Population Pharmacokinetic and Pharmacodynamic Modeling for Assessing Risk of Bisphosphonate-related Osteonecrosis of the Jaw
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80 and over
Bisphosphonate-Associated Osteonecrosis of the Jaw
Bone and Bones
Bone Density Conservation Agents
Case-Control Studies
Diphosphonates
Female
Humans
Jaw Diseases
Male
Middle Aged
Regression Analysis
Risk Assessment EMTREE drug terms bisphosphonic acid derivative
bone density conservation agent
pamidronic acid EMTREE medical terms aged
article
bone
case control study
chemically induced disorder
female
human
jaw disease
jaw osteonecrosis
male
metabolism
middle aged
regression analysis
risk assessment
very elderly
Dentistry
Oral Biology and Oral Pathology
Periodontics and Periodontology
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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. Study Design: 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. © 2013 Elsevier Inc.