title: Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate-related osteonecrosis of the jaw.
abstract: OBJECTIVE
  We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ.
  
  
  METHODS
  Using the Pmetrics package and published data, we designed a population pharmacokinetic model of pamidronate concentration in plasma and bone and derived a toxic bone BP threshold of 0.2 mmol/L. With the model, and using patient individual BP duration and bone mineral content estimated from lean body weight, we calculated bone BP levels in 153 subjects.
  
  
  RESULTS
  Mean bone BP in 69 BRONJ cases was higher than in 84 controls (0.20 vs 0.10 mmol/L, P < 0.001), consistent with the toxic bone threshold of 0.2 mmol/L. BRONJ was also associated with longer duration BP therapy (5.3 vs 2.7 years, P < 0.001), older age (76 vs 70 years, P < 0.001), and Asian race (49% vs 14%, P < 0.001).
  
  
  CONCLUSIONS
  Our model accurately discriminated BRONJ cases from controls among patients on BP therapy.
authors.affiliation: USC Center for Biofilms, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089, USA. sedghiza@usc.edu
authors.forename: Parish P
authors.initials: PP
authors.lastname: Sedghizadeh
authors.forename: Allan C
authors.initials: AC
authors.lastname: Jones
authors.forename: Chris
authors.initials: C
authors.lastname: LaVallee
authors.forename: Roger W
authors.initials: RW
authors.lastname: Jelliffe
authors.forename: Anh D
authors.initials: AD
authors.lastname: Le
authors.forename: Peter
authors.initials: P
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: Kiss
authors.forename: Michael
authors.initials: M
authors.lastname: Neely
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001842:Bone and Bones / Q000378:metabolism*; D016022:Case-Control Studies; D004164:Diphosphonates / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007571:Jaw Diseases / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077268:Pamidronate; D012044:Regression Analysis; D018570:Risk Assessment
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000077268:Pamidronate