The researchers conducted various experimental animal studies (e.g., on sheep, dogs, pigs, rats, and rabbits) to evaluate the BIC of titanium implants in dental implant studies
3,4,6,10-13. Rats are preferred in such studies because of their advantages, such as ease of use, appropriate bone size, and cheapness. In addition, rats had an earlier tissue reaction to the administered drug than the other experimental animals, such as rabbits, cats, and dogs, and the shorter working time makes them preferential in experimental animal studies
10,11. Therefore, this study was conducted with a well-established rat model for investigating the process of titanium implant osseointegration after the BIC period.
According to the results of our work, we thought that systemic ZA application could be effective for the improvement and maintaining of osseointegration after a 4-week BIC period. Data from bone cell culture studies showed that, even at very low concentrations, the use of BPs increases bone formative parameters. BPs have a direct inhibitor effect on osteoclasts and can affect bone formation due to this property. Osteoclast function may be modified by the production of an osteoclast inhibitor factor produced by osteoblasts after exposure to BPs 3,9,14. Bone remodulation, a lifelong process that continues after a successful BIC period, is an important factor for maintaining osseointegration. During bone remodeling process, the cells of the osteoblastic line control the activity of osteoclast cells 15. Bisphosphonates are known to increase the growth and maturation and reduce apoptosis of osteoblastic cells. All these data support the suggestion that BPs have an enhancing effect on bone tissue and promote bone tissue formation. Therefore, target cells of BPs may also include osteoblastic-derived cells. In past studies, BPs have been shown to increase the proliferation of osteoblasts and the biological synthesis of collagen and osteocalcin by bones at the cellular level 3,7,10.
The maxillary and mandibular bones tissue differ from long bones in several ways. The jawbone is made up of the neural crest mesoderm, mainly occurring by intramembranous ossification, mostly containing fat marrow. The jawbone is chronically exposed to the external environment and microorganisms. Another distinct feature of the jaw bones is their susceptibility to osteonecrosis associated with BP treatment 15,16. Although BP related osteonecrosis of the jaws is a rare side effect of BP treatment, the severity of the cases and the absence of any known pathophysiology or effective treatment methods make it an important problem in dentistry. To our knowledge, there is no data on the association between single-dose administration and possible side effects of BPs after the BIC period 7,17,18.
The effects of ZA on the osseointegration of implants in various animal models was investigated (rabbit, rat, and dog), and in all of them, ZA has been reported to increase bone implant fusion with systemic ZA application 3,7,10,11,19. Moreover, mechanical attachment of the orthopedic implant and peri-implant bone density has been shown to be enhanced by dose-dependent systemic ZA administration. In an experimental animal study, Yıldız et al. 20 evaluated whether ZA affects bone healing around titanium implants placed in ovariectomized rabbits. The authors concluded that ZA can inhibit the negative effects of estrogen hormone deficiency on bone healing around titanium implants placed in ovariectomized rabbits. Dundar et al. 3 reported that both systemic and local ZA application increased the BIC in a female rabbit model with 2 different implant surfaces. Additionally, Dundar et al. 3 reported that systemic ZA is a more effective method of improving BIC when compared with the local application. Dikicier et al. 10 reported similar results in their ovariectomized rat study. They reported that ZA application increased the BIC in ovariectomized rat tibias. In another study, Wise et al. 21 reported that ZA affects some of the material properties of cortical bone tissues and enables the newly formed subperiosteal bone to remain and, therefore, affects the overall quality of the bone in total hip arthroplasty. In addition, single-dose ZA application significantly reduced bone resorption in orthopedic joint replacement. After the repair of low trauma hip fracture, annual ZA infusion was associated with a reduction in the rate of new clinical fractures and improvement in survival 22.
In the present study, ZA was systematically administered as a single dose of 0.1 mg/kg and 0.2 mg/kg after the 4-week BIC period. The blood concentration of the drug has been shown to decrease gradually over a 28-day period. Thus, a repeat dose of ZA could be administered 28 days after the initial single dose, if required, so we waited 28 days after the application of the ZA 4. Therefore, in the present study, we thought the administration of a systematic single dose of 0.1 mg/kg and 0.2 mg/kg of ZA would be effective to improve and provide long-term protection of the osseointegration of the titanium implants after the 4-week BIC period.
In conclusion, our results confirmed that systemic zoledronic acid could increase the bone implant connection after the osseointegration period. Additionally, while the results of previously conducted studies and the present study show positive effects, new studies on an optimum dosage that can possibly affect the bone implant connection after the osseointegration period and a mode of application have yet to be conducted. Additional studies are required to evaluate the effects of re-dosing on enhancing the bone implant connection of the dental implant after the osseointegration period compared with the application of a single dose.
Acknowledgement
The authors wish to thank Implance Dental Implant System, AGS Medical, Istanbul, Turkiye for providing the implants.
Conflict of Interest
The authors declere that there is no conflict of interest.