Early Implant Failure in Patients Using Antihypertensive Medications: A Retrospective Cohort Study

Abstract

Introduction and aims

Antihypertensive medications increase osteoblasts differentiation and bone mineral formation. Osseointegration of dental implants depends on new bone formation and remodelling. Consequently, improved osseointegration may be speculated in patients receiving antihypertensive drugs. Aim – Asses the effect of antihypertensive medications on osseointegration of dental implants.

Methods

Retrospective cohort study. All individuals (792) who received at least one dental implant during a 6-year period at a single medical centre. The cohort was divided into three groups: normotensive (74.8% – 593) patients (NT group), hypertensive (23.4% – 185) patients using antihypertensive medications (HTN +med group), and hypertensive patients not using (1.8% – 14) antihypertensive medications (HTN -med group). Interventions—Installation of dental implants by experienced oral and maxillofacial surgeons with or without bone augmentation. Main measures – Early implant failure (EIF) (≤12 months from loading) reflects lack of new bone formation or excessive bone turnover during osseointegration.

Results

The study included 792 individuals, 14 in the HTN-med group, 185 in the HTN +med group and 593 in the NT group. At the patient level, the HTN -med group were most likely (P = .041) to experience EIF 28.60% (4/14 patients). Due to the small sample of the HTN -med group, an additional analysis was carried out excluding this group. EIF of 9.70% (18/185 patients) in the HTN +med group was significantly (P = .047) lower than the NT group 14.50% (86/593 patients). 2971 implants were inserted in all study groups, 71.4% (2123) in the NT group, 26.4% (784) in the HTN +med group and 2.2% (64) in the HTN -med group. Collectively, EIF was recorded for 114 (3.84%) implants. In the HTN -med group, EIF of 6.25% (4 implants), was significantly (P < .001) higher than the two other groups. The EIF rate of the HTN +med group was 2.29% (18 implants) which was significantly less than that of the NT group 4.33% (92 implants). Controlling modifying parameters, using antihypertensive medication yielded lower EIF with marginal significance (P = .059) and OR = 0.618.

Conclusion

Based on statistically significant lower EIF rate found in the HTN +med group, antihypertensive medications may decrease the EIF rate of dental implants.

Clinical relevance

Clinicians should be encouraged to treat hypertensive patients with implant-supported prostheses, provided patient compliance regarding medications intake is good.

Introduction

Hypertension is a common (1.56 billion adults globally by 2025) risk factor for mortality.¹ It is estimated that. Hypertension (HTN) is defined as systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg.² HTN is a common problem in older adults (age > 60years), reaching a prevalence as high as 70%->80%. More than 50% use antihypertensive medications.^3,4 Most common of which are the beta-blockers (BB), thiazide diuretics, angiotensin-converting-enzyme inhibitors (ACEi), and angiotensin II receptor blockers (ARBs).⁵

Increased bone resorption is promoted by stimulation of osteoclast differentiation and activity. Beta-2 adrenergic medications increase cellular differentiation and activity both osteoblasts and osteoclasts.^6,7 Sympathetic system inactivation in rats results in a significant decrease in osteoclast number and activity.8, 9, 10 Propranolol enhances bone healing and implant osseointegration in rats tibiae.¹¹

The available data, from both animal experiments and observational studies, suggest that BB use is associated with higher bone mineral density (BMD) and may be independently associated with a reduced risk of fracture.¹² Recent studies indicate that renin-angiotensin-aldosterone system (RAAS), which plays a central role in modulating blood pressure and remodelling vasculature, might also contribute to bone health.¹³ Angiotensin-II induces the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) in osteoblasts, leading to activation of osteoclasts, whereas this effect is blocked by an ARB medication.¹⁴ Thiazide diuretics affects the kidneys, intestines, and bone, and thereby modulate calcium homeostasis. In the intestines, thiazides enhance calcium uptake and suppress parathyroid hormone secretion.¹⁵ Furthermore, thiazides exert direct effects on bone by stimulating osteoblast differentiation and bone mineral formation.¹⁶

More than two-thirds of hypertensive individuals cannot be controlled solely on one drug and will require two or more antihypertensive agents from different drug classes.¹⁷

Studies indicated a link between HTN and periodontitis (a similar underlying pathology) tissue metabolism and diseases.^18,19 Preclinical studies provided evidence that RAAS-inhibitors reduce periodontal inflammation and increase alveolar bone volume.20, 21, 22, 23

Osseointegration of dental implants depends on new bone formation and remodelling. The physiological events occurring during osseointegration resemble bone fracture healing.²⁴ Thus, bone metabolic activity may benefit from antihypertensive medications. Consequently, improved osseointegration may be speculated in patients receiving antihypertensive drugs.

Implant failure may be defined as early and late.²⁵ Early implant failure (EIF) (≤12 months from loading) may reflect lack of new bone formation or excessive bone turnover during osseointegration. The literature regarding the relationship between antihypertensive medications and EIF is scarce.

Patients with hypertension are classified as either ASA 2 or ASA 3 depending on whether they are well controlled or poorly controlled, respectively. The purpose of the ASA system is to assess and communicate a patient's pre-anaesthesia medical co-morbidities.²⁶

Correlations between antihypertensive medication use and improved outcome of clinical parameters in anodized peri-implant tissue has been suggested.²⁷ A recent review on the subject concluded that limited available evidence showed that patient taking antihypertensive medications had comparable success rate and implant stability to patients not taking medications. Further studies were suggested to determine the effects of antihypertensive medications on dental implants.²⁸

The hypothesis of the present study was that the use of antihypertensive medications might have a positive impact on implant osseointegration, and subsequently yield lower EIF rates. The aim of the study was to evaluate whether antihypertensive medications decrease EIF.

Materials and methods

The present retrospective, cohort study was based on dental records of the Department of Oral and Maxillofacial Surgery, Rabin Medical Center, Campus Beilinson, Israel. Dental records of all individuals who received a dental implant from 2013-2018 were extracted automatically (electronically). All treatments were performed by experienced oral and maxillofacial surgeons. Three types of implants were installed:

• 1.Molecular precision implant (MPI™), endosseous, conical, sand-blasted and acid-etched surfacing (Ditron Dental, Israel)
• 2.Blasting soluble hydroxyapatite particles surfacing (Zimmer, USA)
• 3.Sand blasted and acid-etched surfacing, LANCE PLUS (MIS, Israel)

Inclusion criteria

• 1.Follow-up for at least 12 months following prosthetic delivery
• 2.Age above 18
• 3.Implants inserted by a specialist oral and maxillofacial surgeon
• 4.Sufficient data in the medical records

Exclusion criteria

• 1.History of head and neck cancer
• 2.Immune deficiency
• 3.Immunosuppressant medication
• 4.Heavy smoking (≥10 cigarettes a day for ≥10 years)²⁹
• 5.Untreated periodontal disease (patients not addressing an anti-inflammatory phase)
• 6.Hypertensive urgency/malignant hypertension
• 7.ASA 4

The present study was approved by the ethics committee of the Rabin Medical Center, Campus Beilinson, Israel (0674-19 RMC).

Study groups

The cohort was divided into three groups

• •Normotensive patients (NT group)
• •Hypertensive patients taking antihypertensive medications (HTN +med group)
• •Hypertensive patients which were not under hypertensive medication use (HTN -med group)

Antihypertensive medication definition

Antihypertensive medications users were defined as patients who reported to have consumed any type of medication for hypertension including beta-blockers, thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers or any combination of these groups during the pre-surgery appointment for at least one year prior to implant insertion. All antihypertensive drugs were included as one group due to the fact that most of them have a positive effect on bone turnover.

Parameters

The following parameters were recorded using a structured form:

• •Age – divided into three groups – <65; 65-80; >80
• •Gender (Male/Female)
• •Physical status according to American Society for Anesthesiology (ASA1-ASA3)²³
• •HTN (yes/no)
• •HTN medications
• •EIF (yes/no, primary outcome parameter)
• •Implant location and dimensions (length, diameter)
• •Bone augmentation prior to or simultaneously with implant installation (yes/no)
• •Number of implants installed per individual

Statistical analysis

The data was analysed using R software version 4.1.0 and R-Studio version 2022.07.1.

Descriptive statistics was performed using means and standard deviations for the continuous variables, and frequencies for the discrete variables. Univariate correlations with categorical variables (e.g., gender) were performed using the chi-square (${\chi }^2$) test. Tests between independent samples in continuous variables (e.g., age) were performed using the Kruskal Wallis tests with pairwise post hoc comparisons of Bonferroni correction. Significance was considered for a P-value lower than 5%.

Results

The cohort consisted of 792 individuals (498 females and 294 males). The NT group was the largest 74.8% (593) followed by the HTN +med 23.4% (185), and the HTN -med 1.8% (14). The NT group was the youngest with a mean age of 58.6 ± 15.4 vs. 68.7 ± 10.3 and 69.6 ± 10.9 (P = .001) respectively (Table 1).

Table 1.

Demographic and clinical characteristics at patient level.

	NT				HTN -med				HTN +med
Variable	N	%	M	SD	N	%	M	SD	N	%	M	SD	Test	P
Age	593		58.6	15.4	14		69.6	10.9	185		68.7	10.3	KW = 62.63	< .001
Age groups	593				14				185				X2 = 46.64	< .001
<= 65	378	63.7			4	28.6			77	41.6
66-79.9	182	30.7			6	42.9			77	41.6
80+	33	5.6			4	28.6			31	16.8
Gender	593				14				184				X2 = 0.613	.736
Female	368	62.1			9	64.3			120	65.2
Male	225	37.9			5	35.7			64	34.8
Implant number per patient	593		3.6	3.3	14		4.6	3.9	185		4.2	3.8	KW = 7.89	.021
Smokers	31	5.2			1	7.1			8	4.3			X2 = 0.37	.831
Implant brand	593				14				185				X2 = 3.076	.545
Ditron	82	13.8			0	0			26	14.1
MIS	148	25.0			4	28.6			52	28.1
Zimmer	363	61.2			10	71.4			107	57.8
ASA	593				14				185				X2 = 138.7	< .001
1	258	43.5			0	0			0	0
2	189	31.9			7	50			80	43.2
3	146	24.6			7	50			105	56.8

KW – Kruskal-Wallis one-way analysis of variance test.

X^{2 –} Chi square test.

The 65-year-olds and younger group were more likely to be NT (P < .001).

Number of implants per case ranged from 1-22 (mean = 3.75). Patients in the NT group received a mean of 3.58 implants per patient, significantly less than the two other groups (P = .021).

The most frequently used medication was BB (112/185, 61%) followed by ACEi (75/185, 41%), ARBs (38/185, 21%), CCB (35/185, 19%), Fusid (19/185, 10%), Thiazides (9/185, 5%).

EIF at patient level

The HTN -med group were most likely (P = .041) to experience EIF 28.60% (4/14) (Table 2). Due to the small sample of the HTN -med group, an additional analysis was carried out excluding this group. EIF 9.70% (18/185) in the HTN +med group was significantly (P = .047) lower than the NT group 14.50% (86/593).

Table 2.

EIF at patient level.

	NT		HTN -med		HTN +med
Variable	N	%	N	%	N	%	P-value
Failure	86	14.50	4	28.60	18	9.70	.041
Failure	86	14.50	Excluded		18	9.70	.047

A total of 2971 implants were inserted, 71.4% (2123) in the NT group, 26.4% (784) in the HTN +med group and 2.2% (64) in the HTN -med group (Table 3).

Table 3.

Demographic and clinical characteristics at implant level.

	NT group				HTN -med group				HTN +med group
Variable	N	%	M	SD	N	%	M	SD	N	%	M	SD	Test	P-value
Age	2123		59.63	14.53	64		65.62	11.45	784		68.18	9.80	KW = 187.72	< .001
Smoking	142	6.70			16	25			37	4.7			X2 = 39.87	< .001
Implant brand	2123				64				784				X2 = 11.62	.02
Ditron	297	14			0	0			106	13.5
MIS	550	25.9			17	26.6			216	27.6
Zimmer	1276	60.1			47	73.4			462	58.9
Bone augmentation
Total	2123				64				784				X2 = 25.62	< .001
Augmented	1344	63.3			23	35.9			451	57.5
Pristine	779	36.7			41	64.1			333	42.5
Implant characteristics
Implant length (mm)	2123		11.34	1.64	64		10.97	1.39	784		11.53	1.47	KW = 12.78	.002
Implant width (mm)	2123		3.85	0.41	64		3.80	0.27	784		3.84	0.42	KW = 2.76	.252
Implant location
Anterior maxilla	332	15.6			4	6.2			119	15.2			X2 = 4.23	.12
Premolar maxilla	385	18.1			14	21.9			149	19			X2 = 0.8	.67
Posterior maxilla	328	15.4			7	10.9			110	14			X2 = 1.74	.418
Anterior mandible	265	12.5			7	10.9			133	17			X2 = 10.17	.006
Premolar mandible	351	16.5			19	29.7			135	17.2			X2 = 7.66	.022
Posterior mandible	457	21.5			14	21.9			135	17.2			X2 = 6.66	.036

KW – Kruskal-Wallis one-way analysis of variance test.

X^{2 –} Chi square test.

Fewer 1153 (38%) implants were inserted in pristine vs. 1818 (62%) augmented bone. Implants placed in augmented bone were more likely to be in the NT group (63.3% of implants), or in the HTN +med group (57.5% of implants) than in the HTN -med group (35.9% of implants) (P < .001).

The fraction of smokers in each study group was not statistically different (P = .821) at the patient level. At the implant level, the HTN -med group had the highest rate of implants inserted in smoking patients with 16 implants (25%). This rate was statistically higher than that of the two other groups. 142 implants (6.7%) and 37 implants (4.7%) were inserted in smoking patients in the NT group and HTN +med group respectively.

Implant length ranged between 6-13 mm with a mean of 11.38 mm. and the diameter range was 3.3-6.0 mm with a mean of 3.85 mm.

EIF was recorded for 114 implants, yielding a cumulative EIF rate of 3.84% at implant level. A total of 4 Implants (1 in each patient) in the HTN -med group failed early, yielding an EIF rate of 6.25%, significantly (P < .001) higher than the two other groups (Table 4). Due to the small sample of the HTN -med group, an additional analysis was carried out excluding this group. EIF 2.29% (18 implants) in the HTN +med group (1 in each patient) was significantly (P = .01) lower than the NT group 4.33% (92- 80 patients with 1 EIF and 6 patients with 2 EIF).

Table 4.

EIF at implant level.

	NT		HTN -med		HTN +med
Variable	N	%	N	%	N	%	P-value
Failure	92	4.33	4	6.25	18	2.29	< .001
Failure	92	4.33	Excluded		18	2.29	= .01

Multivariate logistic regression model at patient level

Controlling age, gender and number of implants per patient (Table 5), the HTN +med group had lower EIF rate compared to the NT group with marginal significance (P = .059) and OR = 0.618.

Table 5.

Logistic regression coefficients predicting failure.

	B	S.E.	OR	P-value
Age	0.012	0.001	1.09	.192
Gender (Male)	-0.085	0.182	0.903	.701
Total implant number	0.103	0.078	1.051	.202
HTN +med (vs. NT group)	-0.311	0.119	0.618	.059

Discussion

Animal, clinical, and some epidemiological evidence suggests that high blood pressure is associated with abnormalities of calcium metabolism, leading to increased calcium losses, secondary activation of the parathyroid gland, and increased movement of calcium from bone.³⁰ On the other hand, antihypertensive drugs have a positive effect on bone, especially in bone formation, metabolism, and healing.³¹ Therefore, antihypertensive medications may have a 2-fold positive effect on bone – eliminating the negative effects of hypertension and improving bone metabolism by the medications themselves. This 2-fold effect may influence osseointegration and dental implant success.

To the best of our knowledge this is the first study to assess the impact of antihypertensive medications on EIF specifically and not failure in general. The results of the present study are based on a relatively large patient cohort (n = 792) and implant sample (n = 2971). The cumulative EIF rate was 3.84% on the implant, and 13.6% on the patient level. The EIF rate of patients receiving antihypertensive drugs, was 2.29% and 9.70% respectively. These rates were significantly lower vs normotensive patients, and vs hypertensive patients not under hypertensive medication. Moreover, the hypertensive group that were not using medications, showed the highest rate of EIF both at the implant (6.25%) and at the patient level (28.60%). These results strengthen the hypothesis that HTN negatively affects bone formation and support the hypothesis that antihypertensive drugs on the contrary have a positive effect on bone formation and subsequently on lower EIF. With that being said, hypertensive patients no taking their medications could be extrapolated for lack of compliance with postoperative instructions, which could also be a confounder to higher failure rate in this group.

In the present study, there is a large fraction (42.0%) of patients >65 years old (n = 333). Majority of them suffer from at least one systemic disease, and they use medications to balance their comorbidity. Our department serves a referral for patients refused dental treatment in the community clinics due to systemic diseases. The high prevalence of ASA 2 and 3 in the present study explains this fact. Hence, the present study illustrates the impact of aging and the accompanying comorbidities. The HTN +med group was older and received more implants per patient on average, than the NT group. Nonetheless, the uptake of antihypertensive medications resulted in lower EIF rate, strengthening our hypothesis.³² Clinicians should be encouraged to treat hypertensive patients with implant-supported prostheses, provided patient compliance regarding medications intake is good.

The data existing in the literature regarding the effect of antihypertensive medication on dental implant survival is scarce, with few studies addressing this issue. Torres et al. 2013³³ were the first to link antihypertensive medication with lower implant failure. A statistically significant lower dental implant failure in anti-hypertensive drug medication users following sinus augmentation was reported. The hypothesis was that the relationship between antihypertensive drugs and bone metabolism was the cause for the lower failure rate. The insufficient number of patients (n = 19) limited thy likelihood to draw a conclusion.

In 2016 Wu et al.³⁴ published a retrospective cohort study with a large number of patients (728) and dental implants (1499), of which 327 implants were placed in 142 antihypertensive medication users. In their study, the statistically significant failure rate after a mean follow-up of 17.1 months was 0.6% in hypertensive medications users vs. 4.1% in non-users. They also linked the relationship between antihypertensive drugs and bone metabolism as the reason for the lower failure rate.

Tonini et al.³⁵ investigated retrospectively the association of antihypertensive medications and implant failure. Their study comprised 602 patients and 1887 implants. No statistically significant difference was found between normotensive and hypertensive patients, as well as no difference between drug users and non-drug users in the hypertensive group. No comparison was made between drug users and normotensive patients, as 29.8% of hypertensive patients did not take their medications. They stated higher rates of failure in older age groups, but it was not clear from the results whether age was a significantly different between normotensive and hypertensive patients. No multivariate analysis was carried out.

The limitations of the present study include its retrospective nature. A well planned randomized controlled trial may lead to stronger conclusion. In addition, this study lacks information regarding oral hygiene, blood pressure classification and degree of hypertension control. Furthermore, the effects of antihypertensive medications on primary³⁶ and secondary³⁷ soft tissue wound healing were not assessed. In addition, all drugs were viewed as one. no drug specific analysis was carried, as well as period of intake and other comorbidities specifically diabetes mellitus. All of the abovementioned could be used as ideas for future research.

Conclusion

Within its limitations, the present study suggests that using antihypertensive medications may decrease the EIF of dental implants.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.