Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer.
OBJECTIVE
The development of bone metastases depends on tumor-induced osteoclastic resorption of bone, which may be inhibited by the antiosteolytic bisphosphonate clodronate. Given to patients with primary breast cancer, clodronate might reduce the subsequent incidence of bone metastases.


METHODS
This double-blind, multicenter trial accrued 1,069 assessable patients with operable breast cancer between 1989 and 1995. All patients received surgery, radiotherapy, chemotherapy, and tamoxifen as required. Patients were randomized to receive oral clodronate 1,600 mg/d or a placebo for 2 years starting within 6 months of primary treatment. The primary end point was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). Secondary end points were relapse in other sites, mortality, and toxicity.


RESULTS
During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (clodronate, n = 63; placebo, n = 80; hazards ratio [HR], 0.77; 95% confidence interval [CI], 0.56 to 1.08; P =.127). During the medication period there was a significant reduction in the occurrence of bone metastases (clodronate, n = 12; placebo, n = 28; HR, 0.44; 95% CI, 0.22 to 0.86; P =.016). The occurrence of nonosseous metastases was similar (clodronate, n = 112; placebo, n = 128; P =.257), but there was a significant reduction in mortality (clodronate, n = 98; placebo, n = 129; P =.047) during the total follow-up period.


CONCLUSIONS
Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.
Powles
Trevor
T
Royal Marsden National Health Service Trust, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. trevor.powles@rmh.nthames.nhs.uk
Paterson
Sandy
S
Kanis
John A
JA
McCloskey
Eugene
E
Ashley
Sue
S
Tidy
Alwynne
A
Rosenqvist
Kirsi
K
Smith
Ian
I
Ottestad
Lars
L
Legault
Sandra
S
Pajunen
Marjo
M
Nevantaus
Auli
A
Männistö
Esa
E
Suovuori
Anne
A
Atula
Sari
S
Nevalainen
Jaakko
J
Pylkkänen
Liisa
L
D000284:Administration, Oral; D000963:Antimetabolites / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004002:Clodronic Acid / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D016016:Proportional Hazards Models; D016019:Survival Analysis; D016896:Treatment Outcome
D000963:Antimetabolites; D004002:Clodronic Acid