title: The use of bone markers in a 6-week study to assess the efficacy of oral clodronate in patients with metastatic bone disease.
abstract: Biochemical markers of bone metabolism are strongly associated with skeletal complications in metastatic bone disease. The bisphosphonate clodronate reduces skeletal morbidity by inhibiting bone resorption. This study investigated the use of bone markers to assess the efficacy of oral clodronate across a range of clinically relevant doses. There were 125 patients with metastatic bone disease randomized to daily oral clodronate (800, 1,600, 2,400 and 3,200 mg) or placebo in a double-blind, multicenter study. Urinary N-terminal telopeptide of type I collagen (U-NTX), serum C-terminal telopeptide of type I collagen (S-CTX), urinary calcium (U-Ca), and bone alkaline phosphatase were measured weekly for a 6-week treatment period. Doses of >or=1,600 mg clodronate produced mean reductions of >40% in U-NTX, S-CTX and U-Ca, all significantly different from placebo (P=0.0015, 0.001, 0.0036, respectively), after 6 weeks. Evaluation of least significant changes in markers suggested that the commonly used 1,600 mg dose was most appropriate for breast cancer patients. However, this dose was suboptimal for other (mainly prostate cancer) patients, who showed better response to 2,400 mg. The number of adverse events in the treatment arms was not significantly different from that in placebo, but a higher number of patients had diarrhea in the 3,200 mg arm and withdrew from the study. This trial is the first to explore the dose-response relationship of clodronate in oncology using specific markers of bone turnover. It has confirmed that the 1,600 mg dose is safe and effective for breast cancer patients but may be suboptimal for the other tumors studied.
authors.affiliation: Academic Unit of Clinical Oncology, Weston Park Hospital University of Sheffield, Sheffield S10 2SJ, UK. J.E.Brown@leeds.ac.uk
authors.forename: J E
authors.initials: JE
authors.lastname: Brown
authors.forename: E V
authors.initials: EV
authors.lastname: McCloskey
authors.forename: J A
authors.initials: JA
authors.lastname: Dewar
authors.forename: J J
authors.initials: JJ
authors.lastname: Body
authors.forename: D A
authors.initials: DA
authors.lastname: Cameron
authors.forename: A N
authors.initials: AN
authors.lastname: Harnett
authors.forename: M
authors.initials: M
authors.lastname: Ruutu
authors.forename: O P
authors.initials: OP
authors.lastname: Purohit
authors.forename: R
authors.initials: R
authors.lastname: Tähtelä
authors.forename: R E
authors.initials: RE
authors.lastname: Coleman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000032:analysis / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000150:complications* / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001943:Breast Neoplasms / Q000473:pathology*; D002118:Calcium / Q000032:analysis / Q000652:urine; D004002:Clodronic Acid / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis / Q000097:blood / Q000652:urine; D010919:Placebos; D011237:Predictive Value of Tests; D011347:Procollagen / Q000032:analysis / Q000097:blood / Q000652:urine; D011471:Prostatic Neoplasms / Q000473:pathology*; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D010446:Peptide Fragments; D010919:Placebos; D011347:Procollagen; C047202:procollagen Type I N-terminal peptide; C042813:procollagen type I carboxy terminal peptide; D004002:Clodronic Acid; D000469:Alkaline Phosphatase; D002118:Calcium