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.
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Article info
Publication history
Published online: December 14, 2012
Accepted:
August 27,
2012
Received in revised form:
August 20,
2012
Received:
June 6,
2012
Footnotes
This publication was supported by NIH/NCRR SC-CTSI Grant UL1 RR031986 in addition to an LRP grant to the primary author (PPS) from the NIH/NIMHD. MN is supported by NIH-NIGMS R01 GM068968 and NIH-NICHD R01 HD070996. The abstract of this work was recently accepted for oral presentation at the upcoming annual meeting of the American College of Clinical Pharmacology in September in San Diego. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
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© 2013 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
