Bisphosphonates – A
review
Bisphosphonates



1st generation Etidronate
2nd generation Clodronate, Pamidronate
3rd generation Zoledronic Acid
Ibandronate
Bisphosphonates

Etidronate



Clodronate


Acts as a direct poison to the osteoclasts
Pamidronate




Weak inhibitor of bone resorption
Inhibits bone mineralisation and can produce osteomalacia
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