title: Skeletal retention of bisphosphonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases.
abstract: Bisphosphonate pharmacokinetics may affect individual responses. Skeletal retention of pamidronate infused monthly to patients with bone metastases was highly variable (12-98%) and did not diminish with time, showing the capacity of the skeleton to retain large amounts of bisphosphonate. Relationships between skeletal retention of pamidronate and rate of bone resorption are complex and depend on previous treatment and the total amount of retained bisphosphonate.
  
  
  BACKGROUND
  Bisphosphonates (BPs) given intravenously every 3-4 weeks are effective in the management of metastatic bone disease from breast cancer, but responses among patients vary, and it is not known whether current dose and dose intervals are appropriate for an individual patient. An influence of pharmacokinetics of BPs on antiresorptive action may contribute to this variation in response. To test this hypothesis, we determined the skeletal retention of intravenous pamidronate and its association to the rate of bone resorption in patients with bone metastases from breast cancer.
  
  
  METHODS
  In a cross-sectional study, 24-h urinary excretion of pamidronate and the biochemical marker of bone resorption N-terminal telopeptide of type 1 collagen and serum alkaline phosphatase were measured in 40 patients with bone metastases from breast cancer at the beginning, after 3-6 months, and after 1 year of treatment with intravenous pamidronate 90 mg every 3-4 weeks.
  
  
  CONCLUSIONS
  Skeletal retention (dose--amount excreted into urine) 2 days after infusion varied between 12% and 98% (mean, 62%) of the administered dose, but there were no differences in retention between patients receiving pamidronate for the first time or after 3-6 months or after 1 year of treatment. Retention of pamidronate was related to the prevalent rate of bone turnover in previously untreated patients, whereas no such relationship was found in previously treated patients. Rate of bone resorption after treatment seemed to be related to the amount of pamidronate retained. During 1 year of treatment, retention of pamidronate remained constant, indicating no saturation of skeletal binding sites with treatment. The variability in retention among individual patients can be attributed to the number of available binding sites. This is related, however, to bone turnover only before the start of treatment. The apparent relationships between skeletal retention and antiresorptive effect could have implications for the design of optimal therapeutic regimens with BPs in patients with bone metastases from breast cancer.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Serge C L M
authors.initials: SC
authors.lastname: Cremers
authors.forename: Socrates E
authors.initials: SE
authors.lastname: Papapoulos
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Jan
authors.initials: J
authors.lastname: den Hartigh
authors.forename: Pieter
authors.initials: P
authors.lastname: Vermeij
authors.forename: Carin C D
authors.initials: CC
authors.lastname: van der Rijt
authors.forename: Lia
authors.initials: L
authors.lastname: van Zuylen
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D050071:Bone Density Conservation Agents / Q000493:pharmacokinetics*; D001859:Bone Neoplasms / Q000556:secondary*; D001862:Bone Resorption; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D003094:Collagen / Q000652:urine; D024042:Collagen Type I; D004164:Diphosphonates / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D015233:Models, Statistical; D009362:Neoplasm Metastasis; D000077268:Pamidronate; D010455:Peptides / Q000652:urine; D013997:Time Factors
chemical_list: D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen; D000469:Alkaline Phosphatase; D000077268:Pamidronate