A rational pharmacokinetic model for predicting osteonecrosis of the jaws related to alendronate and pamidronate

Alendronate is the most frequently prescribed drug for the treatment and prevention of low bone mineral density worldwide. It is nearly identical to pamidronate, the first aminobisphosphonate used for therapeutic inhibition of bone resorption. Approved in 1991, pamidronate has become widely used as an intravenous drug for treatment of metastatic lesions of cancer in bone since 2000. In 2003, osteonecrosis of the jaws was discovered to occur in cancer patients treated with pamidronate and, to a much lesser degree, those who were treated with oral alendronate for osteopenia and osteoporosis. The necrotic lesions of the jaws occurred in dental patients who had undergone surgery. This malady is now commonly described as bisphosphonate-related osteonecrosis of the jaws.;There is controversy in the dental profession regarding the route of administration in the pathogenesis of this disease. Organized dentistry, with no rational basis, has promulgated the opinion that alendronate, though nearly identical in all manner of pharmacological behavior, carries less risk for causing osteonecrosis. It is the opinion of two prominent dental organizations that there is no risk of osteonecrosis for patients undergoing oral surgical procedures for the first three years of therapy with oral alendronate.;A recent USC School of Dentistry study disagrees. Here it was discovered that surgery patients were at risk for this disease within one year of initiated oral therapy with alendronate. This study shows that oral bisphosphonates do indeed pose the same risk as intravenous bisphosphonates.;Intravenous pamidronate and oral alendronate differ only in the dosing and rate of accumulation in the skeleton. This thesis is a rational attempt to quantify the time required for oral pamidronate and, by analogy oral alendronate, to reach the toxic threshold for induction of osteonecrosis. This threshold was recently proposed through in vitro methodology by Landesberg et al.;Serge Cremers, the Dutch pharmacokinetics expert, developed a model in 2002 for bisphosphonate accumulation in bone that comingled data for alendronate. He reasoned, as we do in this study, that the molecular features of the two drugs would confer similar pharmacokinetic characteristics. The urine and serum data from this study were provided to the Laboratory of Applied Pharmacokinetic (LAPK), Keck School of Medicine of USC. This allowed for the creation of a new model of pamidronate accumulation in skeletal tissues with nonparametric adaptive grid software (NPAG), LAPK's Bayesian approach to nonparametric pharmacokinetic studies. As a coauthor with Landesberg et al, Cremers and his colleagues established an in vitro threshold for toxicity to keratinocyte migration that defines the most plausible mechanism to date for bisphosphonate-related osteonecrosis of the jaws. Specifically, they determined a threshold concentration for pamidronate in solution wherein cellular migration essential to healing is completely inhibited without apoptosis. LAPK determined the concentration of accumulated oral pamidronate and alendronate in skeletal tissues required to reach this threshold when liberated by osteoclastic resorption.;A novel factor in the LAPK model is the use of total bone mineral content as a parameter for quantifying individual differences in the rate of accumulated concentration of alendronate and pamidronate. For the first time it is shown mathematically that with current fixed regimes of alendronate, those with less total bone mass will reach toxic levels more quickly.;The last simulation investigated the effect of impaired kidney function. With renal clearance reduced by 50%, no significant change in the rate of accumulation was predicted. Reduced renal clearance does not enhance the accumulation of oral bisphosphonate in bone mineral.