Osseointegration of implants is highly dependent on the quality of the recipient bone ( Wong et al. , 1995 ), and since SSRIs seem to have a negative effect on bone formation ( Battaglino et al. , 2004 ; Gustafsson et al. , 2006 ; Diem et al. , 2007 ), we hypothesize that SSRI treatment might have a negative effect on titanium implant osseointegration and survival rate. Given the large portion of the population taking SSRIs, and the increased number of surgeries using osseointegated implants, it is vital to investigate whether SSRI treatment can affect osseointegated implant survival rate. In order to test our hypothesis, a cohort study was carried out on patients treated with one type of osseointegrated medical devices, titanium dental implants, to investigate whether the use of SSRIs is associated with higher risk of titanium implant failure.

Analyses were adjusted to the following potential confounders: sex, age, implant diameter, implant length, bone augmentation, smoking habit. These covariates were selected because of their associations with bone status or dental implant survival rate and have been controlled for in studies of similar design ( Verdel et al. , 2010 ). Statistical analysis was performed with the software SPSS 19.0 and STATA13 for Windows. The results were considered statistically significant if the corresponding p value was < .05. Post hoc power calculation was done with Cohen’s F test. Kaplan-Meier survival curves were plotted for the primary outcome “dental implant failure.”

Comparison between SSRI users and nonusers in terms of demographic systemic conditions and other factors, as well as the healing period calculation, was done through the chi-square test. Cox proportional hazards model was performed to assess the association between potential risk factors, including SSRI usage, and dental implant failure rate, adjusting for potential confounders factors. In addition, we used generalized estimating equation (GEE) models and multilevel mixed effects parametric survival analysis ( Stephenson et al. , 2010 ) to account for cluster effects of multiple implants when placed and evaluated in a single patient (repeated observations; Zeger and Liang, 1986 ; Stephenson et al. , 2010 ).

This cohort study was designed to examine the association between dental implant failure and SSRI treatment along with other factors. Sample size calculation based on Cohen’s F test indicated that a minimum of 645 implants was required to achieve a power of 0.8 at an effect size ( f 2 ) of 0.25 and a probability level of 0.05 with 8 covariates ( Kemp, 2003 ). Accordingly, differences were considered of no clinical relevance if <1.1% based on Cohen’s F test with a 25% standard deviations difference between the 2 groups’ means ( Pjetursson et al. , 2012 ).

The primary study endpoint was a binary dental implants outcome, comprising successful implants and failed implants. For either outcome, we followed patients until they experienced dental implant failure, died, or were censored for losing the track or reaching the end of the study period, whatever came first. The following parameters were retrieved from the patients’ files and standardized questionnaires: patient age, sex, implant dimensions, bone augmentation, smoking habit, physical condition, medicine undertaken, and follow-up time.

Patients were seen for follow-up examinations 10 d after surgery; all sutures were removed; and hygiene instructions were reinforced. Before delivery of the final implant-supported prosthesis, osseointegration was evaluated clinically by assessing vertical, lateral, and rotational signs of mobility. Implants with at least one of the following complications were defined as failures: pain on function; mobility; radiographic bone loss equivalent to one-half of the implant length; uncontrolled exudate; or implant no longer in mouth ( Misch et al. , 2008 ).

The use of antibiotics in implant dentistry is controversial, so postoperatively, patients were instructed to rinse 4 times per day for a period of 7 d with 0.2% chlorhexidine solution (Peridex, Periogard, Allentown, PA, USA) and to follow a soft diet. They also received prophylactically a prescription of antibiotics for a period of 7 d (amoxicillin, 500 mg, orally, 3 times per day [GlaxoSmithKline, Middlesex, UK], or clindamycin, 300 mg, orally, 4 times per day [Sandoz, Boucherville, Canada]).Analgesic agents were prescribed as needed (acetaminophen, 500 mg, 3 times per day [Tylenol, McNeil Consumer Healthcare, Fort Washington, PA, USA]; or ibuprofen, 400 mg, 3 times per day [Advil, Wyeth Consumer Healthcare, Madison, NJ, USA]).

In patients with sufficient native bone, implant (Nobel Biocare) surgery was performed under local anaesthesia, with or without intravenous sedation, according to the manufacturer’s recommended protocol ( Finkemeier, 2002 ). In cases with inadequate bone volume for implant placement, bone augmentation ( i.e. , lateral bone grafting, sinus lifting) was performed 6 mo prior to implant placement via a mixture of autogenous and allogenic bone substitutes (allogeneic bone, Straumann, Andover, MA, USA; Finkemeier, 2002 ).

Records of patients with dental osseointegrated prosthesis for this retrospective cohort study were identified in the clinic database, and the original hard copy files were retrieved for manual examination. The overall study period was 6 yr, between January 1, 2007, and September 8, 2013. Preoperative patient information, including medication, habits, and behavioral factors, was self-reported through a standardized questionnaire that was filled prior to the surgical intervention. Patients were excluded if they had a severe systemic disease (American Society of Anaesthesiology III or IV), were pregnant, or had a medical disorder known to substantially affect bone metabolism, such as osteoporosis, osteomalacia, Paget’s disease, vitamin D deficiency, hyperthyroidism, cancer (excluding nonmelanoma skin cancer), or alcoholism, as were those on corticosteroids, antiepileptic drugs, antihypertensive drugs, proton pump inhibitors, or bisphosphonates ( Tamimi et al. , 2012 ). Smoking habit was considered in our analysis; subjects who smoked more than 10 cigarettes per day were defined as smokers ( Tonetti et al. , 1995 ).

Approval (12-321 GEN) was obtained from the Ethical Committee for Clinical Trials of McGill University to carry out a retrospective cohort study in the dental clinic East Coast Oral Surgery (Moncton, Canada). Written informed consent was granted from all subjects. Our study is a human observational study and has conformed to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

During the entire observation period, 868 implants survived and 48 failed. The failure rates were 4.6% for SSRI nonusers and 10.6% SSRI users. SSRI users and nonusers were comparable in terms of age, sex, bone augmentation, smoking habit, implant diameter, implant length, implant torque, and follow-up period ( Table 1 ). Risk analysis confirmed our hypothesis by revealing that SSRI treatment ( p = .03) was associated with an increased risk of implant failure ( Table 2 ). Also, smoking habit ( p = .01) and small (≤4 mm) implant diameter ( p = .02) were associated with an increased risk of implant failure ( Table 3 ). Multilevel survival analysis adjusted for potential confounding factors is shown in Table 1 and 2 . Patient’s age, sex, bone augmentation, follow-up period, implant length, and torque had no significant association with implant survival rate ( Table 3 ). The post hoc power was 0.93. Kaplan-Meier survival curves for dental implant failure in terms of SSRI use, bone augmentation, smoking habit, and implant diameter are shown in Figure 2 .

During the study period between 2007 and 2013, 42 implants in 23 patients were excluded for bone-related diseases and medications ( Fig. 1 ). In sum, the 490 patients who met our inclusion consisted of 292 women and 198 men, with ages spanning 17 to 93 yr, averaging 56.4 ± 13.7. A total of 916 dental implants were placed in the included patients, out of which 94 were placed in SSRI users whereas 822 were placed in SSRI nonusers. Also, 436 implants were placed in nonsmokers, whereas 54 were placed in smokers. Implants had diameters ranging from 3.0 to 5.5 mm, lengths ranging from 7.0 to 42.0 mm, and torque at insertion from 10 to 65 N·cm (Appendix Table 2). The healing period for all implants was ranging from 0 to 8 mo (5.1 ± 1.6). Other relevant information is shown in Appendix Tables 1 and 3.

Discussion

Our hypothesis was confirmed by the present study, showing through a multivariate analysis that SSRI usage, as well as other factors, increases the risk of osseointegrated dental implant failure. Each of these factors is discussed in detail.

Bone Augmentation and Dental Implant Failure In our study, bone augmentation seemed to be associated with higher dental implant failure in GEE analysis, but the association was not significant on the basis of multilevel mixed effects parametric survival analysis in STATA. Bone augmentation is essential for placement of implants when bone volume is insufficient. However, previous studies (Yamazaki et al., 2012) indicated that higher implant survival rate can be expected when there is no need for bone regeneration procedures. The negative impact might indicate that the quality and quantity of regenerated bone are often deficient (Yamazaki et al., 2012). Moreover, bone surgeries may require more maintenance of bone integrity and more firm immobilization after surgeries (Yamazaki et al., 2012).

Smoking Habit and Dental Implant Failure In this study, we observed a significant increased risk of dental implant failure associated with smoking habits. This was in agreement with previous studies recognizing a higher rate of dental implant failure in smokers (odds ratios ranging from 3.6 to 4.6; Alsaadi et al., 2008), probably because smoking impairs bone healing after dental implant surgical treatment. The adverse effect during the early stage of osseointegration may be explained by the influence of smoking on the wound-healing process (Alsaadi et al., 2008) through a direct toxic effect (Krall and Dawson-Hughes, 1991) on the bone around implants. Smoking, especially nicotine, impairs new bone formation, reduces calcium absorption, and decreases bone mineral density transiently (Riebel et al., 1995).

Implant Dimensions and Dental Implant Failure We demonstrated that smaller implant diameters were associated with higher risk of implant failure, which was confirmed by other studies (Davarpanah et al., 2000). The use of narrow-diameter implants has been proposed to avoid bone augmentation procedures and reduce surgical complexity (Davarpanah et al., 2000). However, they have less surface area for interaction and anchorage, which may lead to insufficient bone integration, as well as unfavorable distribution of biomechanical forces, causing reduced resistance to fracture (Davarpanah et al., 2000). In our study, we did not observe a significant association between short implant length and increased failure. The implant length may be a factor in survival (Porter and von Fraunhofer, 2004), but in our study, it does not appear to be as critical as SSRI treatment, bone quality, smoking habits, and implant diameters.