The Management Of Bone Metastases : Role Of Bisphosphonate.

(1)

The management of bone

metastases : role of bisphosphonate

Amaylia Oehadian

(2)

The management of bone

metastases : role of bisphosphonate

• Incidence of bone metastases

(3)

The management of bone

metastases : role of bisphosphonate

(4)

Incidence of bone metastase

• Incidence of bone metastases in cancer :

95-100

65-75

Incidence (%) Cancer type

(5)

The management of bone

metastases : role of bisphosphonate

• Complication of bone metastases

(6)

Complication of bone metastases

• Bone pain

• Hypercalcemia

• Pathologic fractures

(7)

The management of bone

metastases : role of bisphosphonate

• Complication of bone metastases

• Patophysiology of bone metastase

(8)

(9)

(10)

Pathophysiology of bone metastases

(11)

Pathophysiology of bone metastases :

2 ways

• Osteolytic :

– Most common way

– Stimulated normal bone resorbing cells : osteoclast

– Breast ca, lung ca, myeloma • Osteoblastic :

(12)

Osteolytic



(13)

The management of bone

metastases : role of bisphosphonate

• Complication of bone metastases • Patophysiology of bone metastase

• Bisphosphonate in breast cancer

(14)

Bone metastases : bisphosphonate

• Anti resoptive drugs for the treatment of

diseases arising from excess bone resorption • Bisphophonate :

– Nitrogen containing

(15)

Bisphosponate : mechanism of action

Metabolized within osteoclasts

Do not inhibit protein prenylation

Rapidly causes apoptosis of ostoclasts

Anti-inflammatory Not metabolized within

osteoclast

Inhibit protein prenylation within osteoclast

Graduallly causes

apoptosis of osteoclasts Not anti-inflammatory

Non-nitrogen containing (clodronate)

(16)

(17)

Bisphosphonate in bone metastatic

• Rosen LS (2001):

– Phase III randomized trial

– 4 or 8 mg zoledronic acid vs 90 mg

pamidronate every 3 to 4 weeks in multiple myeloma or breast ca with lytic disease

(18)

Bisphosphonate in primary breast ca with bone metastase : clodronate 1600 mg/day PO

144

Double blind,

randomized, multicenter

Prolongation by 35% of the time to bone disease

progression (244 vs180 days)

100

Design

Result

Tubiana (2001) Kristensen

(19)

Bisphosphonate in primary breast ca without bone metastase : clodronate 1600 mg/day PO

299

Double blind, randomized

Randomized, non placebo

8% vs 17%

Design

Bone

metastases Visceral

metastase

Relative risk

Saarto (2001) Powles (2002)

(20)

Bisphosphonate : adjuvant therapy

• NSABP trial B34 :

– 2400 early stage breast ca – Clodronate vs placebo

• North American Intergroup : S0307

(21)

Bisphosphonate : toxicity

14,3 22,3

7 5,3 Skin disorders

Upper gastrointestinal Hepatic

Renal

Percentage Toxicity

(22)

The management of bone

metastases : role of bisphosphonate

• Complication of bone metastases • Patophysiology of bone metastase • Bisphosphonate in breast cancer

(23)

Bisphosphonate : recommendation : ASCO 2003

Pamidronate 90 mg IV (2 h) or zoledronic acid 4 mg (15 min) every 3-4 weeks

Considered reasonable

Not recommended

Continued until substantial decline in performans status lytic disease (+)

(rontgen)

Bone scan (+), normal rontgen, bone

destruction on CT/MRI

Bone scan (+) only

Duration

(24)

Creatinine <3 mg/dl : no change in dosage or interval

monitor : creatinine (prior to each dose)

Ca,phosphate, magnesium, Hb

Not sugggested for routine care

Current standard care, concurrent with chemotherapy and/or

hormonal Safety

Biochemical markers

Pain control secondary to bone metastases

(25)

Not recommended

Not recommended outside of clinical trial

Recommended an algorithm Ekstraskeletal metastases

Adjuvant therapy

Osteoporosis prevention in breast ca

(26)

Bisphosphonate : Cohrane Breast Cancer

Review Group

• 8 studies : 1962 women with advanced breast ca and bone metastase

– Bisphosponate reduced the risk of skleletal event by 14%

– For IV pamidronate 90 mg, the reduction was 23%

– For oral clodorate, the reduction was 16 % – Compared with placebo, bisphosphonates

(27)

Bisphosphonate : Cancer Care Ontario

(2002)

• Women with breast cancer who have bone metastases should be offered treatment with oral clodronalte or intravenous pamidronate • Intravenous zoledronic acid was considered

(28)

Osteoporosis risk in breast ca

• Age > 65 years

• Age 60-64 years with : – Family history

– Body weight < 70 kg

– Prior non-traumatic fracture – Other risk factors

(29)

Osteoporosis risk

Low risk High risk

Life style , Ca, vit D

Monitor annualy

BMD hip + spine

T score

< -2.5 _{Between -1 and -2,5} _{> -1}

Repeat BMD annualy

(30)

Take home messages

• Bone metastases in breast cancer is a complex proccess , involving interaction :

– Breast cancer cells – Osteoclasts

(31)

Take home messages

• Breast cancer cells produce PTHrP which stimulates osteoclast

(32)

Take home messages

• Bisphosphonate :

– Osteoclast activity inihibition – Apoptosis cancer cell

– Angiogenesis inhibition

• Bisphosphonate effective in reducing skeletal events in breast cancer patients with bone

metastases

• Ongoing studies to determine the role of

(33)