Locally released BP from either ALN- or RIS-HA composite coating could induce peri-implant bone mass augmentation, BMD increment, and the improvement of bone architecture, which significantly improved the bone-implant integration (BIC increment), at each time point (Figures , (left tibia) and 4).
Early bone-implant integration that can provide a sealed interface is important to implant stability because it can inhibit the migration of debris and cytokines [13
]. In addition, implant stability is also influenced by peri-implant bone architecture. Architecturally compromised trabecular bone will transmit a lesser load to the cortical bone. Thus, stress will concentrate at the bone-implant interface, which ultimately results in implant loosening. Rod-like trabecular bone (SMI
3) had poorer biomechanical properties than plate-like trabecular bone (SMI
0). After the particle stimulation, SMI of the peri-implant bone was higher than 2.0 (Figure , SMI, left tibia, group I). However, locally released BP from BP-HA composite coatings significantly reduced SMI to almost 1.5 (Figure , SMI, left tibia, groups II and III) and led to higher implant stability, which was confirmed by the results of push-out test (Figure ).
It was obvious that ALN was more potent than RIS on peri-implant bone due to their different mineral-binding affinities [8
], especially at week 24. ALN has high mineral-binding affinity and intermediate inhibitory potency on FPPS. It can keep a stable concentration in peri-implant bone and will hardly be delivered far away. Therefore, previous studies [1
] on enhancing bone-implant integration almost focused on such high-affinity BPs. Oppositely, RIS has low mineral-binding affinity and high inhibitory effect on FPPS [7
]. Such low-affinity BPs will be delivered to the entire osteocyte network through the canalicular compartment by extracellular fluid [3
] that effective peri-implant drug concentration may not be sustained for a long lime. Therefore it is used for treating non-vertebral fractures but not for enhancing bone-implant integration [3
However, as we know, revision patients are averagely older than the primary patients that they have a higher incidence rate of systemic osteopenia or osteoporosis. Therefore, in addition to enhancing implant stability, it is better for the composite coatings to have systemic effects of bone mass augmentation and BMD increment which may benefit the recovery of revision patients. However, the HA coating composed with high-affinity BPs may not fit the needs as Jakobsen et al.
] confirmed that locally released ALN did not have systemic effects. Thus, we should re-consider the possibility of using low-affinity BPs as coating materials.
The histomorphometric and BMD results of the contralateral tibias and lumbar vertebrae (Figure ) indicated that RIS-HA composite coating could induce bone mass augmentation and BMD increment significantly in non-peri-implant region, especially lumbar vertebrae. Oppositely, ALN had very limited systemic effects. This difference suggests that low-affinity BPs are more systemically effective than high-affinity BPs. Additionally, the variations of serum cytokine levels can reflect their systemic effects more directly and precisely compared to histomorphometric parameters. The significant lower serum concentrations of B-ALP, TRACP-5b and RANKL in group III than in groups I and II at week 12 also supported our histomorphometric results (Figure ). The effects of RIS were more pronounced in lumbar vertebrae than contralateral tibias (Figure ), because BPs tend to bind with the bone which has the highest turnover rate [25
]. Kimmel et al.
] confirmed that lumbar vertebrae and proximal humerus have the highest turnover rates.
Local BP administration (BP-HA composite coating) is the best way for enhancing implant stability and preventing aseptic loosening. Because of the binding selectivity of BPs, they will almost concentrate in the bone with the highest turnover rate, such as the lumbar vertebrae, but not in the peri-implant bone if they are administrated systemically. The drug potency is then diminished. Especially in the osteoporosis patients who are usually in the state of systemic high bone turnover, BP is more likely to be consumed by non-peri-implant bone. Additionally, local administration has many advantages such as lower initial dosage, higher peri-implant drug concentration and fewer side effects compared to systemic administration.
For inhibiting peri-implant bone resorption, low-affinity BPs have some limitations that peri-implant drug concentration may not sustain for a long time and their effects on peri-implant bone will become weaker than high-affinity BPs. In our study, it is obvious that BIC, BV/TV, Tb.Sp, SMI, ASS, and TEA in group III became significantly worse than in group II at week 24, and BFR/BV and MAR showed no significant differences compared to the control group (Figures (left tibia) and 5). Therefore, low-affinity BP alone is not suitable for revision patients who suffer from osteoporosis simultaneously. Composing HA with both high- and low-affinity BPs may be feasible. Recently, Abtahi et al.
] composed both high- (pamidronate) and low-affinity (ibandronate) BPs to the fibrinogen matrix as the coating material, and each oral implant was then screwed into the upper jaw in five patients. The results indicated that this composite coating could successfully improve implant stability. However, they did not explain why they composed two kinds of BPs, and they did not compare it with single BP composed coatings.
The mechanism by which BPs released from either pure HA in vitro
or bone in vivo
are crucial to further studies on composite HA coatings. In addition to different mineral-binding affinities, the release duration of BPs also depends on the bone remodelling activity that BPs will be consumed more rapidly in the sites with high turnover rates. Thus, for further evaluating peri-implant concentration and the release duration of BP-HA composite coatings, detecting drug concentration in plasma or bone is meaningful. Tanzer et al.
] used a spectrophotometric method [1
] to investigate the in vitro
release characteristic of ZOL from pure HA but it cannot precisely reflect the release duration in vivo
, because in addition to chemical desorption, osteoclastic resorption also plays an important role. Legay et al.
] developed a highly sensitive radioimmunoassay (RIA) method to detect ZOL concentration, and the limit of quantification was 0.4
ng/mL in plasma and 5
ng/mL in urine, respectively. Yun et al.
] developed a high-performance liquid chromatography (HPLC) method to detect ALN concentration, and the limit of quantification was 1
ng/mL in plasma. These methods are not sensitive enough for our study because the doses of ALN and RIS were 100-μg and 50-μg, respectively, per implant, that the drug concentration was too low to detect, especially in plasma. Recently, Stadelmann et al.
] developed a novel mathematic-based modelling method for evaluating peri-implant BP concentration and bone density. Using this method, they found the optimal coating dose of ZOL per implant. All these efforts mentioned above will help us further realise the characteristic of BP-HA composite coatings.
The results of this study are instructive and meaningful to further clinical studies that we could choose different BP-HA composite coatings according to the patient’s condition. In brief: 1) In primary TJA patients without systemic high bone turnover-related diseases (osteopenia or osteoporosis), we can prefer ordinary non-BP-composed prostheses; 2) In primary TJA patients with systemic high bone turnover-related diseases, we can prefer low-affinity BP-composed prostheses. Their significant systemic effects may cooperate with the BP which is systemically administrated. The systemic bone mass augmentation and BMD increment can result in earlier movement and shorter recovery time for patients; 3) In revision patients without systemic high bone turnover-related diseases, we can prefer high-affinity BP-composed prostheses which can significantly reduce peri-implant high bone turnover rate and improve implant stability due to the stable peri-implant drug concentration and long release duration; 4) In revision patients with systemic high bone turnover-related diseases, the HA coating composed with both high- and low-affinity BPs may be preferable, in addition to improving implant stability, it can result in systemic bone mass augmentation and BMD increment.
Nevertheless, our study has some limitations. Firstly, the homogenous distribution of the BP solution on the implant surface could be guaranteed due to the implant size and the BP solution volume in our study. However, in further studies, if the implant is bigger or the solution amount is less, the homogenous distribution may not be guaranteed. Therefore, other loading methods like spraying may be possible if the drug amount can be controlled at the same time. Secondly, we compared local and systemic inhibitory effects on bone resorption only between high- and low-affinity BPs. In further studies, an additional group that the HA coating is composed with both high- and low-affinity BPs should be added and an appropriate ratio of high-/low-affinity BPs should be investigated. Finally, the animal model used in this study was to induce peri-implant (local) high bone turnover. In further studies, these composite coatings should be studied in osteoporosis models which have systemic high bone turnover rate.