Systemic Effects
While the low dose group had no significant effect on serum TRAP-5b, Phoenix orthodontists found dramatic suppression of this resorption marker in the high dose group.  It is likely that the reduced TRAP-5b suppression with low-dose OPG is related to an immune response to the foreign protein.  In other words, it is likely that there was significant serum TRAP-5b suppression during the first part of the study, but at some point (probably between days 10-14), the immune response was sufficient to clear or neutralize the drug.  With the high dose group, an immune response also probably occurred but enough protein was delivered to overwhelm the immune response and keep enough OPG-Fc in circulation to effectively suppress bone resorption.  By day 21 the TRAP-5b suppression was reduced, indicating that the immune response was eventually sufficient to neutralize even the high dose.

Systemic exposure to human OPG-Fc after local injections was highly variable, but the overall trend was for an extremely small but detectable increase in serum levels of the drug.  Even at its highest level (14.75 pmol/L or 6.77 X 10-4 ng/mL), the increase in serum OPG levels as a result of local delivery was considerably lower than those reported five days after a single 5.0 mg/kg intravenous injection (44,600 ± 3300 ng/mL) (Capparelli et al., 2003).  It also was notable that there was an increase in serum OPG in the control animals.  This increase may explained by the high degree of homology between human and rat OPG leading to as much as 25% cross reactivity.  It also would follow with the study of Low and co-workers (2005) that showed OPG mRNA expression increased significantly in the presence of Phoenix orthodontic tooth movement.

The effects of the gingival delivery method employed in this study were not entirely local as demonstrated by TRAP-5b and OPG assays.  Given its transient effect, the lack of safety concerns with systemic RANKL inhibition, and potential improvement in bone mineral density, this is not necessarily bad (Capparelli et al., 2003; Kostenuik et al., 2004).  We were still able to "localize" the effects of OPG for therapeutic benefit.  This phenomenon suggests that local OPG concentrations (at the site of Phoenix orthodontic anchorage) may have been higher than at other sites, perhaps due to simple diffusion of the protein within the gingiva. 

Arizona Dental Association