The Effect of Antihypertensive Agents on Dental Implant Stability, Osseointegration and Survival Outcomes: A Systematic Review

: Antihypertensive agents are commonly prescribed to manage hypertension and are known to be beneficial for bone formation and remodeling. The aim of this systematic review was to assess the impact that antihypertensive agents have on dental implant stability, osseointegration, and survival outcomes. A review of the literature was conducted using articles from 11 data sources. PRISMA guidelines were followed, and a PICO question was constructed. The search string “Antihypertensive* AND dental implant* AND (osseointegration OR stability OR survival OR success OR failure)” was used for all data sources where possible. The Critical Appraisal Skills Programme (CASP) was used for study appraisal, including the risk of bias. The search resulted in 7726 articles. After selection according to eligibility criteria, seven articles were obtained (one randomized control trial, two prospective cohort studies, three retrospective cohort studies, and a case control study). Five papers investigated the effects of antihypertensive agents on primary stability, but there were discrepancies in the method of assessment. Inhibition of the renin–angiotensin–aldosterone system was linked to higher primary stability. Secondary stability was usually higher than primary stability, but it is unknown if antihypertensive agents caused this. Survival outcomes were increased with certain antihypertensive agents. It is possible that inhibition of the renin–angiotensin–aldosterone system may lead to greater bone mineral density, improved primary stability, and improved survival outcomes although the effects on osseointegration are unknown. However, more research is needed to confirm this theory.


Introduction
In the UK, once over a third of the population was edentulous; this figure is now closer to 6% nowadays [1][2][3].This has led many, particularly the older generation over 50, to explore dental implants as a replacement option for missing teeth [4][5][6].Managing patients within this age bracket comes with a unique set of problems, which can include reduced plaque control, poor oral health, and polypharmacy [7][8][9][10][11].Many commonly prescribed medications are known to have a negative effect on dental implants, such as proton pump inhibitors and selective serotonin reuptake inhibitors [12][13][14][15].There is evidence to suggest that antihypertensive (AH) agents may also have an effect on dental implants [16,17].
AH agents are used for the management of hypertension.Hypertension refers to consistently raised blood pressure and can negatively affect health [18].It increases the risk of heart, brain, and kidney damage, leading to poorer health outcomes (WHO, 2022).The World Health Organisation estimates that over 1.2 billion adults worldwide have hypertension, with almost half unaware they have the condition (WHO, 2022).The European Society of Hypertension and The European Society of Cardiology recommend five drug groups for the management of hypertension: Beta blocker (BB), Calcium channel blocker (CCB), Angiotensin receptor blocker (ARB), Angiotensin converting enzyme (ACE) inhibitor, and Thiazide diuretic (TD) Previous research has shown interesting results regarding the use of AH agents and their effects on bone.Rejnmark et al. found beta blockers (BB), angiotensin covering enzyme (ACE) inhibitors, and calcium channel blockers (CCB) were shown to have a protective effect on bony fracture [19].There is also evidence to suggest that AH agents show anabolic properties regarding bone metabolism and can even increase bone mineral density within the mouth [20,21].It is possible that this effect on bone may lead to improved osseointegration and overall survival.
When assessing the success of an implant [22], developed criteria that are recognized as the gold standard for implant survival.The five criteria described by (Albrektsson et al., 1986) [22] are as follows: No mobility, no evidence of periapical radiolucency as seen on a radiograph, vertical bone loss of <0.2 mm yearly after the first year of service, absence of signs of pain, infection, neuropathies, paraesthesia, or violation of the mandibular canal, success rate of 85% and 80% at the end of 5 years and 10 years of functioning Stability and osseointegration of the implant are paramount to success, according to Albrektsson.Adequate primary stability improves the chances of successful osseointegration, leading to better outcomes [23].Primary stability is achieved when an implant is firmly placed within the cortical bone.At this stage, the bone and implant are held together by friction instead of integration.Secondary stability, also known as osseointegration, occurs a few months later when the bone fuses with the implant.There are various methods to assess implant stability, including resonance frequency analysis and insertional torque testing for primary stability, and resonance frequency analysis, reverse torque testing, histologic analysis, and radiographs or computed tomography for secondary stability.
The aim of this review is to assess the impact AH agents have on dental implant stability, osseointegration, and survival outcomes through a review of the relevant literature.The rationale for this review emerges from clinical observations and a burgeoning interest in how systemic medications influence dental treatment outcomes.Specifically, the use of AH drugs has been associated with alterations in blood flow and angiogenesis, processes that are fundamental to the healing and integration of dental implants.Furthermore, the potential effects of AH drugs on bone metabolism and the inflammatory response present a complex interplay that could significantly impact implant success rates.

Materials and Methods
This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.The protocol was registered with PROSPERO CRD48209589262.

Eligibility Criteria
The following eligibility criteria were developed for the review:

Inclusion
All adults (18 or over) Any number of endosseous dental implants fitted within the maxilla or mandible Research was published from October 2001-October 2024.This is to exclude olderdesign implants, such as those with smooth/polished surfaces or those without surface treatment [24][25][26].
Original studies (any prospective or retrospective cohort, case-control, cross-sectional, or randomized controlled trials looking at the effects of AH drugs on dental implants) Any AH agent and its interaction with dental implants.Intervention: Dental implants fitted within the maxilla or mandible to be restored with any prostheses.
Comparison: Individuals with dental implants who are not taking AH agents.
Outcomes: Effect on dental implant stability, osseointegration, and survival outcomes Articles were divided into three groups for synthesis, depending on the content.The headings of these groups were: stability, osseointegration, and survival outcomes.Eleven databases plus relevant 'grey' literature and a manual search were identified as sources of information.
The following information sources were identified as containing relevant articles: PubMed, Wiley Online Library, SCOPUS, Google Scholar, VHL Regional Portal, LILACS, Cochrane database, OVID, Dental Update, Journal of Dental Research, International Journal of Oral and Maxillofacial Surgery, EMBASE, EBSCO, and Web of Science.

Search Strategy
In order to generate a useful search string, "Antihypertensive* AND dental implant* AND (osseointegration OR stability OR survival OR success OR failure)" was used for all databases but had to be adapted for Dental Update in order to obtain sufficient results.The search strategy for each information source is described above.
This revealed 7726 articles that could meet the aim of this study.Studies were screened by title, abstract, full text available, and full text screening.The final report generated seven records for discussion.For a visualization of the selection process, please refer to the Prisma Flowchart at the end of this section (Figure 1).
The critical Appraisal Skills Programme (CASP) was used for study appraisal, including the risk of bias.This system was used to assess the relevance of each paper.No papers were excluded after the CASP review.The primary outcomes of this review were to assess the effects of AH agents on dental implant stability, osseointegration, and longevity.The CASP tool version 2018 is used to systematically evaluate the trustworthiness, relevance, and results of published papers.The tool typically includes checklists that can be applied to qualitative, quantitative, and mixed-method research.These checklists help assess aspects like the clarity of research aims, appropriateness of methodology, transparency in reporting results, and significance of the findings, as can be seen in the Appendix A.

Results and Discussion
This review identified one randomized control trial, two prospective cohort studies, three retrospective cohort studies, and a case control study.These studies, along with their results, can be seen in Table 1.The selected study discussion will focus on three main sections: primary stability, secondary stability (osseointegration), and survival outcomes.
In performing the risk of bias assessment [27], the study displayed moderate risk due to limitations in the blinding of participants to the intervention.
Carr et al., 2019 [15] showed a low risk of bias; the study methodology was robust with clear data collection and analysis procedures.

Primary Stability
Five of the seven papers identified in this review investigated the effect of primary stability on dental implants [17,27,[29][30][31].Primary stability is the wedging effect that occurs when an implant is initially placed in bone.The implant is held by frictional forces rather than osseointegration, which occurs during secondary stability.Saravi et al. [27] and Alam-Eldein et al. [30] assessed primary stability by resonance frequency analysis, while Wu et al. used the insertional torque test [17].
Wu et al. [17] report that insertional torque is not associated with an increased risk of implant failure when comparing those medicated with AH agents to HNU.Approximately one-third of the AH and HNU cohorts had an insertional torque of <35 Ncm, while the remaining two-thirds had >35 Ncm.As a result of both groups experiencing the same ratios of insertional torque, this was not shown to have an effect on survival outcomes.
Studies conducted by Malm et al. [31] and Garcia-Denche et al. [29] report that participants were medicated on AH agents, so no deductions can be made relating to AH use.Alam-Eldein et al. [30] and Saravi et al. [27] investigated primary stability using resonance frequency analysis.Both studies concluded that patients medicated on ARBs had higher primary stability than the comparison groups.Only the results obtained by Saravi et al. [27] were shown to be statistically significant.These results should be viewed with caution due to the low number of ARBs included within their sample (9/22) with the remainder being ACE inhibitors.This would suggest that improvements in stability could be linked to inhibition of the renin-angiotensin-aldosterone system (RAAS).Saravi et al. [27] demonstrated that diameter was shown to be a statistically significant factor leading to increased implant stability (4.1 mm/4 mm > less than 4 mm).Other factors linked to improved stability are the type of implant (Straumann > Thommen) and region placed (maxilla > mandible).The higher primary stability achieved by the ARB group could be explained by these factors, as 93.5% of implants within this group had a diameter of 4 mm/4.1 mm when compared to 81.9% in HNU.This is supported by Barikani et al. [32], who found that increasing implant diameter from a narrow platform (3.4 mm) to regular (4.3 mm) led to an increase in the implant stability quotient.Interestingly, in their study, they found this relationship did not exist when further increasing a regular platform to a wide platform and incurred a decrease in stability.This may be explained by a loss of available bone by increasing the width of the osteotomy.This could also explain the difference in values obtained from Saravi et al. [27] and Alam-Eldein et al. [30], as Alam-Eldein et al. [30] used narrow-diameter implants, which led to a reduction in stability when compared to Saravi et al. [27].A comparison of the two would suggest that implant diameter has an effect on primary stability.While the effect of AH agents is still controversial, it is likely that inhibition of the renin-angiotensin-aldosterone system by renin angiotensin aldosterone system inhibitors will have an effect on bone remodeling.

Secondary Stability (Osseointegration)
Secondary stability (osseointegration) was assessed by Alam-Eldein et al. [30] and Saravi et al. [27] using resonance frequency analysis.The results of both studies demonstrated that secondary stability is greater than primary stability when the implant has successfully osseointegrated.This is likely due to the remodeling process that occurs during osseointegration, which anchors the implant to bone.Both studies did not include a histologic analysis as part of their measure of osseointegration, and so we are unable to measure the bone-to-implant contact percentage of the implants, but its relevance to osseointegration should be discussed.
Folkman et al. [33] found that bone-to-implant contact increased over a 3 week period in implants placed in rabbit tibias.It is not clear whether this increase in contact percentage led to an increase in secondary stability, as this was not an outcome measure.Jung et al. [34] evaluated the contact percentage of implants used as anchorage devices for orthodontic treatment.They found that 42% is enough to establish and maintain osseointegration.The implants used in the study were under relatively low forces, 2 N-6 N, compared to implants used to functionally replace teeth [34].Interestingly, the contact percentage of implants within this study was not dissimilar to those reported by Linares et al. [35], who measured bone-to-implant contact in immediate and early-loaded implants in an animal model.Based on these studies, it is unclear if loading forces have a positive effect on contact percentage, although we can postulate that a larger contact percentage would lead to higher levels of stability and greater osseointegration.
Several factors have been linked to increased secondary stability, such as healing time and primary stability [36].Secondary stability takes around 4 weeks to occur, during which time a decrease in implant stability is known to occur, known as the 'stability gap' [37].During this time, the bone remodels and is relatively weak compared to fully mineralized bone.Failure is more likely to occur due to the increased micromotion experienced by the implant, and so higher ISQ values are better able to withstand these destabilizing forces [38,39].Achieving an implant stability quotient between 60 and 70 can reduce micromotions by 50%, allowing for better osseointegration [30].Alam-Eldein et al. [30] used immediate loading for their implants, while Saravi et al. [27] used implants that were buried until exposure.Immediately loaded implants would be expected to experience greater micromotion and failure, which did not occur in this study.This expectation would be enhanced by a low implant stability quotient (ISQ) at placement (<60), but could be accounted for by the small number of implants used within the study [32] or low occlusal forces acting on the implants by an upper complete denture (which was constructed alongside the lower implant-supported denture), and so this may not be a reliable assessment of results.
Both studies gave adequate time to allow osseointegration to occur.Saravi et al. [27] measured secondary stability at 117 ± 56.6 days, while Alam-Eldein et al. [30] reviewed stability measurements at 6 month intervals up to 2 years.In both studies, implant stability quotient values increased over time.Saravi et al. [27] showed that renin-angiotensinaldosterone system (RAAS) inhibitors had the highest ISQ values (outside of the combined group, which failed to reach significance due to a low sample), which echoed results from Alam-Eldein et al. [30].This is similar to the primary ISQ results obtained during the assessment of primary stability.This is logical, as primary stability is an excellent predictor of secondary stability and osseointegration [40,41].

Survival Outcomes
Five papers considered the link between AH agents and survival outcomes [17,27,[29][30][31].Wu et al. [17] and Garcia-Denche et al. [29] found that patients who were medicated on AH agents had improved survival outcomes when compared to those who were unmedicated, and it could be due to the possibility that the renin-angiotensin-aldosterone system is actually the cause of these changes in the bone cellular capacity in favor of implant integration, Garcia-Denche et al. [29] do not reveal which agents were included in their study, which limits further discussion on the effect of each subgroup.
Reported long-term survival rates of dental implants range from 93.3 to 98% [42][43][44].The survival rate of those medicated on AH agents (99.6%) in the study by Wu et al. [17] exceeds this range, but this may be explained by a smaller sample size and reduced follow-up time.Those unmedicated reached a survival rate of 96.9%, which is within the parameters of a good survival outcome.One possible risk of medicating a normotensive person would be the increased risk of hypotension and resultant falls.Although the literature would suggest those medicated with certain AH agents would have a reduced risk of a bony fracture, the patient would still be liable for other risks of falling: skin abrasions, lacerations, head injuries, etc.These risks may not outweigh the benefits of medication, considering the high survival rate regardless of treatment.It is worth noting that the survival rates of both AH users/HNU were significantly lower in the trial by Garcia-Denche et al. [29] when compared to Wu et al. [17].
Garcia-Denche et al. [29] opted for a combination of simultaneous and delayed implant placement.It is accepted that it is more difficult to achieve adequate levels of primary stability during simultaneous placement when compared to a delayed approach due to the differing levels of bone density, and as such, we would expect studies consisting exclusively of simultaneous placement to have relatively low levels of implant survival.However, it is worth noting that immediate implant placement offers several advantages over a delayed approach, such as reduced overall surgical time, which is beneficial to both clinician and patient.It also allows a relative preservation of both hard and soft tissue, although some reduction is to be expected due to the loss of the periodontal ligament, which acts as a blood supply for the surrounding tissue [45,46].
Cha et al. [47] managed to achieve a survival rate of 98.91% during a follow-up period of 57.1 months-nearly five times longer than Garcia-Denche et al. [29].The differences between the two studies may be explained by the sample size.Garcia-Denche et al. [28] included 19 patients who were medicated on AH agents while 85 were not.In comparison, Cha et al. [47] recruited 161 patients.A small sample results in each patient representing a larger overall percentage of the total, and so failures have a greater effect on overall survival, thus increasing the effects of sample bias.Wu et al. [17] included five subgroups of AH agents: ACE inhibitors, ARBs, TDs, BBs, and "other drugs".Interestingly, 54% of patients included in the study were medicated on RAAS inhibitors (which include ACE inhibitors and ARBs).It is prudent to remember that previous studies have found that inhibition of the RAAS has been linked to greater implant stability, which in turn leads to better osseointegration and improved survival outcomes [24,25,30].It could be that including a large proportion of RAAS inhibitors led to greater survival outcomes.However, the patients within this study were followed up for just over 17 months, so midto long-term survival is unknown.
Malm et al. [31], in their case control study, found that AH agents were not linked to early implant failure (failure within 1 year of functioning).Small numbers were included in both the AH group and the control group, which limits the validity of the results.Furthermore, the study was a case control, so a causal link cannot be produced.
Carr et al. [15] and Alam-Eldein et al. [25] both found that CCBs were not linked to an increased risk of implant failure.Alam-Eldein et al. [30] included a relatively low, heterogeneous sample size of 20 males, while [15] included an improved sample of 548 men and women.Carr et al. [15] do not include any data regarding region of placement, implant length/diameters, loading protocol, or bone quality, all of which have an effect on implant survival.As such, it is difficult to explore any reasons behind their results.The results by Alam-Eldein et al. [30] may be explained by all implants being placed within the mandible, which, as discussed earlier, has a higher chance of survival than the maxilla.All implants were fitted with an overdenture and occluded against an upper denture, which, due to the reduced contact forces when compared to natural teeth, is favorable for success [23].Additionally, Mishra et al. 2023 [48], in their systematic review, aimed to compare the clinical outcomes of dental implants in individuals using antihypertensive medications versus non-users.The databases suggested by studies involved a total of 959 patients, primarily using renin-angiotensin system (RAS) inhibitors.Findings indicated that the implant survival rate was notably higher in users of antihypertensive medications (99.4%) compared to non-users (96.1%).Additionally, a study within this review reported greater implant stability quotient (ISQ) scores in medicated patients (75.7 ± 5.9) than in nonmedicated patients (73.7 ± 8.1).Despite these positive outcomes, the evidence remains limited and heterogeneous, particularly regarding the specific types of antihypertensive medications used.As such, more targeted research is necessary to isolate the effects of different antihypertensive drugs on dental implant success and stability [48].
The varying levels of risk of bias across the studies critically influence the systematic review's overall conclusions.For studies like Wu et al., 2016 [17], and Alam-Eldein et al., 2017 [30], the high risk of bias might undermine the reliability of their conclusions, suggesting a potential overestimation or underestimation of the treatment effects.Conversely, studies with a low risk of bias, such as Carr et al., 2019 [15], and Malm et al., 2021 [31], provide stronger evidence and add more weight to the systematic review's findings.The mixed levels of bias underscore the necessity for cautious interpretation of the overall evidence and highlight the importance of considering bias in the aggregation of study results [48].

Conclusions
It is possible that inhibition of the renin-angiotensin-aldosterone system may lead to greater bone mineral density, improved primary stability, and improved survival outcomes for dental implants.There are, however, several animal studies that indicate that AH agents, especially BBs such as propranolol, may increase the amount of BIC experienced during.This will likely lead to a stable implant due to increased surface attachment and may possibly have an effect on long-term survival.More research is required to investigate the effects of antihypertensive drugs on the higher survival rate of dental implants.
The potential inhibition of the renin-angiotensin-aldosterone system may contribute to an increase in bone mineral density, which could enhance the primary stability and survival outcomes of dental implants.
The findings indicate that inhibition of the renin-angiotensin-aldosterone system is positively associated with the higher primary stability of dental implants.While secondary stability generally exceeded primary stability, the direct influence of antihypertensive agents on this aspect remains unclear.Moreover, some antihypertensive agents were associated with improved survival outcomes for implants.Despite these promising results, discrepancies in the assessment methods of primary stability and limited data on osseointe-gration highlight the need for further research.Future studies should aim to standardize evaluation techniques and expand the understanding of how antihypertensive agents affect implant success over time.
Wu et al., 2016 [17]  presented a high risk of bias due to selective reporting and incomplete outcome data.Seki et al., 2020 [28]  demonstrated a low risk of bias with comprehensive data reporting and analysis.Garcia-Denche et al., 2013[29] displayed Moderate risk due to an inadequate sample size, which could affect the generalizability of the results.Malm et al., 2021 presented Low-risk: the study used a strong experimental design with clear, transparent reporting.Alam-Eldein et al., 2017[30] noted a high risk due to potential conflicts of interest and a lack of participant blinding.

Table 1 .
(a) Study the characteristics of patients taking different classes of antihypertensive drugs with reference to their bone density, plaque, gingival index, probing depth, and marginal bone loss.(b) Effect of antihypertensive drugs on primary and secondary stability and their effect on implant survival, success, and failure.