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.
JM0520

Product Monograph
Hypercalcemia of Malignancy

Contents

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 (0.6mg2mg) 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

6. Bondronat in metastatic bone disease

6.1 Introduction 6.2 Bondronat in patients with breast cancer and metastatic bone disease 6.3 Bondronat in patients with prostate cancer and painful metastatic bone disease 6.4 Short infusion time 6.5 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. Ongoing research with Bondronat

7.1 Introduction 7.2 Bondronat i.v. in patients with opioid-resistant pain 7.3 Preclinical studies of the antitumor effect of Bondronat 7.4 Studies in other indications 7.5 Rapid infusion

8. References

1. Executive summary

This monograph focuses on the treatment of hypercalcemia of malignancy with Bondronat. It provides a brief overview of the epidemiology, diagnosis, etiology and current approaches to management of hypercalcemia of malignancy. The chemistry, pharmacology and pharmacokinetics of Bondronat are also reviewed and the results of clinical trials with Bondronat in hypercalcemia of malignancy are presented. Finally, the monograph focuses on administration of Bondronat and briefly looks at the ongoing clinical development of Bondronat in other indications. Bondronat is effective for the treatment of hypercalcemia of malignancy: Bondronat i.v. rapidly reduces elevated serum calcium levels1 more than 75% of patients achieved normocalcemia with Bondronat 4mg1,2 normocalcemia is maintained for a mean of 14 days compared with pamidronate (4 days).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.1 Bondronat is given by i.v. infusion over 2 hours; recent studies suggest that a bolus injection (2mg dose)3 or 30-minute infusion (4mg dose)4 are well tolerated. Shorter administration times are expected to be beneficial to healthcare providers and patients by improving dosing convenience and reducing associated nursing care costs. This monograph focuses on the use of i.v. Bondronat in patients with hypercalcemia of malignancy. Further data on the use of Bondronat 50mg oral and 6mg i.v. in metastatic bone disease will be available in early 2004.

2. Disease overview: hypercalcemia of malignancy

2.1 Definition
Hypercalcemia can be life-threatening . . . Hypercalcemia of malignancy is defined as elevated serum calcium in patients with cancer either with or without metastatic bone disease. Hypercalcemia can be life-threatening; as calcium levels increase, irregular heartbeats may develop and may lead to cardiac arrest. Most laboratories define normal serum calcium as 2.122.57mmol/L (8.510.3mg/dL).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.6,7 Hypercalcemia is therefore defined as serum calcium levels above the normal upper range. The degree of severity of hypercalcemia is commonly divided into three categories: mild, moderate, and severe (Table1).5,8,9

Table 1. Severity of hypercalcemia of malignancy.

Stage Normal Mild Moderate Severe Serum calcium (mmol/L) 2.12.57 <2.8 2.83.3 >3.3 Serum calcium (mg/dL) 8.510.3 <12 1214 >14

2.2 Pathology and presentation

Hypercalcemia can occur in patients with or without bone metastases. Most often there is widespread bone destruction due to metastases in patients with hypercalcemia of malignancy.10 In patients with hypercalcemia there is increased bone resorption, which releases calcium, resulting in elevation of serum calcium levels. Impaired renal clearance of circulating calcium also occurs, associated with increased renal tubular resorption of calcium, further elevating serum calcium levels (see section 2.5).

2.3 Epidemiology
Up to 40% of all patients with cancer will develop hypercalcemia . . . Hypercalcemia is the most common life-threatening complication in patients with cancer. In hospitalized patients who develop hypercalcemia, or complications of hypercalcemia such as hypercalcemic nephropathy, the majority have a malignancy. 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.11,12 The development of hypercalcemia is usually an indicator of poor prognosis and short life expectancy. Risk factors for hypercalcemia of malignancy include tumor site (e.g. lung and breast), sex (increased risk in women) and malignancy duration.

2.4 Prevalence by tumor type

Hypercalcemia occurs more frequently in patients with certain types of tumor. It is most common in patients with breast cancer, squamous cell lung cancer and multiple myeloma (Table 2).

Table 2. Most common causes of hypercalcemia in malignant disease.13

Tumor site Lung Breast Hematologic malignancies (myeloma, lymphoma) Head and neck Renal Prostate Unknown primary Other Frequency (%) 35 25 14 6 3 3 7 7

2.5 Etiology and physiologic fundamentals

2.5.1 Normal calcium and bone homeostasis Most of the calcium in the body is found in the bones. Therefore, the pathogenesis of hypercalcemia is linked to regulation of bone metabolism as well as calcium metabolism. Bone is a unique tissue that is affected by cancer since it is a tissue that is normally continuously undergoing remodeling. This process of remodeling is regulated by both systemic hormones (e.g. parathyroid hormone [PTH], calcitonin and calcitrol [or 1,25-(OH)2D3], PTH-related peptide [PTHrP]) and local growth factors that are released by bone (e.g. transforming growth factor-beta [TGF-], interleukin-6 [IL-6], tumor necrosis factor [TNF], insulin-like growth factor I [IGF-I] and IGF-II). In healthy individuals, resorption of bone and formation of new bone occurs continuously, and is mediated by osteoclasts (involved in resorption) and osteoblasts (involved in new bone formation). 2.5.2 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. Humoral factors secreted by tumors which act on bone, kidney and intestine to disrupt calcium homeostasis 2. Local factors secreted by bone metastases acting directly on the osteoclasts 3. Coexisting primary hyperparathyroidism. 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

. . . the pathogenesis of hypercalcemia is linked to regulation of bone metabolism as well as calcium metabolism.

act both as humoral and local mediators. However, some authors consider that altered humoral regulation of calcium is the most common mechanism occurring in up to 80% of cases of hypercalcemia15,16 with local osteolytic hypercalcemia occurring in up to 30% of cases. 2.5.3 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.17 Local inflammatory factors are osteolytic and stimulate osteoclasts to resorb and destroy bone, thus releasing calcium, leading to hypercalcemia. 2.5.4 Humoral hypercalcemia This mechanism may predominate in most patients who have less severe hypercalcemia. Hypercalcemia occurs when the normal process of bone resorption and bone formation is uncoupled and bone resorption predominates. In contrast, in metastatic prostate cancer the lesions are predominantly osteoblastic resulting in increased bone formation and, therefore, hypercalcemia is less common in these patients.

2.6 Symptoms and clinical manifestations

Patients with mild or moderately elevated serum calcium levels may have few or no symptoms. Hypercalcemic symptoms may be non-specific and accompanied by an increased pain threshold. The extent and type of symptoms parallels the severity of hypercalcemia9 and also the rate at which serum calcium levels increase (Table 3).14

Table 3. Symptoms of hypercalcemia according to body system.

Body system Gastrointestinal CNS Renal Cardiovascular Other Symptoms Anorexia, vomiting, nausea, constipation, muscle weakness Mental confusion, lethargy, stupor, coma Impaired renal function, polyuria and polydipsia (in early/mild stages), oligosuria, uremia (in later stages) Cardiac arrest, electrocardiogram changes Weight loss, dehydration, corneal calcification, pyrexia

2.7. Therapeutic management of hypercalcemia

In managing hypercalcemia of malignancy, it is important to treat the underlying tumor since factors released by tumor cells and metastases can cause the hypercalcemia. Further action is also required to normalize calcium levels, stabilize the metabolic state and treat the symptoms associated with hypercalcemia of malignancy, including:

rehydration therapy improvement of renal calcium excretion prevention of calcium uptake from the intestine reduction of bone resorption supportive measures (e.g. mobilization, diet).

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.11

The approach to treatment of hypercalcemia depends on the severity and duration of the disease, and the patients clinical condition.11 Therapy to manage symptoms and to stabilize metabolic status is sufficient for symptomatic patients with mild hypercalcemia of malignancy. Symptoms generally dictate the level of treatment for patients with moderate hypercalcemia, whereas patients with severe hypercalcemia require immediate and aggressive intervention (Table 4).18

Table 4. Therapeutic measures for patients with mild, moderate and severe hypercalcemia.
Moderate (33.5mmol/L or 1214mg/dL ) Mild hypercalcemia (<3mmol/L or <12mg/dL ) Rehydration Stabilize the metabolic state Supportive measures for: nausea and vomiting mobilization febrile episodes to severe (>3.5mmol/L or >14mg/dL) hypercalcemia Rehydration Correct renal calcium clearance once rehydrated loop diuretics e.g. furosemide (frusemide) Anticalcemic therapies bisphosphonates e.g. Bondronat

2.8 Role of bisphosphonates

Bisphosphonates are well established as the standard treatment for controlling hypercalcemia of malignancy. These agents inhibit bone resorption by modulating osteoclast activity and recruitment, decreasing serum calcium levels.19 Bisphosphonates may also inhibit tumor development.20 In general, bisphosphonates are administered in conjunction with rehydration and loop diuretics, most typically in patients with moderate to severe hypercalcemia.8 Between 70 and 90% of patients achieve normocalcemia with i.v. bisphosphonate treatment ameliorating symptoms and improving their quality of life.21 Bisphosphonates are . . . the standard treatment for controlling hypercalcemia of malignancy.

3. Bondronat: product description

3.1 Chemical structure

Bondronat [is] one of the most potent inhibitors of osteoclastic activity . . . Ibandronate (Bondronat) is a third-generation bisphosphonate with a hydroxyl group at the R position, and methyl and pentyl substituents at the nitrogen atom at R (Figure 1). It is this latter side chain that makes Bondronat one of the most potent inhibitors of osteoclastic activity in clinical use.22,23

CH3

O
OH

N
H 3C

P
O Na+ H2O

P O
OH
Figure 1. Chemical structure of ibandronate (Bondronat).

OH OH

3.2 Mechanism of therapeutic effect

Bondronat reduces serum calcium in patients with hypercalcemia of malignancy. 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 function22,23 reducing tumor growth by apoptosis24 reducing tumor adhesion to bone.23 Bondronat regulates osteoclast action by inducing osteoclast apoptosis. Primarily, Bondronat regulates osteoclast action by inducing osteoclast apoptosis. Bondronat preferentially binds to resorption surfaces of bone, probably due to the high calcium concentrations. When taken up by osteoclasts, Bondronat instigates osteoclast apoptosis by inhibiting farnesyl pyrophosphate synthetase in the mevalonate metabolic pathway and the prenylation of proteins.24 As a result of these actions, Bondronat reduces the excessive destruction and resorption of bone, causing calcium efflux to decrease. The reduction in calcium causes PTH levels to increase, leading to a decrease in serum phosphate levels due to decreased renal tubular resorption.

3.3 Preclinical pharmacology

Bondronat has been evaluated in animal models of tumor-induced hypercalcemia. Preclinical models show that Bondronat: dose-dependently inhibits the development of hypercalcemia reduces serum calcium for 2 weeks after a single dose i.v. administration is equivalent to subcutaneous administration Bondronat is more potent than risedronate, aldendronate, pamidronate and clodronate (2-, 10-, 50- and 500-fold, respectively).

3.3.1 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. In this model Bondronat both prevented this deterioration and increased bone mineral density.25 3.3.2 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. Bondronat prevents the development of these changes associated with the tumor.26 3.3.3 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, peripheral nervous system, cardiovascular system, respiratory system or gastrointestinal system.27 3.3.4 Relative potency of bisphosphonates In preclinical studies, Bondronat prevents bone resorption to a similar extent as other bisphosphonates (Figure 2), but at considerably lower doses both in vitro and in vivo in animal models. This supports Bondronat administration at doses lower than those of most other bisphosphonates allowing more practical oral dosing and shorter intravenous administration times. . . . no clinically significant renal

3.4 i.v. administration

Hypercalcemia is frequently a medical emergency, therefore, serum calcium levels must be rapidly reduced. In these patients i.v. administration of Bondronat quickly and effectively reduces hypercalcemia. Unlike some other bisphosphonates, no clinically significant renal toxicity or infusion site reactions have been reported with Bondronat bolus injection or i.v. infusion.27

toxicity or infusion site reactions have been reported with Bondronat bolus injection or i.v. infusion.

104 Relative potency in vitro IC50 Zoledronate 103 Bondronat Risedronate 102 Clodronate 101 Dimethyl-APD Alendronate

Pamidronate Neridronate

100 10
Figure 2. Relative potencies of Bondronat and other bisphosphonates.
0

Etidronate 101 102 103 104 Relative potency in vivo (rat) ED50 105

3.5 Pharmacokinetics
The pharmacokinetics of Bondronat have been studied extensively following i.v. administration in healthy volunteers (Table 5).27,28

Table 5. Pharmacokinetic parameters after i.v. administration of Bondronat 6mg to healthy volunteers (Study BP16145).30
Infusion time Parameter AUC (hng/mL) Cmax (ng/mL) t1/2(h) CL (mL/min) Vz (L) CLr (mL/min) fe (% dose)

60 minutes (n=19) 787128 30844.8 10.61.1 13018.3 11817.7 70.614.4 51.67.30

30 minutes (n=20) 73084.4 38441.3 12.12.3 13916.6 14742.6 78.911.0 53.84.84

15 minutes (n=18) 643104 39794.5 10.32.0 16026.7 14132.1 88.224.0 52.310.3

MeanSD

AUC = area under the curve extrapolated to innity Cmax = maximum plasma concentration t1/2 = half life CL = clearance rate Vz = volume of distribution CLr = renal clearance fe = fraction excreted

10

The pharmacokinetics of Bondronat are linear after i.v. administration (dose range 0.56mg). Serum concentrations are proportional to dose and fall rapidly in a multi-exponential manner. As expected, the infusion rate affects the pharmacokinetic profile of Bondronat, but without changing the AE profile (Table 5). A shorter infusion time of Bondronat 6mg in healthy individuals over 15 minutes, in comparison to 30 and 60 minutes, increased the maximum plasma concentration (Cmax) and clearance rate (CL) and reduced the area under the curve extrapolated to infinity (AUC). In contrast, the volume of distribution (Vz), half life (t1/2), renal clearance (CLr), and fraction excreted (fe) were similar. The incidence of renal adverse events was similar with the shorter infusion time (indicated by unchanged serum creatinine, creatinine clearance and markers of tubular or glomerular damage). Bondronat can be administered at a lower dose than many other bisphosphonates (due to its greater potency). For example, the dose of pamidronate used to restore normocalcemia ranges from 30 to 90mg, whereas 2mg or 4mg Bondronat is given depending on the baseline calcium level.2 3.5.1 Distribution In human plasma, 85% of Bondronat is protein bound at therapeutic concentrations. The plasma half-life of Bondronat is relatively short due to rapid uptake in the bone.29 Preclinical studies have shown that Bondronat is widely distributed throughout the body, primarily in the bone (4050% of the circulating dose), with small amounts having been recovered in the spleen, liver and kidney.27 At the bone surface, Bondronat principally binds to calcium binding sites, particularly at sites of bone resorption. As the surface to volume ratio of cancellous bone is 10-fold greater than that of cortical bone,30 uptake is expected to be proportionally higher in cancellous bone. Within the skeleton, the t1/2 of bisphosphonates is long (months to years depending on the rate of bone turnover).29 3.5.2 Metabolism Bondronat is not metabolized in humans or animals. No affinity for cytochrome P450 isoenzyme specific substrates is expressed by Bondronat at clinically relevant concentrations. 3.5.3 Elimination The kidneys excrete almost 5060% of circulating Bondronat into the urine by glomerular filtration and a specialized secretary pathway. 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.27 In healthy individuals, circulating Bondronat has a renal clearance of approximately 60100mL/min, with half of the absorbed oral dose being found in the urine within 24 hours. Renal clearance is directly related to creatinine clearance, and therefore declines in patients with intrinsic renal disease when renal function is impaired. 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. Please see prescribing information for dosing recommendations.

Bondronat can be infused quickly as a bolus injection or 15-minute infusion . . . without adverse renal effects.

11

3.6 Clinical pharmacology studies in populations of special interest

In addition to studies in healthy volunteers described above, the effect of gender, race, renal impairment and metastatic bone disease on the pharmacokinetic profile of Bondronat has been studied. 3.6.1 Gender and race The bioavailability and pharmacokinetic profile of Bondronat is similar in both men and women.27 No clinically relevant interethnic differences were detected between Asian and Caucasian subjects.27 3.6.2 Patients with renal impairment The effect of renal impairment on the pharmacokinetics of Bondronat has been investigated (Study MF 7148). Both oral and i.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. A linear relationship was observed between Bondronat renal clearance and creatinine clearance (Figure 3).27 In subjects with end-stage renal disease, Bondronat can be dialyzed. Approximately 37% of the administered dose is removed during a 4-hour hemodialysis (Study MF 7168).27

140 120 100 CLr (mL/min) 80 60 40 20 0

Figure 3. Relationship between Bondronat renal clearance (CLr) and creatinine clearance (CLcr) (Study MF 7148).29

CLcr <30 CLcr 4070 CLcr >90 r2=0.771

20

40

60

80

100

120

140

CLcr (mL/min)

3.6.3. 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

12

There is limited experience with Bondronat in patients with hypercalcemia of malignancy and severe renal impairment (serum creatinine 5mg/dL or >442mol/L), therefore it is advised that Bondronat is only given if the benefits outweigh the risks. 3.6.4 Patients with hepatic impairment Bondronat has not been investigated in patients with hepatic impairment. However, as the liver has no significant role in the metabolism of Bondronat, dose adjustment should not be necessary in patients with hepatic impairment.

3.7 Drug interactions

Due to the lack of metabolism and renal route of elimination of Bondronat, clinically significant pharmacokinetic drug interactions have not been shown and are considered unlikely: In-vitro studies indicate that drugdrug interactions through biotransformation by cytochrome P450 are unlikely as Bondronat is not metabolized by the liver. Drug interaction studies have been performed with reference drugs which may be administered in conjunction with Bondronat and no meaningful interactions were observed.27 These included: H2 antagonists (ranitidine) hormone replacement therapy (estrogen) tamoxifen melphalan/prednisolone. . . . clinically significant pharmacokinetic drug interactions [with Bondronat] have not been shown and are considered unlikely.

13

Clinical efficacy and safety: experience in 4. hypercalcemia of malignancy

4.1 Introduction
This section focuses on clinical trials investigating the efficacy and safety of Bondronat in the treatment of hypercalcemia of malignancy. 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. The efficacy and safety of Bondronat has been studied in clinical trials involving more than 500 patients with hypercalcemia of malignancy (Table 6).

Table 6. Studies with Bondronat i.v. in the treatment of hypercalcemia of malignancy.

No. of Study MF 4104 Phase I patients 36 Design Open, multicenter pilot study to investigate the efficacy and tolerance of a single i.v. dose of Bondronat Open, randomized, multicenter dose-finding study to evaluate efficacy and safety of a single infusion of Bondronat Double-blind, randomized, multicenter dose-finding study to evaluate efficacy and safety of a single infusion of Bondronat Open, multicenter study to describe the safety of a single administration of Bondronat Multicenter, single dose, open, randomized, controlled study over 4 weeks on the efficacy and safety of Bondronat (2mg and 4mg) versus pamidronate (15mg, 30mg, 60mg and 90mg) Dose regimen (mg) Single infusion of 0.22.0mg i.v. in steps of 0.2mg

MF 4223

II

174

Single infusion of 0.6mg, 1.1mg or 2mg i.v.

MF 4302

II

147

Single infusion of 2mg, 4mg or 6mg i.v.

MF 4442

IV

124

Single infusion of 2mg or 4mg i.v.

MF 4490

II

72

Single infusion of of Bondronat 2mg or 4mg i.v or of pamidronate 15mg, 30mg, 60mg or 90mg i.v.

4.2 Pilot study (Study MF 4104)

The efficacy and tolerability of a single infusion of Bondronat (0.22.0mg in 0.2mg steps i.v.) was investigated in an open, multicenter phase I pilot study involving 36 patients with tumor-induced hypercalcemia.

14

4.2.1 Efficacy The minimum dose required to achieve normocalcemia was 0.8mg. Among all patients who achieved normocalcemia (2.65mmol/L/10.6mg/dL), the time to the first normal value ranged from 1 to 7 days, and the duration of response ranged from 0 to 23 days.29 4.2.2 Tolerability None of the adverse events (AEs) reported were dose dependent. Malignancy progression was the most common AE.27

4.3 Dose-finding study (0.6mg2mg) by single i.v. infusion (Study MF 4223)

The efficacy and safety of a single infusion of Bondronat (0.6mg, 1.1mg or 2mg i.v. over 2 hours), was evaluated in a phase II, open, randomized, multicenter study involving 174 patients with cancer, and serum calcium levels >2.7mmol/L (>10.8mg/dL).31 Patients were considered to have responded when they became normocalcemic. 4.3.1 Efficacy Bondronat dose-dependently reduced serum calcium (Figure 4). Response rates of 44%, 52% and 67% were achieved for patients receiving Bondronat 0.6mg, 1.1mg and 2mg, respectively. The response to Bondronat negatively correlated with the initial serum calcium level. The median time-to-relapse of hypercalcemia was 11 days, 17 days and 12 days for the 0.6mg, 1.1mg and 2mg groups, respectively.31 Response rates of 44%, 52% and 67% were achieved for patients receiving Bondronat 0.6mg, 1.1mg and 2mg, respectively.

80 * Patients normalized (%) 60

40

20

0 0.6
*p=0.028 vs 0.6mg

1.1 Bondronat dose (mg)

2
Figure 4. Bondronat normalizes serum calcium levels in a dose-dependent manner.31

4.3.2 Safety There were 195 AEs of which 99 were considered serious and 96 non-serious. There was an equal distribution of non-serious AEs between the groups. More serious AEs

15

Because the overall incidence of AEs was low, regardless of dose, this enabled further dose escalation studies to be performed.

were observed in patients receiving Bondronat 1.1mg than those receiving 0.6mg or 2.0mg. Only three serious AEs and 16 non-serious AEs were considered to be related to treatment with Bondronat (Table 7). Bondronat did not adversely affect renal function.31 Because the overall incidence of AEs was low, regardless of dose, this enabled further dose escalation studies to be performed.

Table 7. Serious and non-serious AEs possibly related to Bondronat treatment.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)

4.4 Dose-response study in cancer-associated hypercalcemia (Study MF 4302)

The efficacy and safety of Bondronat (2mg, 4mg and 6mg) i.v. was evaluated in a phase II, multicenter, double-blind, randomized, dose-finding study involving 147 patients with cancer-associated hypercalcemia resistant to rehydration alone.1 Of these patients, 131 patients were eligible for evaluation. 4.4.1 Efficacy Serum calcium levels decreased from Day 2 with Bondronat, reaching a nadir by Day 5. Some patients maintained normocalcemia for up to 36 days (Figure 5).1 Bondronat showed a dose-dependent effect up to 4mg. The Bondronat 4mg and 6mg doses were significantly more effective than the 2mg dose in correcting hypercalcemia (p<0.05), with 50% of patients in the 2mg group achieving serum calcium levels below 2.7mmol/L (10.8mg/dL) compared with 75.6% in the 4mg group and 77.5% in the 6mg group (Figure 6).1 Bondronat therefore, 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.1 4.4.2 Safety There was no significant difference between the three treatment groups in the number or type of recorded AEs.1 The incidence of AEs with Bondronat was not dose-dependent. Among patients who received Bondronat 2mg there were 133 AEs reported compared with 117 AEs among patients on 4mg and 104 AEs on 6mg. No injection site reactions were reported.1 Fever was observed in 21.6% of patients.

16

3.80 Serum calcium (mmol/L) 3.60 3.40 3.20 3.00 2.80 2.60 2.40 0 * **

2mg 4mg 6mg

**

** **

**

**

**

**

**

4 5 6 7 Days after infusion

10

14

21

28
Figure 5. Effect of Bondronat infusion on serum calcium levels by time. (Reproduced from Ralston et al. 1997).1

*p<0.05; **p<0.01, signicant change from Day 0 p<0.05, signicant difference between 2mg vs 4mg and 6mg group upper limit of normal for adjusted calcium (2.7mmol/L)

80

Patients normalized (%)

60

40

20

0 2
*p0.05 vs 2mg Bondronat

4 Bondronat dose (mg)

Figure 6. Patients (%) achieving normocalcemia (<2.7mmol/L or <10.8mg/dL) according to Bondronat dose. (Reproduced from Ralston et al. 1997).1

This was considered to be possibly related to Bondronat in 12.9% of cases, but was not dose dependent.1 Hypocalcemia was reported in two patients receiving Bondronat 4mg and four patients receiving Bondronat 6mg. No renal events were reported.

17

4.5 Safety of a single dose infusion of Bondronat 2mg or 4mg i.v. (Study MF 4442)
The safety of a single i.v. infusion of Bondronat 2mg or 4mg was evaluated in 124 patients with hypercalcemia of malignancy in a phase IV post-marketing surveillance study. A total of 43 patients with serum calcium levels between >2.7mmol/L (>10.8mg/dL) and <3.0mmol/L (<12mg/dL) received Bondronat 2mg, and 81 patients with serum calcium 3.0mmol/L (12mg/dL) were given Bondronat 4mg.27 4.5.1 Efficacy Serum calcium levels were normalized in 85.4% and 74.7% of patients receiving Bondronat 2mg and 4mg, respectively. The difference in response rate may have been due to the higher baseline calcium levels in the 4mg group. The response rate was lower (67%) for a subgroup of patients with baseline calcium values >3.5mmol/L (>14mg/dL) who received Bondronat 4mg.27 4.5.2 Safety Both doses were well tolerated.29 The incidence of AEs was similar for patients receiving Bondronat 2mg (83.7%) and 4mg (88.9%). No renal events were reported. None of the serious AEs were considered to be treatment related.

Serum calcium levels were normalized in 85.4% and 74.7% of patients receiving Bondronat 2mg and 4mg, respectively.

4.6 Comparison with pamidronate (Study MF 4490)

The efficacy and safety of Bondronat was compared with pamidronate in a phase II, open-label, multicenter, stratified, randomized trial involving 72 patients with hypercalcemia of malignancy (albumin-corrected serum calcium >2.7mmol/L [10.8mg/dL]). Patients received either a single infusion of Bondronat (2mg or 4mg) i.v. or pamidronate (15mg, 30mg, 60mg or 90mg) on Day 0. The dose was determined by the severity of hypercalcemia: the most frequently administered dose of Bondronat was 4.0mg (78.4%) and of pamidronate was 60mg (50.0%).2 4.6.1 Efficacy The reduction in serum calcium levels on Day 4 was similar with Bondronat (0.6mmol/L [2.4mg/dL]) and pamidronate (0.41mmol/L [1.64mg/dL]). Overall 76.5% of patients receiving Bondronat and 75.8% receiving pamidronate responded to treatment. The median time to relapse was significantly longer for Bondronat (14 days) than pamidronate (4 days) (p=0.03). 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. In the per protocol population, Bondronat was significantly more effective than pamidronate for patients who had high baseline serum calcium levels (p<0.05, Table 8).2 In both the subgroups of patients with baseline calcium levels of 3.54.0mmol/L and 4.0mmol/L the fall in serum calcium levels was significantly greater with Bondronat at Day 4 than in patients treated with pamidronate. These results indicate that Bondronat is as effective as pamidronate in the treatment of hypercalcemia of malignancy, with potential for added benefits.

Bondronat was significantly more effective than pamidronate for patients who had high baseline serum calcium levels.

18

Table 8. Reduction in serum calcium levels on Day 4 following Bondronat or pamidronate treatment presented according to baseline serum calcium levels (per protocol analysis).
Baseline serum calcium 3.5<4.0mmol/L (14<16mg/dL) Bondronat 1.43mmol/L (5.72mg/dL) Pamidronate 0.65mmol/L (2.6mg/dL) Baseline serum calcium 4.0 mmol/L (16mg/dL) Between treatment difference

1.56mmol/L (6.24 mg/dL) p=0.03 0.77mmol/L (3.08mg/dL) p=0.046

4.6.2 Safety The safety profiles were similar for Bondronat and pamidronate (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. No renal AEs occurred in patients taking Bondronat whereas one patient in the pamidronate group had kidney failure.2

No renal AEs occurred in patients taking Bondronat . . .

Table 9. AEs with possible/probable causal relationship to the study medication.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.

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

5. Clinical use of Bondronat

5.1 Indications
This monograph focuses on the Bondronat indication for hypercalcemia of malignancy with or without accompanying bone metastases.

5.2 Dosage and administration

Bondronat is available as an i.v. formulation for the treatment of hypercalcemia of malignancy. Bondronat is also awaiting regulatory approval as both 6mg i.v. and 50mg tablet forms for the treatment of metastatic bone disease in patients with breast cancer. For availability in your country, please contact your local Roche representative. 5.2.1 Recommended dose The recommended dose of Bondronat i.v. for patients with hypercalcemia of malignancy is 2mg or 4mg, depending on the baseline serum calcium levels. Albumin-corrected serum calcium concentrations (total serum calcium, less total serum albumin) can be used to determine the dose and to assess the response to Bondronat. 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

5.2.2 Duration of administration In the treatment of hypercalcemia of malignancy Bondronat is licensed for infusion over 2 hours. However, 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.3,4 5.2.3 Administration Care must be taken to ensure Bondronat is administered intravenously, as intra-arterial and paravenous administration can lead to tissue damage. Bondronat is infused after dilution in either 500mL of isotonic sodium chloride solution or 500mL of 5% dextrose solution. 5.2.4 Further therapeutic considerations When using Bondronat for hypercalcemia, additional therapeutic factors should be taken into consideration: Patients should be adequately hydrated with 0.9% saline solution before the initiation of Bondronat therapy, and must remain so over the course of treatment. Over-hydration should be avoided, particularly for patients with cardiovascular disease. Patients should not receive diuretics until sufficient hydration has been achieved.

20

5.3 Use in special patient populations

There is no need to adjust the dose of Bondronat in elderly patients, or according to race or gender. Renal function and levels of serum calcium, 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. There are no clinical data available for the use of Bondronat in patients with severe hepatic insufficiency, therefore no dose recommendations can be made. There is no clinical experience with Bondronat in children.

21

6. Bondronat in metastatic bone disease

6.1 Introduction
Bondronat is being studied in patients with metastatic bone disease in addition to the existing use in hypercalcemia of malignancy. To date, clinical studies of Bondronat have been performed in patients with metastatic bone disease and various primary cancers including: breast cancer prostate cancer. Studies have evaluated Bondronat in metastatic bone disease both: as an i.v. infusion (predominantly as a standard 12 hour infusion but a few studies have been performed with 15- and 30-minute bolus injections) as an oral tablet. . . . Bondronat has not been shown to have marked renal toxicity. It is anticipated that shorter infusion times (1530 minutes) will be well tolerated since Bondronat has not been shown to have marked renal toxicity. Further data on oral Bondronat will be presented in a metastatic bone disease monograph in early 2004.

6.2 Bondronat in patients with breast cancer and metastatic bone disease
6.2.1 Phase II dose-finding study (Study MF 4328) One dose-finding study was performed to determine the efficacy and safety of Bondronat i.v. treatment of metastatic bone disease due to breast cancer. In an open-label, multicenter, phase II, single-dose study in 147 normocalcemic patients with metastatic bone disease due to breast cancer, Bondronat i.v. significantly reduced urinary calcium excretion in a dose-dependent manner. Serum calcium and phosphate decreased, in addition to the bone resorption markers, urinary hydroxyproline, pyridinoline and deoxypyridinoline. 6.2.2 Phase III: efficacy and safety of Bondronat i.v. in breast cancer patients with metastatic bone disease (Study MF 4265) The efficacy and safety of Bondronat (2mg and 6mg i.v. every 34 weeks to a total of 24 doses over 2 years) was evaluated in a phase III, multicenter, double-blind, placebo-controlled, parallel group, randomized study involving 466 women with breast cancer and bone metastases.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=0.004) significant reduction in mean number of bone events requiring radiotherapy (p=0.012) and number of vertebral fractures (p=0.023) significant reduction in the proportion of patients with new bone events (p=0.032) significant increase in time to first new bone event on Bondronat 6mg (p=0.0018) significant relief of bone pain with Bondronat 6mg maintained below baseline over duration of study (p<0.001)

Bondronat 6mg significantly reduces the bone events and pain associated with bone metastases.

22

 trend towards reduced analgesic consumption (p=0.083) significant improvement in quality of life on the Quality of Life Scale (QLQ-C30)32 with Bondronat 6mg (p=0.005) over 96 weeks33 improvement in symptoms including reduction in fatigue (p<0.05), appetite, nausea and vomiting, insomnia, dyspnea and constipation over 96 weeks reduction in urinary markers of bone turnover including pyridinoline, deoxypyridinoline, calcium levels and calcium excretion. The frequency or type of AE did not significantly differ between the Bondronat and placebo groups. The most common treatment-related AEs were asthenia, fever, flu syndrome, bone pain, headache, nausea and diarrhea which were reported in up to 6.6% of patients in any treatment group. Renal events were similar to placebo.

The frequency or type of AE did not significantly differ between the Bondronat and placebo groups.

6.3 Bondronat in patients with prostate cancer and painful metastatic bone disease
The efficacy and safety of Bondronat i.v. in 25 patients with hormone-refractory prostate cancer and symptomatic bone metastases was evaluated in an open, prospective study.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.v. Bondronat 6mg infused over 1 hour every day. Intravenous Bondronat 6mg was repeated monthly. Twenty-three patients (92%) achieved a significant reduction in bone pain (p<0.001) from baseline (visual analog score). Of these patients, nine became completely pain-free and 14 decreased their daily use of analgesics. The onset of the analgesic effect of Bondronat was rapid with a mean onset of Day 3 (range 15 days). In parallel with the improvement in bone pain, there were improvements in both mean Karnofsky index and Eastern Cooperative Oncology Group (ECOG) performance status. Both scales evaluate performance status including the effects of disease on daily life and help determine prognosis. Whereas ECOG performance status is scored on a scale of 0 (fully active) to 5 (dead), Karnofsky performance scale is scored on 100% (no evidence of disease) to 0 (dead). Treatment with Bondronat was well tolerated; the use of a loading dose did not increase the risk of AEs. Four patients (16%) reported fever on the day after the Bondronat infusion, no patients experienced injection site reactions or other systemic side effects (especially no renal toxicity) associated with treatment throughout all treatment periods. 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.v. every 4 weeks or mitoxantrone/prednisolone 12mg/m2 every 3 weeks.

. . . the use of a loading dose did not increase the risk of AEs.

23

6.4 Short infusion time

A study involving 30 patients with breast cancer (n=16), prostate cancer (n=4) or multiple myeloma (n=10) with bone metastases, investigated the safety and efficacy of Bondronat 4mg i.v. infused over 30 minutes every 34 weeks.4 A total of 198 infusions were administered over 24 months. The results showed that, when infused rapidly, Bondronat had a good efficacy and tolerability profile. Repeated administration reduced the dose of analgesics needed by all patients to treat bone pain. No adverse renal effects with Bondronat were reported. Serum levels of creatinine and urea nitrogen did not significantly increase. This study suggests that the use of a rapid (30 minutes) Bondronat i.v. infusion is well tolerated and could be administered in the setting of a day care unit. This is supported by preclinical data showing no acute or accumulating renal toxicity issues with rapid dosing.

. . . when infused rapidly, Bondronat [4mg i.v. over 30 minutes] had a good efficacy and tolerability profile.

6.5 Introduction of oral Bondronat in the treatment of metastatic bone disease

An oral formulation of Bondronat is under development. Unlike oral clodronate, the Bondronat tablet is small and easily administered once daily. The Bondronat tablet will offer an alternative to the i.v. formulation while delivering efficacy comparable to i.v. bisphosphonates. For example, a recent meta-analysis reported that oral clodronate reduced the risk of a skeletal event by 16%, while i.v. pamidronate was associated with a risk reduction of 23%.35 In contrast, oral and i.v. Bondronat reduced the risk of an event by 3840%.36 Estimates suggest that zoledronate reduces the risk of an event to a similar extent as Bondronat (~37% risk reduction).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. Oral convenience also lowers the burden on healthcare resources versus i.v. administration (e.g. nursing time, occupancy of day beds). Patients also will be able to avoid regular i.v. infusions which can be painful and inconvenient, and switch from i.v. to oral Bondronat when they return home from hospital. The incidence of gastrointestinal events, a problem commonly associated with oral bisphosphonates,38 is low with Bondronat.39 In patients with metastatic bone disease treatment-related gastrointestinal AEs were similar in the placebo and Bondronat 50mg p.o. groups (14.0% and 9.4%, respectively).40

. . . oral and i.v. Bondronat reduced the risk of an event by 3840%.

24

7. Ongoing research with Bondronat

7.1 Introduction
In addition to hypercalcemia of malignancy and metastatic bone disease, Bondronat has been investigated in other disease settings. Its antitumor effect has also been evaluated. The settings in which Bondronat has been studied in are: patients with opioid-resistant pain treatment and prevention of postmenopausal osteoporosis (see separate monograph). More than 7,000 patients have been treated with Bondronat in the clinical trial program including approximately 1,300 patients with metastatic bone disease. No further AEs other than those already described in chapter 4, were identified during these studies.

7.2 Bondronat i.v. in patients with opioid-resistant pain

A preliminary open-label, 6-week study of Bondronat i.v. was performed in 18 patients with severe opioid-resistant pain and either breast cancer (10 patients) or other tumors (eight patients).41 These patients received Bondronat 4mg i.v. over 2 hours daily for 4 days and were then followed for 6 weeks or until death. There was a rapid and significant decrease in both bone pain scores (p<0.05, Figure 7) and analgesic consumption (reflected in the morphine equivalent daily dose [MEDD]) after Bondronat infusion. Quality of life was significantly improved from baseline with Bondronat administration (p<0.05). Bone resorption markers such as pyridinoline and deoxypyridinoline decreased up to Day 21 but then increased and returned to baseline levels at Day 42.

7 6 5 Pain (VAS) 4 3 2 1 0 * MEDD (mg, mean SEM)

600 500 400 300 200 100 0

*p<0.05

21 Time (days)

42

21 Time (days)

42
Figure 7. Effects on bone pain and MEDD with Bondronat. (VAS=visual analog scale).

25

 Non-standard, intensive treatment with Bondronat i.v. was well tolerated in this study. The use of a loading dose was not associated with an increased incidence of AEs. Four patients reported AEs: bone pain in two patients, fever in one patient and flu-like symptoms in one patient. There was no evidence of renal toxicity with Bondronat. Bondronat provides beneficial analgesic effects in patients with opioid-resistant pain . . . This study suggests that Bondronat provides beneficial analgesic effects in patients with opioid-resistant pain with either breast or other primary tumors. Further studies to investigate this are planned.

7.3 Preclinical studies of the antitumor effect of Bondronat

In addition to managing hypercalcemia and metastatic bone disease, Bondronat has been shown to inhibit endothelial cell functions in vitro and in vivo in animal models. In vitro, Bondronat (10-4M) inhibits human umbilical vein endothelial cell proliferation and capillary-like tube formation.42 As cell proliferation and angiogenesis are essential for the growth of metastases of solid tumors, these findings suggest that Bondronat may also prevent the formation of bone metastasis. Studies in vivo showed that Bondronat induced a 50% reduction of the revascularization of the prostate gland in castrated rats, with a 17% reduction in prostate weight. If these data are confirmed in the clinic, they suggest that Bondronat acts by regulating cell proliferation and angiogenesis.42

7.4 Studies in other indications

The efficacy and safety of ibandronate is being studied in other disease areas, including the treatment and prevention of postmenopausal and secondary osteoporosis, involving more than 9,000 patients to date.43, 44 Clinical trials are also being conducted in patients with Pagets disease.

7.5 Rapid infusion

Shorter infusion times without monitoring requirements are more convenient for patients as they reduce the time patients spend in hospital receiving treatment. A more rapid infusion also eases the burden on healthcare resources. Rapid zoledronate infusion has been associated with acute renal failure. To determine whether Bondronat 6mg can be infused rapidly without compromising renal safety, a parallel-group, renal safety/pharmacokinetic study was performed in healthy male and female volunteers (see section 3.5).28 In this study, 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. 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 may be given as a rapid infusion. This would provide greater convenience and flexibility for the patient. Further experience with a shorter Bondronat infusion time is provided by Syrigos et al. described in section 6.5. In their study infusion of Bondronat over 30 minutes was well tolerated.4

26

8. References

1. Ralston SH, Thiebaud D, Herrmann Z, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer 1997;75:295300. 2. Pecherstorfer M, Steinhauer EU, Rizzoli R, Wetterwald M, Bergstrom, B. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomised multicentric comparison to pamidronate. Support Care Cancer. In press. 3. 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. In press. 4. Syrigos KN, Michalaki V, Mitromaras A, et al. Safety and efficacy of the new bisphosphonate ibandronate in the management of bone metastasis following rapid infusion. In Vivo 2002;16:3614. 5. Merck manual of diagnosis and therapy. Beers MH, Berkow R, Burs M, editors. Merck manual of diagnosis and therapy. 17th ed. Merck & Co., 1999. 6. Oxford handbook of clinical medicine. Longmore M, Wilkinson I, Torok E, editors. Oxford handbook of clinical medicine. 5th ed. Oxford University Press Inc., 2001. 7. Desai SP, Pratt, I. Clinicians guide to laboratory medicine. Hudson OH: Lexi-Comp 2000. p. 201. 8. Warrell RP Jr. Metabolic emergencies. In: DeVita VT Jr, Hellman S, Rosenburg SA, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997. p. 248693. 9. Watts RWE. Hypercalcaemic nephropathy. In: Weatherall DJ, Ledingham JGG, Warrell DA, editors. Oxford Textbook of Medicine, 3rd ed. 1996 p. 32279. 10. Kanis JA. Endocrine disorders. In: Weatherall DJ, Ledingham JGG, Warrell DA, editors. Oxford Textbook of Medicine, 3rd ed. 1996 p. 16369. 11. Bajorunas DR. Clinical manifestations of cancer-related hypercalcemia. Semin Oncol 1990;17:1625. 12. McCloskey BV, Dunn JA, Kanis JA, MacLennan ICM, Drayson MT. Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol 2001;113:103543. 13. Mundy GR, Martin TJ. The hypercalcemia of malignancy: pathogenesis and management. Metabolism 1982;31:124777. 14. Guise TA, Mundy GR. Cancer and bone. Endocr Rev 1998;19:1854. 15. Rankin W, Grill V, Martin TJ. Parathyroid hormone-related protein and hypercalcemia. Cancer 1997;80(Suppl. 8):156471. 16. Godsall JW, Burtis WJ, Insogna KL, et al. Nephrogenous cyclic AMP, adenylate cyclase-stimulating activity, and the humoral hypercalcemia of malignancy. Recent Prog Horm Res 1986;42:70550. 17. Kenan S, Hortabagyi GN. Skeletal complications. In: Bast RC, Kufe DW, Pollock RE, Weichselbaum RR, Holland JF, editors. Cancer medicine. 5th ed. c2000 (chap 145). 18. Ritch PS. Treatment of cancer-related hypercalcemia. Semin Oncol 1990;17:2633. 19. Rogers MJ, Watts DJ, Russell RGG. Overview of bisphosphonates. Cancer 1997;80 (Suppl. 1):165260. 20. Clzardin P. The antitumor potential of bisphosphonates. Semin Oncol 2002;29 (6 Suppl. 21):3342. 21. Coleman RE. Pamidronate disodium in the treatment and management of hypercalcaemia. Reviews in Contemporary Pharmacotherapy 1998;9:14764. 22. Mhlbauer RC, Bauss F, Schenk R, et al. BM21.0955, a potent new bisphosphonate to inhibit bone resorption. J Bone Miner Res 1991;6:100311. 23. Bauss F, Muhlbauer RC. Ibandronate, monosodium salt monohydrate. Drugs Fut 1994;19:1316. 24. Van Beek E, Lowik C, Van der Pluijm G, Papapoulos S. 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. J Bone Miner Res 1999;14:7229. 25. Kurth AH, Kim SZ, Sedlmeyer I, Hovy L, Bauss F. Treatment with ibandronate preserves bone in experimental tumour-induced bone loss. J Bone Joint Surg Br 2000;82:12630.

27

26. Juraschek M, Seibel MJ, Woitge HW, Krempien B, Bauss F. Association between histomorphometry and biochemical markers of bone turnover in a longitudinal rat model of parathyroid hormone-related peptide (PTHrP)-mediated tumor osteolysis. Bone 2000;26:47583. 27. Roche data on file. 28. Neugebauer G, Khler W, Akinkunmi L, Pinner J, Kletzl H, Banken L. Influence of peak ibandronic acid concentrations after 6mg iv administration with shortened infusion time (15 and 30 minutes) on renal safety in man [abstract]. Proc Am Soc Clin Oncol 2001;20:122a (abstract 486). 29. Paterson AHG. Bisphosphonates: Biological response modifiers in breast cancer. Clin Breast Cancer 2002;3:20616. 30. Johnson LC. The kinetics of skeletal remodelling. In: Structural organisation of the skeleton. National Foundation, New York, 1966. 31. 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;14:26876. 32. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: A quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:36575. 33. Diel IJ, Body JJ, Lichinitser MR, et al. Improved quality of life after long-term treatment with ibandronate in patients with metastatic bone disease due to breast cancer. J Clin Oncol submitted. 34. Heidenreich A, Elert A, Hofmann R. Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 2002;5:2315. 35. Pavlakis N, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2002;(1):CD003474. 36. Body JJ, Kanis J, Diel I, Bergstrom B, for the Bondronat Study Group. Risk reductions in metastatic breast cancer: multivariate Poisson regression analyses of oral and i.v. ibandronate. 39th ASCO Annual Meeting, Chicago, Illinois, USA, 31 May 3 June 2003. 37. Coleman RE, Rosen LS, Gordon D, et al. 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. 355]. Presented at the 25th San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 1114 December 2002. 38. Body JJ. Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 2001;28(Suppl. 11):4953. 39. 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;10:31116. 40. Diel I, Body JJ, Tripathy D, Bergstrom B. Oral daily ibandronate in women with metastatic breast cancer: a pooled safety analysis. Presented at the 39th ASCO Annual Meeting, Chicago, Illinois, USA, 31 May 3 June 2003. 41. Mancini I, Duman JC, Toth C, Body JJ. Short-term treatment with the bisphosphonate ibandronate for opioid-resistant metastatic bone pain. Bone 2002;30 (Suppl. 3):51 (abstract B56). 42. Fournier P, Boissier S, Filleur S, et al. Bisphoshonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002;62:653844. 43. Schimmer R, Bauss F. Effect of daily and intermittent use of ibandronate on bone mass and bone turnover in postmenopausal osteoporosis: a review of three phase II studies. Clin Ther 2003;25:1934. 44. Delmas P, Recker R, Stakkestad JA, et al. 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. Osteoporosis Int 2002;13(Suppl. 1):S15 (Abstract O37).

28