Bisphosphonates – A review

Bisphosphonates 1st generation Etidronate 2nd generation Clodronate, Pamidronate 3rd generation Zoledronic Acid Ibandronate

Bisphosphonates Etidronate Clodronate Pamidronate Weak inhibitor of bone resorption Inhibits bone mineralisation and can produce osteomalacia Clodronate Acts as a direct poison to the osteoclasts Pamidronate The first nitrogen containing BP More potent than Clodronate Inhibits osteoclastic activity and the proliferation of precursor cells Zoledronic Acid /Ibandronate Further increase in anti-resorptive activity by substitution of the nitrogen atom from pamidronate with a methyl and pentyl residue

Bisphosphonates - Mechanisms of action Adsorbed onto hydroxyapatite crystals in the bone Inhibit the osteoclast mediated bone resorption and cause OC apoptosis (also aiding cancer therapy induced bone loss) Directly induce tumour cell apoptosis, reduce cell adhesion and invasion in pre-clinical models (?adjuvant role)

Cancer Induced Bone Pain (CIBP) Rich innervation of bone by primary afferents Tumours Alter the OB/OC balance (RANK,OPG) Induce a pronounced inflammatory infiltrate Release growth factors, cytokines and prostanoids causing ↓pH, ischaemia, apoptosis ►directly deforms the primary afferents ►activates nociceptors ►allows further resorption of bone by OC ►gross bone destruction and pathological fractures

Hypercalcaemia of malignancy (HCM) Mediated by soluble factors secreted by tumour cells and the immune system eg parathyroid hormone-related protein (PTHrP), prostaglandins and cytokines Stimulate excess bone resorption and release of calcium from the bone matrix PTPrP also stimulates increased renal Ca reabsorption

Indications Prevention and treatment of osteoporosis Treatment of Pagets disease Hypercalcaemia of malignancy Prevention of skeletal fracture events Ross 2003 Beneficial effects are time dependent; significant benefits were only seen after six months of treatment

Efficacy of bisphosphonates Prevention of skeletal related events (SRE) SRE’s include pathological #,SCC, RT to bone,surgery to bone and some studies include hypercalcaemia in this category Pamidronate and Clodronate proven in patients with breast and MM to ↓ SRE’s Pamidronate 90mg >Clodronate 1600mg (PO/IV)

Efficacy – SRE’s cont. Breast and MM patients 4mg Zometa (n=561) vs 90mg Pamidronate (n=555) Primary end point –Proportion of pts with at least 1 SRE Secondary endpoint – Time to first SRE 25/12 SRE Pam ≡ Zometa Zometa reduced the risk of developing skeletal complication by 16%>Pamidronate

Efficacy – SRE’s Prostate cancer patients Zometa Zometa 4mg vs placebo (n=643) After 24 months SRE Zometa 38% vs Placebo 49% (P=.028) Zometa significantly ↓ risk of skeletal complications by 36% vs placebo (P=0.002)

Efficacy – SRE’s Prostate Cancer patients (cont) Pamidronate 236 pts No more effective than placebo after 6/12 BUT Bone pain was Primary end point in this study, patients had more advanced disease (so difficult to compare this with previous study)

Efficacy – SRE’s Lung and other solid tumours Zometa 4mg IV vs placebo 9/12 Primary endpoint - % pts with a SRE Zometa ≡ Placebo 21/12 NSCLC and renal cell CA Taking secondary endpoints Zometa showed a 32% reduction in relative risk of SRE’s vs Placebo in the NSCLC group and 58% in the renal cell cancer group

Efficacy – SRE’s Ibandronate Trialled only in breast cancer patients Ibandronate 6mg IV vs placebo (1) Ibandronate 50mg PO vs placebo (2) Primary endpoint = SMPR (the no of 12/52 periods with skeletal complications ÷ total observation time) Secondary endpoints = multiple events analysis of skeletal events Both IV and PO ibandronate significantly ↓ the SMPR vs placebo Significant ↓ SRE’s vs placebo (approx 40%)

Efficacy – Bone pain and QOL Bone pain, analgesic use, QOL, functioning and performance statushave been used as secondary endpoint in some studies Clodronate Breast cancer pts – significant ↓ in pain and analgesic use MM patients – Significant ↓ Back pain However other studies in breast, prostrate and other neoplasms showed no benefit

Efficacy – Bone pain and QOL Pamidronate 1.Short term study (3/12) Pamidronate 90mg more effective than Clodronate 2. RCT(x2) Pamidronate vs placebo in breast cancer pts – pain scores increased in both groups over 2 yrs but significantly less so with Pamidronate

Efficacy –Bone pain and QOL Zoledronic Acid Breast Ca pts 1 Zometa 4mg = Pamidronate 90mg at reducing pain and analgesic scores @ 13/12 2 Zometa 4mg vs placebo. Significant ↓ pain scores in Zometa group after 1yr

Efficacy – Bone pain and QOL Ibandronate Breast cancer pts PO and IV ibandronate reduced pain scores on VAS for 2 yrs Also significant improvements in QOL, physical functioning vs placebo group. Cochrane review (Wong 2004) There is evidence to support the use of bisphosphonates in providing some pain relief. It is insufficient to recommend their use as first line or to define the most effective bisphosphonate or the relative effectiveness of bisphosphonates for different primary neoplasms

Safety considerations Hypocalcaemia PO bisphosphonates Nausea, epigastric pain and oesophagitis IV bisphosphonates Injection site reaction Flu-like syndrome Renal toxicity – may vary between agents because of differential protein binding ? Ibandronate safer? Osteonecrosis of the jaw

Practical recommendations for use Using early appears to prevent SRE’s ASCO recommend the routine use of IV pamidronate or Zoledronic acid in pts with breast cancer and radiological evidence of bone destruction Continue until there is a substantial decline in the pts performance status Body JJ (2006)– Start when lytic or mixed picture metastatic bone disease in weight bearing bones, painful sites correspond to areas of known disease, following first SRE

Future? Use of bone turnover markers esp as predictors of response “Burst” bisphosphonates to establish more quickly if a patients pain is likely to respond Use as an adjuvant because of anti-tumour properties – can they prevent bone metastases? Prevention of cancer-therapy-induced bone loss - Benefits for all patients even in early stages to preserve bone density?

References Urch C. The pathophysiology of cnacer-induced bone pain:current understanding Palliat Med 2004;18:267-274 Neville-Webbe HL The use of zoledronic acid in the management of metastatic bone disease and hypercalcaemia Palliat Med 2003;17: 539-553 Mannix K et al Using bisphosphonates to cintrol the pain of bone metastaes: evidence-based guidelines for palliative care Palliat Med 2000;14:455-461

References (cont) Body JJ Bisphosphonates for malignancy-related bone disease: current status, future developments Support Care Cancer 2006;14:408-418