Bisphosphonates Bisphosphonates – A review– A review

BisphosphonatesBisphosphonates

11stst generation generation Etidronate Etidronate 22ndnd generation generation Clodronate, Clodronate,

Pamidronate Pamidronate 33rdrd generation generation Zoledronic Acid Zoledronic Acid

IbandronateIbandronate

BisphosphonatesBisphosphonates EtidronateEtidronate

Weak inhibitor of bone resorption Weak inhibitor of bone resorption Inhibits bone mineralisation and can produce Inhibits bone mineralisation and can produce

osteomalaciaosteomalacia

ClodronateClodronate Acts as a direct poison to the osteoclastsActs as a direct poison to the osteoclasts

PamidronatPamidronatee The first nitrogen containing BP The first nitrogen containing BP More potent than Clodronate More potent than Clodronate Inhibits osteoclastic activity and the proliferation of Inhibits osteoclastic activity and the proliferation of

precursor cellsprecursor cells

Zoledronic Acid /IbandronateZoledronic Acid /Ibandronate Further increase in anti-resorptive activity by Further increase in anti-resorptive activity by

substitution of the nitrogen atom from pamidronate with substitution of the nitrogen atom from pamidronate with a methyl and pentyl residuea methyl and pentyl residue

Bisphosphonates - Bisphosphonates - Mechanisms of actionMechanisms of action

Adsorbed onto hydroxyapatite crystals Adsorbed onto hydroxyapatite crystals in the bonein the bone

Inhibit the osteoclast mediated bone Inhibit the osteoclast mediated bone resorption and cause OC apoptosis resorption and cause OC apoptosis (also aiding cancer therapy induced (also aiding cancer therapy induced bone loss) bone loss)

Directly induce tumour cell apoptosis, Directly induce tumour cell apoptosis, reduce cell adhesion and invasion in reduce cell adhesion and invasion in pre-clinical models (?adjuvant role)pre-clinical models (?adjuvant role)

Cancer Induced Bone Pain Cancer Induced Bone Pain (CIBP)(CIBP)

Rich innervation of bone by primary Rich innervation of bone by primary afferentsafferents

TumoursTumours Alter the OB/OC balance (RANK,OPG)Alter the OB/OC balance (RANK,OPG) Induce a pronounced inflammatory infiltrateInduce a pronounced inflammatory infiltrate Release growth factors, cytokines and Release growth factors, cytokines and

prostanoids causing prostanoids causing ↓pH, ischaemia, apoptosis↓pH, ischaemia, apoptosis ►►directly deforms the primary afferentsdirectly deforms the primary afferents ►►activates nociceptorsactivates nociceptors ►►allows further resorption of bone by OCallows further resorption of bone by OC ►►gross bone destruction and pathological fractures gross bone destruction and pathological fractures

Hypercalcaemia of Hypercalcaemia of malignancy (HCM)malignancy (HCM)

Mediated by soluble factors secreted by Mediated by soluble factors secreted by tumour cells and the immune system eg tumour cells and the immune system eg parathyroid hormone-related protein parathyroid hormone-related protein (PTHrP), prostaglandins and cytokines(PTHrP), prostaglandins and cytokines

Stimulate excess bone resorption and Stimulate excess bone resorption and release of calcium from the bone matrixrelease of calcium from the bone matrix

PTPrP also stimulates increased renal PTPrP also stimulates increased renal Ca reabsorption Ca reabsorption

IndicationsIndications

Prevention and treatment of Prevention and treatment of osteoporosisosteoporosis

Treatment of Pagets diseaseTreatment of Pagets disease Hypercalcaemia of malignancy Hypercalcaemia of malignancy Prevention of skeletal fracture eventsPrevention of skeletal fracture events

RossRoss 2003 Beneficial effects are time 2003 Beneficial effects are time dependent; significant benefits were only dependent; significant benefits were only seen after six months of treatmentseen after six months of treatment

Efficacy of Efficacy of bisphosphonatesbisphosphonates

Prevention of skeletal related events Prevention of skeletal related events (SRE)(SRE)SRE’s include pathological #,SCC, RT to SRE’s include pathological #,SCC, RT to bone,surgery to bone and some studies bone,surgery to bone and some studies include hypercalcaemia in this categoryinclude hypercalcaemia in this category

Pamidronate and Clodronate proven in Pamidronate and Clodronate proven in patients with breast and MM to patients with breast and MM to ↓ SRE’s↓ SRE’sPamidronate 90mg >Clodronate 1600mg Pamidronate 90mg >Clodronate 1600mg

(PO/IV)(PO/IV)

Efficacy – SRE’s cont.Efficacy – SRE’s cont.

Breast and MM patientsBreast and MM patients 4mg Zometa 4mg Zometa (n=561)(n=561) vs 90mg Pamidronate vs 90mg Pamidronate

(n=555)(n=555)

Primary end point –Proportion of pts Primary end point –Proportion of pts with at least 1 SREwith at least 1 SRE

Secondary endpoint – Time to first SRESecondary endpoint – Time to first SRE 25/1225/12

SRE Pam SRE Pam ≡ Zometa≡ Zometa Zometa reduced the risk of developing Zometa reduced the risk of developing

skeletal complication by 16%>Pamidronateskeletal complication by 16%>Pamidronate

Efficacy – SRE’sEfficacy – SRE’s

Prostate cancer patients Prostate cancer patients ZometaZometa

Zometa 4mg vs placebo (n=643)Zometa 4mg vs placebo (n=643) After 24 months After 24 months SRE Zometa 38% vs Placebo 49% SRE Zometa 38% vs Placebo 49%

(P=.028)(P=.028) Zometa significantly Zometa significantly ↓ risk of skeletal ↓ risk of skeletal

complications by 36% vs placebo complications by 36% vs placebo (P=0.002)(P=0.002)

Efficacy – SRE’sEfficacy – SRE’s

Prostate Cancer patients (cont)Prostate Cancer patients (cont) PamidronatePamidronate

236 pts 236 pts No more effective than placebo after No more effective than placebo after

6/126/12 BUT Bone pain was Primary end point BUT Bone pain was Primary end point

in this study, patients had more in this study, patients had more advanced disease (so difficult to advanced disease (so difficult to compare this with previous study) compare this with previous study)

Efficacy – SRE’sEfficacy – SRE’s

Lung and other solid tumoursLung and other solid tumours Zometa 4mg IV vs placeboZometa 4mg IV vs placebo 9/12 9/12 Primary endpoint - % pts with a SREPrimary endpoint - % pts with a SRE Zometa Zometa ≡ Placebo≡ Placebo 21/12 NSCLC and renal cell CA21/12 NSCLC and renal cell CA Taking secondary endpoints Zometa Taking secondary endpoints Zometa

showed a 32% reduction in relative risk showed a 32% reduction in relative risk of SRE’s vs Placebo in the NSCLC group of SRE’s vs Placebo in the NSCLC group and 58% in the renal cell cancer groupand 58% in the renal cell cancer group

Efficacy – SRE’sEfficacy – SRE’s IbandronateIbandronate

Trialled only in breast cancer patientsTrialled only in breast cancer patients Ibandronate 6mg IV vs placebo (1)Ibandronate 6mg IV vs placebo (1) Ibandronate 50mg PO vs placebo (2)Ibandronate 50mg PO vs placebo (2) Primary endpoint = SMPR (the no of 12/52 Primary endpoint = SMPR (the no of 12/52

periods with skeletal complications periods with skeletal complications ÷ total ÷ total observation time)observation time)

Secondary endpoints = multiple events Secondary endpoints = multiple events analysis of skeletal eventsanalysis of skeletal events

Both IV and PO ibandronate significantly ↓ the Both IV and PO ibandronate significantly ↓ the SMPR vs placeboSMPR vs placebo

Significant ↓ SRE’s vs placebo (approx 40%)Significant ↓ SRE’s vs placebo (approx 40%)

Efficacy – Bone pain and Efficacy – Bone pain and QOLQOL

Bone pain, analgesic use, QOL, Bone pain, analgesic use, QOL, functioning and performance functioning and performance statushave been used as secondary statushave been used as secondary endpoint in some studiesendpoint in some studies

ClodronateClodronate Breast cancer pts – significant Breast cancer pts – significant ↓ ↓ in pain in pain

and analgesic useand analgesic use MM patients – Significant MM patients – Significant ↓ Back pain↓ Back pain However other studies in breast, prostrate However other studies in breast, prostrate

and other neoplasms showed no benefit and other neoplasms showed no benefit

Efficacy – Bone pain and Efficacy – Bone pain and QOLQOL

PamidronatePamidronate 1.Short term study (3/12)1.Short term study (3/12)

Pamidronate 90mg more effective than Pamidronate 90mg more effective than ClodronateClodronate

2. RCT(x2) 2. RCT(x2) Pamidronate vs placebo in breast Pamidronate vs placebo in breast

cancer pts – pain scores increased in cancer pts – pain scores increased in both groups over 2 yrs but significantly both groups over 2 yrs but significantly less so with Pamidronateless so with Pamidronate

Efficacy –Bone pain and Efficacy –Bone pain and QOLQOL

Zoledronic AcidZoledronic Acid Breast Ca ptsBreast Ca pts

1 1 Zometa 4mg = Pamidronate 90mg at Zometa 4mg = Pamidronate 90mg at reducing pain and analgesic scores @ reducing pain and analgesic scores @ 13/1213/12

22 Zometa 4mg vs placebo. Significant Zometa 4mg vs placebo. Significant ↓ ↓ pain scores in Zometa group after 1yrpain scores in Zometa group after 1yr

Efficacy – Bone pain and Efficacy – Bone pain and QOLQOL

IbandronateIbandronate Breast cancer pts Breast cancer pts

PO and IV ibandronate reduced pain scores on VAS PO and IV ibandronate reduced pain scores on VAS for 2 yrsfor 2 yrs

Also significant improvements in QOL, physical Also significant improvements in QOL, physical functioning vs placebo group.functioning vs placebo group.

Cochrane review (Wong 2004)Cochrane review (Wong 2004) There is evidence to support the use of bisphosphonates in There is evidence to support the use of bisphosphonates in

providing some pain relief. It is insufficient to recommend providing some pain relief. It is insufficient to recommend their use as first line or to define the most effective their use as first line or to define the most effective bisphosphonate or the relative effectiveness of bisphosphonate or the relative effectiveness of bisphosphonates for different primary neoplasmsbisphosphonates for different primary neoplasms

Safety considerationsSafety considerations

HypocalcaemiaHypocalcaemia PO bisphosphonatesPO bisphosphonates

Nausea, epigastric pain and oesophagitisNausea, epigastric pain and oesophagitis IV bisphosphonatesIV bisphosphonates

Injection site reactionInjection site reaction Flu-like syndromeFlu-like syndrome Renal toxicity – may vary between agents Renal toxicity – may vary between agents

because of differential protein binding ? because of differential protein binding ? Ibandronate safer?Ibandronate safer?

Osteonecrosis of the jawOsteonecrosis of the jaw

Practical recommendations Practical recommendations for usefor use

Using early appears to prevent SRE’sUsing early appears to prevent SRE’s ASCO recommend the routine use of IV ASCO recommend the routine use of IV

pamidronate or Zoledronic acid in pts with pamidronate or Zoledronic acid in pts with breast cancer and radiological evidence of breast cancer and radiological evidence of bone destructionbone destruction

Continue until there is a substantial Continue until there is a substantial decline in the pts performance statusdecline in the pts performance status

Body JJ (2006)– Start when lytic or mixed Body JJ (2006)– Start when lytic or mixed picture metastatic bone disease in weight picture metastatic bone disease in weight bearing bones, painful sites correspond to bearing bones, painful sites correspond to areas of known disease, following first SREareas of known disease, following first SRE

Future?Future? Use of bone turnover markers esp as Use of bone turnover markers esp as

predictors of responsepredictors of response ““Burst” bisphosphonates to establish Burst” bisphosphonates to establish

more quickly if a patients pain is likely to more quickly if a patients pain is likely to respondrespond

Use as an adjuvant because of anti-Use as an adjuvant because of anti-tumour properties – can they prevent tumour properties – can they prevent bone metastases?bone metastases?

Prevention of cancer-therapy-induced Prevention of cancer-therapy-induced bone loss - Benefits for all patients even bone loss - Benefits for all patients even in early stages to preserve bone density?in early stages to preserve bone density?

ReferencesReferences

Urch C. The pathophysiology of cnacer-Urch C. The pathophysiology of cnacer-induced bone pain:current understanding induced bone pain:current understanding Palliat Med 2004;18:267-274Palliat Med 2004;18:267-274

Neville-Webbe HL The use of zoledronic acid Neville-Webbe HL The use of zoledronic acid in the management of metastatic bone in the management of metastatic bone disease and hypercalcaemia Palliat Med disease and hypercalcaemia Palliat Med 2003;17: 539-5532003;17: 539-553

Mannix K et al Using bisphosphonates to Mannix K et al Using bisphosphonates to cintrol the pain of bone metastaes: evidence-cintrol the pain of bone metastaes: evidence-based guidelines for palliative care Palliat based guidelines for palliative care Palliat Med 2000;14:455-461Med 2000;14:455-461

References (cont)References (cont)

Body JJ Bisphosphonates for Body JJ Bisphosphonates for malignancy-related bone disease: malignancy-related bone disease: current status, future developments current status, future developments Support Care Cancer 2006;14:408-Support Care Cancer 2006;14:408-418418