Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate-related osteonecrosis of the jaw.

We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ.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.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).Our model accurately discriminated BRONJ cases from controls among patients on BP therapy.