title: Extended safety profile of oral clodronate after long-term use in primary breast cancer patients.
abstract: BACKGROUND
  Long-term safety and tolerance is paramount when treating women who are otherwise healthy after the primary adjuvant therapy of breast cancer. Efficacy and limited safety results of a large-scale clinical trial, using adjuvant oral clodronate to prevent bone metastases in primary breast cancer patients, have been reported previously, demonstrating a reduction in the rate of bone metastases during treatment. Here we present expanded safety and tolerability results for clodronate treatment from this trial (cut-off date extended from June 1997 to June 2000).
  
  
  METHODS
  For this randomised, double-blind, placebocontrolled, multicentre study, patients were enrolled and randomised to receive oral clodronate (Bonefos) 1600 mg/day or placebo for 2 years. The total median treatment period plus follow-up was 5.5 years. Adverse events (AEs) and laboratory parameters were followed up regularly for the total study period. The 95% CIs were estimated for the difference in the rate of AEs between the treatment groups.
  
  
  METHODS
  A total of 1079 women with primary operable breast cancer were enrolled to the study; 538 received clodronate and 541 received placebo.
  
  
  RESULTS
  Overall incidence of AEs (96.5% of the patients) was the same in both treatment groups, although gastrointestinal disorders were significantly more frequent in the clodronate group during the total study period (66% vs 56.2%; 95% CI 4.0-15.6; p < 0.05). This was mainly due to an increase in non-severe diarrhoea beginning 3-4 months after treatment start. Serious AEs (SAEs) were reported for 39.4% of the patients receiving clodronate and 44.5% of those receiving placebo; no drug-related (clodronate or placebo) SAEs were identified. Clodronate significantly lowered mortality (98 deaths vs 129 deaths; hazard ratio 0.77; 95% CI 0.59-1.00; p = 0.047) reducing the risk of death over the total study period by 23%. AEs caused 58 early discontinuations (five drug-related events) in the clodronate group and 43 discontinuations (three drug-related events) in the placebo group.
  
  
  CONCLUSIONS
  These results indicate that in women with early breast cancer receiving adjuvant systemic therapy, oral clodronate for 2 years is generally well tolerated with no serious long-term sequelae, providing a safe, long-term therapy in the adjuvant setting.
authors.affiliation: Schering Oy, Helsinki 00101, Finland. sari.atula@schering.fi
authors.forename: Sari
authors.initials: S
authors.lastname: Atula
authors.forename: Trevor
authors.initials: T
authors.lastname: Powles
authors.forename: Alexander
authors.initials: A
authors.lastname: Paterson
authors.forename: Eugene
authors.initials: E
authors.lastname: McCloskey
authors.forename: Jaakko
authors.initials: J
authors.lastname: Nevalainen
authors.forename: John
authors.initials: J
authors.lastname: Kanis
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D004002:Clodronic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016001:Confidence Intervals; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D016016:Proportional Hazards Models; D013995:Time
chemical_list: D004002:Clodronic Acid