Several studies have demonstrated the utility of locally applied or delivered bisphoshonates for enhancing periimplant bone formation and implant fixation although none have shown to what extent the drug becomes skeletally distributed. It would be preferable for the bisphosphonate to remain localized to the implant site to minimize potential systemic side effects and unnecessary skeletal bone remodeling. This study aimed to quantify to what extent eluted zoledronic acid from porous implants was localized and whether there was systemic exposure after local elution.
There are several limitations to this study. First, the distribution of zoledronic acid was not measured along the length of the implants and it therefore cannot be stated with absolute certainty that an asymmetric dosing was not responsible for the bell-shaped distribution that was measured in periimplant bone. However, as described in prior publications, the zoledronic acid was mixed in an aqueous solution and applied evenly along the implant length and circumference during application; the likelihood was therefore for more even distribution than not. Second, a better estimate of the remaining systemic burden of zoledronic acid could have been made had excreted bisphosphonate in the urine been measured. This was not done due to the practical difficulty in animal handling. Third, no control implants without zoledronic acid were included in the study, thus negating the opportunity to make direct comparisons with the local net bone formation around drug-eluting implants. However, this was not the purpose of the study and such comparisons have been made previously, with clear demonstration of the net bone enhancement caused by local zoledronic acid elution. Fourth, only a single dose of zoledronic acid was studied; it is possible that higher or lower doses would be differently distributed locally and systemically, although the 100 μg dose was at the upper end of what has previously been shown as effective for enhancing net bone formation around and within porous implants. Smaller bisphosphonate doses would be expected to result in lower concentrations in local and remote bone. Of most importance was the relative zoledronic acid concentration that was measured locally compared with systemically. Fifth, studying more implants at each time period might have provided a stronger statistical indication of whether the zoledronic acid concentration in periimplant bone decreased with time, although this was clearly evident in remote bone sites. The data from each of the 3 implants at each period of 6 weeks and 52 weeks were however sufficient to uniformly indicate significantly elevated zoledronic acid concentrations locally compared with systemically. We do not believe any of these limitations substantially influence the data or the study conclusions.
The question about whether eluted bisphosphonate remained primarily localized around the implant was answered in the affirmative using two different experimental techniques. The first technique, liquid scintillation counting of radiolabeled zoledronic acid, revealed drug concentrations immediately adjacent to the implant that were one order of magnitude greater than in bone slightly proximal and distal to the implant and two orders of magnitude greater than in the metaphyseal bone of the implanted femur and in bone at remote sites in the skeleton. The data indicated the zoledronic acid concentration in periimplant bone diminished between 6 weeks and 52 weeks, a statistically stronger result for remote bone sites than periimplant bone because of higher sample size. This suggests that drug diffusion into the circulation and excretion continued beyond 6 weeks, possibly boosted by osteoclastic bone remodeling progressively releasing compound. At both time periods, the zoledronic acid distribution in the bone segments immediately adjacent to the implants was consistently bell-shaped instead of uniform along the implant length, with the peak slightly skewed toward the proximal end of the implant. The proximal skewing might have been due to mechanical removal of surface compound as it was inserted with a press fit within the reamed intramedullary hole, with accumulation more proximally. It might also have been due to proximal pooling of blood with eluted compound. The precise reason for the bell-shaped distribution is uncertain, but ancillary studies describing the net bone-enhancing effect of local zoledronic acid elution have not reported a similar distribution of periimplant bone. Autoradiography was the second technique for demonstrating a strong concentration of drug on and/or within the implant, with marked attenuation millimeters away from the implant, either proximally, distally or radially, and only faint presence within endosteal and periosteal bone. There was a subtle difference in zoledronic acid distribution between the sections studied by autoradiography at 52 weeks in that one dog showed faint evidence of drug at the periosteal border of the cortex while the other did not. In neither dog was drug apparent within the cortex itself; this suggests zoledronic acid may have reached the periosteal region via the circulation as opposed to diffusion through cortical bone. Amanat et al.  also showed with autoradiography the presence of radiolabeled zoledronic acid within rat bone that had been exposed to the drug but since the model did not involve local elution from an implant the drug distribution at and near the implant was not studied.
The presence of very low concentrations of zoledronic acid in the remote skeleton at both time periods answered the question about whether local elution would result in systemic distribution. Presumably this occurred through diffusion of the compound at the implant site into the local circulation. Much of the drug that entered the circulation would have been excreted quite rapidly; up to 50% of systemically injected zoledronic acid is cleared in the urine within 24 hours , with additional clearance thereafter. As would be expected, the drug concentration was somewhat greater in the metaphyses of the long bones where there is more cancellous bone and hence greater surface area than in the diaphysis. There are no other data in the literature that compare exactly with the findings of the present study, however two previous studies using locally applied radiolabeled bisphosphonates described systemic drug distribution. In a rat study of mucoperiosteal flap surgery Yaffe et al.  applied 22 μg of 14C-labeled alendronate directly to alveolar bone via a soaked gelatin sponge. The mean total amount of drug measured in the left tibia after 60 minutes was 3.2% of the applied dose (0.7 μg). In a 6 week rat study in which 14C-labeled zoledronic acid was locally injected as a bolus to closed femur fractures, Amanat et al.  measured drug levels in the contralateral femur averaging approximately 0.7 μg/g bone tissue, about half the concentration measured at the fracture site. Very much lower levels of systemic distribution were measured in the present study involving canines (slower metabolic rate), a surgical model with less direct and acute exposure to the circulation, longer study period(s), lower zoledronic acid dose (by body weight), a different method of drug delivery (slower rate by elution), and more comprehensive sampling of skeletal sites.
Ascertaining that eluted zoledronic acid remained highly localized near the implant site, with minute systemic or skeletal exposure, was important for two reasons. First, the findings suggest that local drug elution would be unlikely to cause adverse effects as are sometimes reported clinically with intravenous administration to patients with osteoporosis. This is further supported by the fact that the initial zoledronic acid dose on the implant was very low compared with amounts used clinically. Second, the very low concentration of zoledronic acid found in remote skeletal sites suggests adverse bone remodeling of the skeleton would be minimal or absent after local drug elution. There is some concern that bone exposed to bisphosphonate therapy in the long term may be prone to adverse changes in strength, fracture toughness, or modulus owing to incomplete remodeling and repair [1, 9, 13, 15]. In the present study, the concentration of zoledronic acid in remote skeletal sites was 50-fold to 200-fold less than the concentration found in periimplant bone, so substantial remodeling effects would not be expected. It should be added that ancillary studies of zoledronic acid-eluting implants have found increases in net periimplant bone formation are very much confined to the immediate space around the implant border [5, 21, 22, 25, 27]. This is consistent with the findings of this study and suggests the relatively low concentrations of zoledronic acid measured one or more cm away from the implant, and therefore even more so at remote skeletal sites, are probably subtherapeutic from a bone-remodeling standpoint.
We thank the Canadian Institutes of Health Research for funding of the study, Zimmer Inc for provision of the implants, Novartis Pharma for provision of the 14C-labeled zoledronic acid, and Dr. Lawrence Joseph for professional statistical advice.
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