The influence of diabetes on the properties of a patient’s bone would impact the outcomes of dental implants. In cases where diabetes cannot be completely cured, clinicians generally use hypoglycemic drugs to reduce the adverse effects of diabetes. Numerous studies have reported the direct effect of hypoglycemic drugs on systemic bone metabolism. However, little attention has been paid to the effect of hypoglycemic drugs on peri-implant bone. In the present study, the peri-implant radiographic parameters showed different characteristics among patients using different hypoglycemic agents. The results could serve as a reference for the direct effect of drugs on systemic bone.
This study showed that MBL among groups was not exactly the same. The MBL parameters in insulin group and metformin group were higher than those in GLP-1 group at 12 months of follow-up. The MBL in metformin group was higher than insulin group and GLP-1 drugs group at 24 months of follow-up. Similarly, the MBL in the percentage of original implant length in insulin group and metformin group was higher than that in GLP-1 drugs group. During these periods, the bone and bone substitution material had experienced the bone healing and remodeling process and this process could be influenced by the bone condition around implants. The difference of MBL among groups showed the possibility of these drugs interfering with bone tissue around the implant in T2DM patients. After controlling for the baseline information variable, the difference in MBL among groups still existed. This means that these confounding variables, including position of fixture and major surface treatment, did not influence the comparative results of MBL among groups. The change of bone levels around implants could show the bone healing and remodeling process and the higher MBL might suffer higher risk of failure. From these results, the medication type might be related to the bone healing and remodeling around implant at the early stage and the potential among medication might be different. However, the present result showed there was no statistically significant difference in clinical parameters, including BOP (+) and PD, among groups. Although the diabetes could be related to the periodontal inflammation, the peri-implant inflammation parameters seem to have nothing to do with the medication type of the T2DM patient.
The results showed that GLP-1 drugs might have a more positive effect on the peri-implant bone than other agents. This is consistent with previous studies. Liang17 indicated that compared with other hypoglycemic drugs, GLP-1 drugs could significantly reduce the risk of fracture. A meta-analysis also supports that exenatide, a GLP-1 receptor agonist (RA), might have advantages in preventing fracture risk over other hypoglycemic drugs18. Preclinical studies have reported the superior osteogenic properties of GLP-1 drugs. GLP-1 receptors are widely distributed, and knockout of the GLP-1 receptor gene leads to severe bone changes related to the abnormality of osteoclasts19, which supports the direct effect of GLP-1 on bone. GLP-1RA might also enhance early osseointegration. GLP-1RA improved factors beneficial to osseointegration around implants in a T2DM animal model20. The injection of GLP-1RA could improve serum osteogenesis factors after dental implant surgery21. However, some researchers believe that the effect of GLP-1RA on bone is neutral22, which may be due to the different eligibility conditions of the study participants. Li23 indicated that there was no difference in the effects of exenatide and insulin on bone turnover markers and bone mineral density, but the observation time was short. More studies are needed to clarify the specific effects of GLP-1RA on bone tissue.
Metformin and insulin are both classic hypoglycemic medications and there are many studies about their positive influence on bone tissue. The results showed that the distal MBL in the metformin group was higher than that in the insulin group (P < 0.05). The most previous comparison of the bone metabolism effect between these two drugs focused on the systematic body. Raj24 pointed out that compared with metformin, insulin could significantly protect bone through osteocalcin and other pathways. However, some fracture risk studies presented different views. Losada25 and Hidayat26 determined that metformin could reduce the fracture risk and protect bone metabolism compared with the effects of insulin. The underlying mechanism of this contradiction is unclear. The explanation may be that diabetes is generally more severe in insulin users than oral medicine users. Patients using insulin could suffer more fall fractures caused by illness complications and hypoglycemic reactions, while metformin users had a lower incidence of fractures due to fewer complications27. Therefore, the fracture risk cannot accurately reflect the influence of drugs on bone metabolism. This study selected patients with good blood glucose control and no severe complications. The interference of different conditions was removed as far as possible to increase the reliability of the results.
There are also many studies on the beneficial bone target mechanism of metformin and insulin. A large number of studies have proven the positive effect of insulin on bone tissue. Insulin has been shown to promote bone formation by upregulating the serum osteogenesis factor28. Some studies have shown that a local injection of insulin can promote early fracture healing in diabetic animals29. Moreover, local or systematic use of insulin could improve implant osseointegration30–31. Another study has shown that insulin could promote angiogenesis32, which is also a conducive factor to early osseointegration. Metformin is a first-line drug for the treatment of diabetes. Its positive mechanism on bone has been confirmed by a large number of preclinical studies. It is reported that metformin could promote osteogenesis and inhibit bone resorption33. However, metformin would reduce the level of bone turnover factors and hinder the bone remodeling34. This effect might compromise the self-repair of minor bone tissue damage. In this study, the MBL in the insulin group was smaller than that in the metformin group, which might be related to their effect on bone metabolism.
At present, the major controversy about the bone target effect of some hypoglycemic drugs entails their indirect effect on bone by controlling blood glucose35. Firstly, it is noteworthy that all T2DM patients included in this study had good controlled blood glucose, with HbA1c less than 8%. And the results showed that MBL was different among groups, even though the patients in each group reported good controlled blood glucose. This meant that these drugs might have different influences on peri-implant bone. The process of bone remodeling around implants requires an environment conducive to bone formation. Therefore, T2DM patients undergoing implant surgery should choose hypoglycemic drugs more conductive to bone formation, such as insulin and GLP-1RA. However, this adjustment in the medication plan should not violate the clinical principle of diabetes treatment. Hence, the results of this study are more useful for patients who have flexibility regarding agent use. One limitation of this study is that blood glucose could not be monitored in real time. Therefore, further laboratory-based investigations should be executed to guarantee blood glucose control more strictly and eliminate bias in this type of research in the future.
Another contribution of the present study is that it provides feedback on clinical systemic bone research. Previous research on the systematic bone target effect of hypoglycemic drugs focused more on the changes in fracture risk, bone mineral density and bone-related biochemical indexes36. However, these indexes could not accurately reflect the influence of drugs on bone. The bone mineral density in patients with T2DM might be higher than that in normal individuals, and the fracture risk in T2DM patients could be high37. The fracture risk reason might be related to damaged bone quality, higher incidence of falls and severe complications of diabetes. While the MBL around the implant is an important criterion for the efficacy of implant treatment and could be affected by bone metabolism38. Therefore, MBL could serve as an indicator of the bone target effect and could be used to supplement relevant research results about systematic bone.
Considering the cost and radiation risk, conventional standard periapical radiography is still the most preferable clinical method to assess MBL around implants. This study focused on the MBL around implants with GBR in different hypoglycemic agent groups. However, it is beyond the scope of this study to examine the horizontal change of the alveolar ridge at the implant site as this study was based on two-dimensional images. Follow-up studies on the horizontal change in the ridge would be executed by cone beam computed tomography.