Mediators in Gingival Crevicular Fluid of Subjects on Bisphosphonate Therapy

Bone osteonecrosis (BON) of the jaw can occur in cancer patients treated with bisphosphonates for hypercalcemia and in patients treated with lower doses of bisphosphonates for osteoporosis. Variations in bone marker and cytokine mediators may occur in these patients and provide an assessment of risk for developing BON. Objectives: To determine the concentration of bone marker and cytokine mediators in gingival crevicular fluid (GCF) of periodontically healthy subjects treated with low dose oral bisphosphonates. Methods: Clinical examinations and GCF samples were obtained from eight periodontically healthy subjects treated with oral bisphosphonates and nine healthy subjects that were not on bisphosphonates. 22 GCF mediators and six human bone mediators were examined using a multiplexed fluorescent bead-based immunoassay (Millipore, Billerica, MA) in the Luminex 100 IS Instrument (Luminex, Austin, TX). Linear mixed modeling (LMM) approaches were used with log-transformed data to evaluate group differences while allowing for subject and tooth location effects. Nonparametric approaches were also used. Medians of subject-specific cytokine responses were compared using exact Wilcoxon Rank Sum tests. Results: In the bisphosphonate group, levels of insulin and PTH were significantly elevated and levels of IL-8 were significantly depressed. When the LMM was fitted, the group effect in each model was significant for insulin, IL-8 and PTH (p<0.05), after consideration of the effects of subject and quadrant location. These results were corroborated by the nonparametric approach (p<0.05 in all instances). Bone marker and cytokine mediator profiles were otherwise similar between the bisphosphonates and non-bisphosphonate treated subjects in these modest samples. Conclusions: Similar Bone marker and cytokine mediator profiles were seen in the GCF of periodontally healthy subjects on bisphosphonates vs subjects not on bisphosphonates. Differences in insulin, PTH, and IL-8 may indicate a subject-specific risk in the development of BON. Supported by T32 DE014678 and NIH NCRR CTSA UL1RR024979.