# Presentation: 717204

## Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonates

**Prof. Robert Coleman, MD, FRCP**
**Cancer Research Centre**
**Weston Park Hospital**
**Sheffield, England**

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## Clinical Importance and Prognosis of Bone Metastases

**Myeloma****	**** 75 - 100****	****70 - 95****	****24**
**Renal****	**** 198****	****20 - 25****	****12**
**Melanoma****	**** 467****	****14 - 45****	****6**
**Bladder****	**** 582****	****40****	****6 - 9**
**Thyroid****	**** 207****	****60****	****48**
**Lung****	**** 386****	****30 - 40****	****7**
**Breast****	**** 1,993****	****65 - 75****	****24**
**Prostate****	**** 984****	****65 - 75****	****36**

**Clinical Importance and Prognosis of ****Bone Metastases**

**C**

**NCI, 1997; International Myeloma Foundation, 2001.**

## Skeletal Complications in Metastatic Bone Disease Are Significant

**	****                                    ****%**** ****of**** ****patients affected in PLACEBO arms of:**
**	****                       ****Pamidronate trials   ****	****         ZOMETA****®**** trials****         **
**Disease****	****Breast****	****Myeloma****	****Prostate ****	****Others****Observation time****	****12 months****	****9 months****	****15 months****	****9 months**
**Radiation to bone****	****33****	****22****	****29****	****32**
**Fractures****	****41****	****30****	****22****	****21**
**Hypercalcaemia****	****of malignancy****	****  9****	****  6****	****  1****	****  3**
**Surgery to bone****	****  8****	****  5****	****  3****	****  4**
**Spinal cord****	****compression****	****  2****	****  3****	****  7****	****  4**

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## Pathophysiology of Bone Metastases

**Role of the osteoclast in bone pathology**

**Growth****factors**

**Osteoclast activity**

**Osteolysis**

**Direct bone destruction**

**Bone**

**Bone secondaries**

**Primary**

**Local factors**

**Systemic factors**

**Tumour cells**

**Bony complications**

**Pathophysiology of Bone Metastases**

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**Activated**
**osteoclast**

## Cancer and Bone Cell Interactions

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**Osteolytic bone disease**

**Osteoblastic bone disease**

**Osteoclast**

**Osteoblast**

**Unknown**
**GFs**

**TGF-******

## Bone RemodellingCancer Effects

**C**

## Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone Disease

**Blastic**

**Mixed**

**X-ray pattern**

**Bone-specific alkaline phosphatase (ng/mL)**

**N-telopeptide (BCE/M Cr)**

**Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone Disease**

**0**

**10**

**30**

**20**

**40**

**50**

**60**

**Lytic**

**Blastic**

**Mixed**

**X-ray pattern**

**0**

**100**

**300**

**200**

**400**

**500**

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**Lipton A. *****Semin Oncol*****. 2001;28:54-59.**

## Consequences of Increased Bone Resorption

**Increased**
**bone**
**resorption**

**Hypercalcaemia**

**Fracture**

**Bone pain**

**Consequences of Increased ****Bone Resorption**

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**Bone**

## Treatment of Bone Metastases

**Traditional treatments**
**Radiotherapy/radionuclides**
**Endocrine treatment**
**Chemotherapy**
**Orthopaedic intervention**
**Analgesi****cs**
**Complementary approach**
**Osteoclast inhibition**

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## Bisphosphonate Pharmacology

**Proposed mode of action**

**Aminobisphosphonates**

**Bisphosphonates**

**Bisphosphonates**

**Precursor**
**cells**

**Mature****osteoclasts**

**Accession**

**Tumour**
**cells**

**Prostaglandins****and other****factors**

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## Prevention of Skeletal-Related Events Phase III Pamidronate Studies

**Prevention of Skeletal-Related Events Phase III Pamidronate Studies**

**Breast cancer**
**Conte, 1996 (N = 295) - chemotherapy****§**
**Increased time to progression - 249 versus 168 days (*****P***** = .02)**
**Hultborn, 1996 (N = 401) - chemotherapy****§**
**Increased time to progression - 14 versus 9 months (*****P***** < .01)**

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**Theriault, 1999 (N = 374) - endocrine**
**Reduced proportion of SREs - 47% versus 57% (*****P***** = .057)**
**Hortobagyi, 1996 (N = 382) - chemotherapy **
**Reduced proportion of SREs - 43% versus 56% (*****P***** = .008)**

**Myeloma**
**Berenson, 1996 (N = 377) - first and second-line therapy**
**Reduced proportion of SREs - 24% versus 41% (*****P***** < .001)**

## Proportion of Patients Having SREsPooled Breast Cancer Clinical Trials (N = 756)

**12 months**

**24 months**

***P *****= .002**

***P *****< .001**

***P *****= .078**

***P *****< .001**

***P *****< .001**

***P *****= .002**

**Lipton A, et al. *****Cancer*****. 2000;88:1082-1090. **
**Novartis. Data on file.**

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## Proportion of Patients Having SREsMultiple Myeloma (N = 377)

**9 months**

**21 months**

***P *****< .001**

***P *****= .049**

***P *****= .004**

***P *****= .015**

***P *****= .060**

***P *****= .255**

**Berenson JR, et al. *****N Engl J Med. *****1996;334:488-493.**
**Berenson JR, et al. *****J Clin Oncol*****. 1998;16:593-602.**

**39**

## Total Number of SREs Recorded During Randomised Clinical Trials of Pamidronate

**	****Breast****	****Breast****	****Myeloma****	****Protocol 19****	****Protocol 18****	****Protocol 12****	****24 mo****	****24 mo****	****21 mo**

**	**** ****Pam ****	****	****Pam****	****	****Pam****	****SRE****	****90 mg****	****Placebo****	****90 mg****	****Placebo****	****90 mg****	****Placebo**

**All SRE (+HCM)****	****387****	****630****	****475****	****648****	****307****	****376**
**Pathologic fracture****	****251****	****349****	****331****	****403****	****170****	****189**
**	****Vertebral fracture****	****103****	****148****	****115****	****143****	****96****	****123**
**	****Nonvertebral fracture****	****148****	****201****	****216****	****260****	****74****	****66**
**Radiation to bone****	****105****	****207****	****114****	****192****	****97****	****129**
**Surgery to bone****	****14****	****28****	****15****	****24****	****15****	****25**
**Spinal cord compression****	****4****	****7****	****7****	****8****	****2****	****8**
**Hypercalcaemia****	****13****	****39****	****8****	****21****	****23****	****25**

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## Effects of Pamidronate on Pain and Analgesic Consumption

**Breast cancer**
**Chemotherapy**
**24 mo**

**Breast cancer**
**Endocrine**
**24 mo**

**Multiple**
**myeloma****9 mo**

***P***** = .028**

***P***** = .009**

***P***** = .011**

***P***** = < .001**

***P***** = .089**

***P***** = .050**

**Pain and analgesic scores at the last measurement mean change from baseline**

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## Prostate Cancer and Other Tumours

**Increased bone resorption with osteosclerotic metastases**
**Useful pain relief from acute high-dose bisphosphonate treatment**
**No previous randomised trial evidence for bisphosphonate effects on SREs**

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## Pamidronate in Prostate CancerNo Effect on Proportion of Patients With SRE and Mean SMR

**Total N = 378**

**24%**

**24%**

***P*****  = 1.0**

**Proportion with SRE (–HCM)**

**SRE**

**SMR**

**Mean SMR (–HCM)**

***P***** = .942**

**17**

**0.30**

**0.29**

**Pamidronate in Prostate Cancer****No Effect on Proportion of Patients With SRE and Mean SMR**

**Lipton A, et al. *****Cancer Invest*****. 2001;20:45-47.**

## Adverse Events Profile of Pamidronate

**Acute phase response**
**Fever, myalgia, arthralgia**
**Anaemia**
**Mineral disorders**
**Renal effects**
**Dose and infusion time related**

## Zoledronic Acid

**Zoledronic acid is a new, highly potent bisphosphonate**
**Heterocyclic nitrogen-containing bisphosphonate composed of**
**A core bisphosphonate moiety **
**An imidazole-ring side chain containing 2 critically positioned nitrogen atoms **

**Green JR, et al.***** J***** *****Bone Miner Res*****. 1994;9:745-751.****Green JR, et al. *****Pharmacol Toxicol.***** 1997;80:225-230.**

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## ZOMETA® Key Preclinical Properties

***In vitro***
**Potently inhibits osteoclast formation and bone resorption regardless of pathogenetic stimulus**

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***In vivo***
**Potently inhibits bone resorption in a variety of  models of benign and malignant bone disease irrespective of tumour types**
**Preserves bone architecture and strength**
**Novel anti-angiogenic and anti-pain effects **
**Reduces the number and size of bone metastases in models of tumour-induced osteolysis**

## ZOMETA®Key Clinical Pharmacology Properties

**Similar to other bisphosphonates *****in vitro***** **
** ****Low protein binding; no uptake by red blood cells**
** ****No interaction with CYP450 metabolising enzymes**
**Similar to other bisphosphonates *****in vivo***** **
**Rapid postinfusion decline of plasma concentrations of drug; plasma drug concentrations are dose proportional **
**Majority of drug is taken up by bone; remainder is rapidly eliminated into urine unchanged (ca. 40% of dose 0-24h)**

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**§Berenson J, et al. *****J Clin Pharmacol.***** 1997;37:285.**

## ZOMETA®Key Clinical Pharmacology Properties

**The increase in AUC****0-24h**** and C****max ****is not affected by cumulative dose**
**Dose adjustments in renal impairment (CL****cr**** 30 - 80 mL/min) are not needed**

**Treatment cycle**

**1**

**2**

**3**

**AUC****0-24h****, ng/mL•h**

**100**

**200**

**300**

**400**

**500**

**600**

**700**

**800**

**900**

**Normal**

**Mild**

**Moderate/Severe**

**ZOMETA****®****Key Clinical Pharmacology Properties**

## Phase II Study (007) Results Support ZOMETA® 4-mg Infusion Every 3 to 4 Wk

**ZOMETA****®**** given every 4 wk produced sustained effects on serum and urinary markers of bone resorption**
**The 4-mg dose was most effective in suppressing markers of bone resorption **
**Skeletal events and pathologic fractures occurred slightly less frequently in patients treated with 4 mg than 2 mg ZOMETA**
**ZOMETA 0.4 mg was clearly ineffective compared with 2 mg and 4 mg**
**Time to first skeletal event in breast cancer patients was almost 2 mo longer in the 4-mg versus 2-mg dose group**

## Urinary N-telopeptide/Creatinine Ratio After the First and Subsequent (q4 wk) Doses of ZOMETA® (Study 007)

**-80**

**-60**

**-40**

**-20**

**0**

**Baseline **

**Wk 1**

**Wk 4**

**Wk 12**

**Wk 24**

**Wk 40**

**ZOMETA dose   1                        2                                 3  4  5   6   7  8  9**

**Median % change from baseline**

## Efficacy in Hypercalcaemia of Malignancy 

**Complete responders (%)**

***Denotes statistical significance versus pamidronate.**
** ****Major**** P,**** et al.***** J Clin Oncol. *****2001;19:558-567. **

**Efficacy in ****Hypercalcaemia of Malignancy**** **

**83.3%**
***P***** = .010***

**56%**
***P***** = .021***

**88%**
***P***** = .002***

**87%**
***P***** = .015***

**82.6%**
***P***** = .005***

**45%**

**33%**

**64%**

**70%**

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**Notes:**
Please add text for each treatment day

## Conclusions

**Metastatic bone disease is an important healthcare problem**
**Pathophysiology is similar across all tumour types **
**Osteoclast activation accompanies all bone metastases**
**Currently available bisphosphonates have a limited****range of activity**
**ZOMETA****®**** is a potent inhibitor of osteoclast activity and provides a bone-specific treatment **

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