.v. These results indicate that Bondronat is as effective as pamidronate in the treatment of hypercalcemia of malignancy.2 Safety Both doses were well tolerated. The median time to relapse was significantly longer for Bondronat (14 days) than pamidronate (4 days) (p=0. (Study MF 4442) The safety of a single i. 18 .8mg/dL) and <3.64mg/dL]).8mg/dL]).27 4.29 The incidence of AEs was similar for patients receiving Bondronat 2mg (83. infusion of Bondronat 2mg or 4mg was evaluated in 124 patients with hypercalcemia of malignancy in a phase IV post-marketing surveillance study. The difference in response rate may have been due to the higher baseline calcium levels in the 4mg group.v.0mmol/L the fall in serum calcium levels was significantly greater with Bondronat at Day 4 than in patients treated with pamidronate. or pamidronate (15mg. with potential for added benefits. 60mg or 90mg) on Day 0. 4. A sub-analysis of the 4mg Bondronat and 60/90mg pamidronate groups showed that the mean decrease in corrected serum calcium was similar between groups.0mmol/L (<12mg/dL) received Bondronat 2mg.5% of patients receiving Bondronat and 75. No renal events were reported.4% and 74.7% of patients receiving Bondronat 2mg and 4mg.7% of patients receiving Bondronat 2mg and 4mg.1 Efficacy The reduction in serum calcium levels on Day 4 was similar with Bondronat (–0. The response rate was lower (67%) for a subgroup of patients with baseline calcium values >3.2 In both the subgroups of patients with baseline calcium levels of 3. The dose was determined by the severity of hypercalcemia: the most frequently administered dose of Bondronat was 4. and 81 patients with serum calcium ≥3. multicenter.7mmol/L [10.5. Table 8).6mmol/L [–2.1 Efficacy Serum calcium levels were normalized in 85.0mmol/L and ≥4. None of the serious AEs were considered to be treatment related.5mmol/L (>14mg/dL) who received Bondronat 4mg. 30mg.v.7%) and 4mg (88.

43mmol/L (5.03 0. No renal AEs occurred in patients taking Bondronat whereas one patient in the pamidronate group had kidney failure.72mg/dL) Pamidronate 0.046 4. AEs with possible/probable causal relationship to the study medication.77mmol/L (3.24 mg/dL) p=0.08mg/dL) p=0.0mmol/L (14–<16mg/dL) Bondronat 1.56mmol/L (6.0 mmol/L (≥16mg/dL) Between treatment difference 1. Table 9. One case of hypocalcemia on Bondronat and one case of fever on pamidronate were considered serious and possibly related to the study drug.6mg/dL) Baseline serum calcium ≥4. Baseline serum calcium 3.2 Bondronat (n=37) Total Flu-like syndrome Respiratory Metabolic Hypocalcemia Hypophosphatemia Hypokalemia Thrombocytopenia Confusion Diarrhea Renal AEs (not related to study medication) considered to be serious.2 No renal AEs occurred in patients taking Bondronat . . Reduction in serum calcium levels on Day 4 following Bondronat or pamidronate treatment presented according to baseline serum calcium levels (per protocol analysis).6. .2 Safety The safety profiles were similar for Bondronat and pamidronate (Table 9).Table 8.5–<4. Pamidronate (n=34) 12 6* 2 0 2 0 1 1 0 1 7 2 1 2* 0 1 0 0 1 0 *One case of hypocalcemia in the Bondronat group and one case of fever in the pamidronate group were 19 .65mmol/L (2.

2. please contact your local Roche representative.v.2 Dosage and administration Bondronat is available as an i.9% saline solution before the initiation of Bondronat therapy.1 Indications This monograph focuses on the Bondronat indication for hypercalcemia of malignancy with or without accompanying bone metastases. particularly for patients with cardiovascular disease.4 Further therapeutic considerations When using Bondronat for hypercalcemia.v.2. less total serum albumin) can be used to determine the dose and to assess the response to Bondronat. However. depending on the baseline serum calcium levels. and 50mg tablet forms for the treatment of metastatic bone disease in patients with breast cancer. Albumin-corrected serum calcium concentrations (total serum calcium. 5. additional therapeutic factors should be taken into consideration: ● Patients should be adequately hydrated with 0. Clinical use of Bondronat® 5.3. for patients with hypercalcemia of malignancy is 2mg or 4mg.2 Duration of administration In the treatment of hypercalcemia of malignancy Bondronat is licensed for infusion over 2 hours. formulation for the treatment of hypercalcemia of malignancy. as intra-arterial and paravenous administration can lead to tissue damage. 5.3 Administration Care must be taken to ensure Bondronat is administered intravenously.2. For availability in your country. Bondronat is infused after dilution in either 500mL of isotonic sodium chloride solution or 500mL of 5% dextrose solution. 20 . 5. Bondronat is also awaiting regulatory approval as both 6mg i.4 5.5.1 Recommended dose The recommended dose of Bondronat i. ● Patients should not receive diuretics until sufficient hydration has been achieved.2. and must remain so over the course of treatment. ● Over-hydration should be avoided. results of studies in healthy volunteers and in patients with hypercalcemia and metastatic bone disease have shown that a bolus injection for 2mg and 30-minute infusion for 4mg are well tolerated.v. The initial Bondronat dose should be based on the following: Corrected serum calcium <3mmol/L (<12mg/dL) ≥3mmol/L (≥12mg/dL) Bondronat dose 2mg 4mg Severity of hypercalcemia Mild/moderate Severe 5.

● Renal function and levels of serum calcium.5. or according to race or gender. ● There is no clinical experience with Bondronat in children. ● There are no clinical data available for the use of Bondronat in patients with severe hepatic insufficiency.3 Use in special patient populations ● There is no need to adjust the dose of Bondronat in elderly patients. serum phosphate and serum magnesium should be monitored in patients as part of good clinical practice for patients with hypercalcemia of malignancy treated with Bondronat. 21 . therefore no dose recommendations can be made.

Bondronat® in metastatic bone disease 6. treatment of metastatic bone disease due to breast cancer. in addition to the bone resorption markers.2 Phase III: efficacy and safety of Bondronat i.2.004) ● significant reduction in mean number of bone events requiring radiotherapy (p=0.001) Bondronat 6mg significantly reduces the bone events and pain associated with bone metastases. urinary hydroxyproline.3 Only patients who received Bondronat 6mg (and not Bondronat 2mg) showed improvements in the following: ● 20% reduction in skeletal morbidity period rate (number of 12-week periods with new bone complications of metastatic bone disease over the total observation time) with Bondronat 6mg compared with placebo (p=0. randomized study involving 466 women with breast cancer and bone metastases.2 Bondronat in patients with breast cancer and metastatic bone disease 6. 6.023) ● significant reduction in the proportion of patients with new bone events (p=0. . Serum calcium and phosphate decreased. multicenter. .1 Phase II dose-finding study (Study MF 4328) One dose-finding study was performed to determine the efficacy and safety of Bondronat i. infusion (predominantly as a standard 1–2 hour infusion but a few studies have been performed with 15. placebo-controlled.1 Introduction Bondronat is being studied in patients with metastatic bone disease in addition to the existing use in hypercalcemia of malignancy. It is anticipated that shorter infusion times (15–30 minutes) will be well tolerated since Bondronat has not been shown to have marked renal toxicity. multicenter.v. Bondronat has not been shown to have marked renal toxicity.032) ● significant increase in time to first new bone event on Bondronat 6mg (p=0.6. Further data on oral Bondronat will be presented in a metastatic bone disease monograph in early 2004.v. parallel group. phase II. Bondronat i.v.and 30-minute bolus injections) ● as an oral tablet. double-blind. every 3–4 weeks to a total of 24 doses over 2 years) was evaluated in a phase III. in breast cancer patients with metastatic bone disease (Study MF 4265) The efficacy and safety of Bondronat (2mg and 6mg i. 6.v.012) and number of vertebral fractures (p=0. To date. single-dose study in 147 normocalcemic patients with metastatic bone disease due to breast cancer.2. significantly reduced urinary calcium excretion in a dose-dependent manner. Studies have evaluated Bondronat in metastatic bone disease both: ● as an i.v. clinical studies of Bondronat have been performed in patients with metastatic bone disease and various primary cancers including: ● breast cancer ● prostate cancer.0018) ● significant relief of bone pain with Bondronat 6mg maintained below baseline over duration of study (p<0. 22 . pyridinoline and deoxypyridinoline. In an open-label. .

Bondronat 6mg infused over 1 hour every day. ● Twenty-three patients (92%) achieved a significant reduction in bone pain (p<0. flu syndrome. prospective study.v. Whereas ECOG performance status is scored on a scale of 0 (fully active) to 5 (dead). no patients experienced injection site reactions or other systemic side effects (especially no renal toxicity) associated with treatment throughout all treatment periods. Of these patients. The frequency or type of AE did not significantly differ between the Bondronat and placebo groups.083) ● significant improvement in quality of life on the Quality of Life Scale (QLQ-C30)32 with Bondronat 6mg (p=0.34 Prior to enrolment the patients had undergone surgical castration or had been treated with luteinizing hormone releasing hormone (LHRH) analogs. Patients were treated with a regimen of intensive Bondronat therapy with a 3-day ‘saturation phase’ in which they received i. nausea and diarrhea which were reported in up to 6. Both scales evaluate performance status including the effects of disease on daily life and help determine prognosis. calcium levels and calcium excretion. Karnofsky performance scale is scored on 100% (no evidence of disease) to 0 (dead). there were improvements in both mean Karnofsky index and Eastern Cooperative Oncology Group (ECOG) performance status.3 Bondronat in patients with prostate cancer and painful metastatic bone disease The efficacy and safety of Bondronat i. . ● In parallel with the improvement in bone pain. nausea and vomiting. ● Treatment with Bondronat was well tolerated. . ● The onset of the analgesic effect of Bondronat was rapid with a mean onset of Day 3 (range 1–5 days).001) from baseline (visual analog score). 23 . fever.6% of patients in any treatment group. deoxypyridinoline. appetite.005) over 96 weeks33 ● improvement in symptoms including reduction in fatigue (p<0. Renal events were similar to placebo. Four patients (16%) reported fever on the day after the Bondronat infusion. The frequency or type of AE did not significantly differ between the Bondronat and placebo groups. The most common treatment-related AEs were asthenia. every 4 weeks or mitoxantrone/prednisolone 12mg/m2 every 3 weeks. . the use of a loading dose did not increase the risk of AEs. headache. in 25 patients with hormone-refractory prostate cancer and symptomatic bone metastases was evaluated in an open. The authors of this study are performing a larger prospective study in which men with hormone refractory prostate cancer and painful bone metastases will be randomized to either Bondronat 6mg i.● trend towards reduced analgesic consumption (p=0. bone pain.05). insomnia. nine became completely pain-free and 14 decreased their daily use of analgesics. the use of a loading dose did not increase the risk of AEs. 6. dyspnea and constipation over 96 weeks ● reduction in urinary markers of bone turnover including pyridinoline.v. Intravenous Bondronat 6mg was repeated monthly.v.

respectively). . Repeated administration reduced the dose of analgesics needed by all patients to treat bone pain.v. The results showed that.35 In contrast.4 A total of 198 infusions were administered over 24 months. bisphosphonates. Bondronat reduced the risk of an event by 38–40%.v.36 Estimates suggest that zoledronate reduces the risk of an event to a similar extent as Bondronat (~37% risk reduction). 6. pamidronate was associated with a risk reduction of 23%. This is supported by preclinical data showing no acute or accumulating renal toxicity issues with rapid dosing. administration (e. . This study suggests that the use of a rapid (30 minutes) Bondronat i.v. Bondronat reduced the risk of an event by 38–40%. to oral Bondronat when they return home from hospital. The Bondronat tablet will offer an alternative to the i. For example. prostate cancer (n=4) or multiple myeloma (n=10) with bone metastases.39 In patients with metastatic bone disease treatment-related gastrointestinal AEs were similar in the placebo and Bondronat 50mg p. oral and i. No adverse renal effects with Bondronat were reported. Oral convenience also lowers the burden on healthcare resources versus i. infused over 30 minutes every 3–4 weeks. Serum levels of creatinine and urea nitrogen did not significantly increase. groups (14.37 The choice of an oral therapy will allow patients to spend more time at home than in hospital/clinics especially after completion of chemotherapy. while i.v. a recent meta-analysis reported that oral clodronate reduced the risk of a skeletal event by 16%.v. the Bondronat tablet is small and easily administered once daily. investigated the safety and efficacy of Bondronat 4mg i.40 . Bondronat had a good efficacy and tolerability profile.38 is low with Bondronat.v.5 Introduction of oral Bondronat in the treatment of metastatic bone disease An oral formulation of Bondronat is under development. Bondronat [4mg i. when infused rapidly. nursing time. when infused rapidly. 24 .v. The incidence of gastrointestinal events. a problem commonly associated with oral bisphosphonates. .0% and 9. infusion is well tolerated and could be administered in the setting of a day care unit.v.v. occupancy of day beds). oral and i. and switch from i.6. formulation while delivering efficacy comparable to i. . .4%. infusions which can be painful and inconvenient.v. over 30 minutes] had a good efficacy and tolerability profile.o. Patients also will be able to avoid regular i.4 Short infusion time A study involving 30 patients with breast cancer (n=16).v. Unlike oral clodronate.g.

25 . mean± SEM) 600 500 400 300 200 100 0 0 7 *p<0. The settings in which Bondronat has been studied in are: ● patients with opioid-resistant pain ● treatment and prevention of postmenopausal osteoporosis (see separate monograph). Figure 7) and analgesic consumption (reflected in the morphine equivalent daily dose [MEDD]) after Bondronat infusion.41 These patients received Bondronat 4mg i.05.7. was performed in 18 patients with severe opioid-resistant pain and either breast cancer (10 patients) or other tumors (eight patients).v.05 21 Time (days) 42 0 7 21 Time (days) 42 Figure 7. 6-week study of Bondronat i. ● Bone resorption markers such as pyridinoline and deoxypyridinoline decreased up to Day 21 but then increased and returned to baseline levels at Day 42. More than 7. ● There was a rapid and significant decrease in both bone pain scores (p<0. (VAS=visual analog scale).v. Ongoing research with Bondronat® 7. were identified during these studies. in patients with opioid-resistant pain A preliminary open-label. 7 6 5 Pain (VAS) 4 3 2 1 0 * MEDD (mg. Effects on bone pain and MEDD with Bondronat.v. Bondronat has been investigated in other disease settings. No further AEs other than those already described in chapter 4.05). Its antitumor effect has also been evaluated.300 patients with metastatic bone disease. ● Quality of life was significantly improved from baseline with Bondronat administration (p<0.1 Introduction In addition to hypercalcemia of malignancy and metastatic bone disease. 7. over 2 hours daily for 4 days and were then followed for 6 weeks or until death.2 Bondronat i.000 patients have been treated with Bondronat in the clinical trial program including approximately 1.

5 Rapid infusion Shorter infusion times without monitoring requirements are more convenient for patients as they reduce the time patients spend in hospital receiving treatment. Further experience with a shorter Bondronat infusion time is provided by Syrigos et al.● Non-standard. 44 Clinical trials are also being conducted in patients with Paget’s disease. . this study suggests that Bondronat may be given as a rapid infusion. described in section 6. The use of a loading dose was not associated with an increased incidence of AEs.v. If these data are confirmed in the clinic. In vitro. 7. Further studies to investigate this are planned. with a 17% reduction in prostate weight. A more rapid infusion also eases the burden on healthcare resources. . these findings suggest that Bondronat may also prevent the formation of bone metastasis.42 As cell proliferation and angiogenesis are essential for the growth of metastases of solid tumors.000 patients to date. Four patients reported AEs: bone pain in two patients.4 26 . Although further studies are required to confirm the safety of repeated infusions of Bondronat 6mg over 15 minutes every 4 weeks. This study suggests that Bondronat provides beneficial analgesic effects in patients with opioid-resistant pain with either breast or other primary tumors. involving more than 9. reducing Bondronat infusion time from 60 minutes to 15 minutes increased the mean peak concentration (Cmax) from 300ng/mL to 400ng/mL without adversely affecting renal function. including the treatment and prevention of postmenopausal and secondary osteoporosis. renal safety/pharmacokinetic study was performed in healthy male and female volunteers (see section 3.3 Preclinical studies of the antitumor effect of Bondronat In addition to managing hypercalcemia and metastatic bone disease.42 7. Studies in vivo showed that Bondronat induced a 50% reduction of the revascularization of the prostate gland in castrated rats. was well tolerated in this study. There was no evidence of renal toxicity with Bondronat.28 In this study.5. a parallel-group. Rapid zoledronate infusion has been associated with acute renal failure. fever in one patient and flu-like symptoms in one patient. 7. This would provide greater convenience and flexibility for the patient. Bondronat provides beneficial analgesic effects in patients with opioid-resistant pain . Bondronat has been shown to inhibit endothelial cell functions in vitro and in vivo in animal models. Bondronat (10-4M) inhibits human umbilical vein endothelial cell proliferation and capillary-like tube formation.4 Studies in other indications The efficacy and safety of ibandronate is being studied in other disease areas.43. they suggest that Bondronat acts by regulating cell proliferation and angiogenesis. To determine whether Bondronat 6mg can be infused rapidly without compromising renal safety.5). intensive treatment with Bondronat i. In their study infusion of Bondronat over 30 minutes was well tolerated.

editors. Clinician’s guide to laboratory medicine. Br J Cancer 1997. Clinical manifestations of cancer-related hypercalcemia. In: Weatherall DJ. Semin Oncol 1990. 8):1564–71. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: a clue to the mechanism of action of nitrogen-containing bisphosphonates. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomised multicentric comparison to pamidronate. J Bone Miner Res 1999. Support Care Cancer. Dunn JA. Burtis WJ. Pecherstorfer M. Bajorunas DR. I. Pratt. Overview of bisphosphonates. Wetterwald M. Insogna KL. Pollock RE. Nephrogenous cyclic AMP. Bauss F. In press. Cancer: principles and practice of oncology. Rankin W. Kufe DW. et al. Semin Oncol 1990. 2. In Vivo 2002.. Berkow R. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Rogers MJ. 12. In: DeVita VT Jr. Rizzoli R. 11.113:1035–43. Beers MH. p. Godsall JW. 1636–9. 16. editors.6:1003–11. Van Beek E. Hypercalcaemic nephropathy. Oxford handbook of clinical medicine. 21):33–42. Holland JF. Semin Oncol 2002. Warrell DA. editors. Kim SZ. Thiebaud D. Treatment with ibandronate preserves bone in experimental tumour-induced bone loss. 6. Wilkinson I. p. Warrell DA. 4. Weichselbaum RR. monosodium salt monohydrate. Br J Haematol 2001. 24.17:26–33. Ralston SH.80(Suppl. Papapoulos S. Oxford Textbook of Medicine. Clézardin P. 5th ed. 3227–9. The antitumor potential of bisphosphonates. adenylate cyclase-stimulating activity. Ann Oncol. 19. Parathyroid hormone-related protein and hypercalcemia. Merck & Co. editors. Warrell RP Jr. Safety and efficacy of the new bisphosphonate ibandronate in the management of bone metastasis following rapid infusion. In press. 8. Kurth AH. Philadelphia. 9.19:18–54. Oxford handbook of clinical medicine. 7. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. J Bone Miner Res 1991. Pamidronate disodium in the treatment and management of hypercalcaemia. Ledingham JGG. BM21. MacLennan ICM. and the humoral hypercalcemia of malignancy. Martin TJ. Body JJ. 15. Hovy L. a potent new bisphosphonate to inhibit bone resorption. 14. The hypercalcemia of malignancy: pathogenesis and management. 20. 5. 18. 1996 p.0955.19:13–16. Endocrine disorders. Michalaki V. 27 . Muhlbauer RC. 23. 3rd ed. Cancer 1997. Mühlbauer RC.9:147–64. Kanis JA. 25. editors. placebo-controlled randomized trial of clodronate in multiple myeloma. Cancer medicine. Martin TJ. Grill V. Torok E. In: Bast RC. Hudson OH: Lexi-Comp 2000. Ledingham JGG. 10. In: Weatherall DJ. Kenan S. 3.17:16–25.31:1247–77. References 1. Merck manual of diagnosis and therapy. Oxford Textbook of Medicine. Mundy GR.16:361–4. 5th ed. Mitromaras A. Endocr Rev 1998. 1999. 17th ed. et al. 5th ed. Diel IJ.42:705–50. Watts RWE. Recent Prog Horm Res 1986. Van der Pluijm G. 13. editors. Kanis JA. Lowik C. Herrmann Z. Coleman RE. Ibandronate. Cancer 1997. Steinhauer EU. 201. Treatment of cancer-related hypercalcemia. 22.14:722–9. Bergstrom. Burs M. 2001. Drayson MT. et al. Desai SP. Longmore M. Reviews in Contemporary Pharmacotherapy 1998.29 (6 Suppl. Mundy GR. Rosenburg SA. Merck manual of diagnosis and therapy. Cancer and bone. 2486–93. Sedlmeyer I. c2000 (chap 145). 1997. Watts DJ. Ritch PS. et al. Russell RGG.8. double-blind. et al. Bauss F.. Lichinitser MR. 3rd ed. Skeletal complications.82:126–30. Bauss F. Oxford University Press Inc. 21. Metabolism 1982. Metabolic emergencies. Drugs Fut 1994. B.80 (Suppl. Hortabagyi GN. 1):1652–60. Hellman S. 17. J Bone Joint Surg Br 2000. 1996 p.75:295–300. Schenk R. Syrigos KN. Guise TA. McCloskey BV. Pa: Lippincott-Raven Publishers. Long-term follow-up of a prospective.

13(Suppl. 31 May – 3 June 2003. Seibel MJ. Bauss F. 38. Body JJ.(1):CD003474.14:268–76. 30. Bauss F. Pecherstorfer M.30 (Suppl. 39. Cancer Res 2002. Kanis J. et al. The kinetics of skeletal remodelling. Coleman RE. Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Coleman RE. 37. Stockler M. 1966. USA.26. Bergstrom B. 35. Rosen LS.85:365–75. Oral ibandronate significantly reduces fracture risk in postmenopausal osteoporosis when administered daily or with a unique drug-free interval: results from a pivotal phase III study. Short-term treatment with the bisphosphonate ibandronate for opioid-resistant metastatic bone pain. New York. Fournier P. randomised. Mancini I. Bergman B. Improved quality of life after long-term treatment with ibandronate in patients with metastatic bone disease due to breast cancer. Aaronson NK. Body JJ. Association between histomorphometry and biochemical markers of bone turnover in a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis.26:475–83. Clin Breast Cancer 2002. Cochrane Database Syst Rev 2002. Body JJ. 3):51 (abstract B56). Gordon D. Recker R. Bisphosphonates for breast cancer. 39th ASCO Annual Meeting. Filleur S. In: Structural organisation of the skeleton. Johnson LC. USA. 1):S15 (Abstract O37). et al. Body JJ. Body JJ. Purohit OP. Zoledronic acid (4mg) significantly reduces the relative risk of developing a skeletal-related event compared with pamidronate (90mg) in patients with breast cancer and bone metastasis [abstract no. San Antonio. Neugebauer G. for the Bondronat Study Group. Osteoporosis Int 2002.25:19–34. Black C. 32. Chicago. Pavlakis N. Woitge HW. et al. Ann Oncol 1999. Schimmer R. 43. Tripathy D. Juraschek M. Effect of daily and intermittent use of ibandronate on bone mass and bone turnover in postmenopausal osteoporosis: a review of three phase II studies. Diel I. Texas. Presented at the 25th San Antonio Breast Cancer Symposium. Krempien B. Akinkunmi L. 40. et al. 44. J Natl Cancer Inst 1993. J Clin Oncol 1996. Delmas P. Banken L. Presented at the 39th ASCO Annual Meeting. Proc Am Soc Clin Oncol 2001. dose-finding study of oral ibandronate in patients with metastatic bone disease.5:231–5.3:206–16.28(Suppl. Illinois. Oral daily ibandronate in women with metastatic breast cancer: a pooled safety analysis. Diel I. Chicago. 29. Bisphosphonates: Biological response modifiers in breast cancer. Lichinitser MR. Elert A. Kletzl H. Prostate Cancer Prostatic Dis 2002.62:6538–44. placebo-controlled. 41. The European Organization for Research and Treatment of Cancer QLQ-C30: A quality of life instrument for use in international clinical trials in oncology. et al. Ahmedzai S. et al. Diel IJ. Boissier S. Bergstrom B. Köhler W. Paterson AHG. Hofmann R. Double-blind. 31. Herrmann Z. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. 28 . Toth C. Dosing regimens and main adverse events of bisphosphonates. Bisphoshonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. 355]. 11–14 December 2002. Duman JC. Illinois.v. USA. 28. Risk reductions in metastatic breast cancer: multivariate Poisson regression analyses of oral and i. Bone 2002. Bone 2000. 36.20:122a (abstract 486). Body JJ. Roche – data on file. 31 May – 3 June 2003. 11):49–53. Pinner J. 33. ibandronate. National Foundation. Clin Ther 2003. Stakkestad JA. et al. Semin Oncol 2001. J Clin Oncol submitted.10:311–16. 27. 42. Influence of peak ibandronic acid concentrations after 6mg iv administration with shortened infusion time (15 and 30 minutes) on renal safety in man [abstract]. 34. Heidenreich A.