The effects of NSAIDs on the osteogenic activity of osteoblasts have been extensively studied at the molecular pharmacological level [23]. However, only two studies have been identified that investigated the effect of NSAIDs on osteoblasts attached to titanium surfaces (Table 6). In the study conducted by Boyan et al., their results demonstrated that a non-selective COX inhibitor (indomethacin, 0.1 μM), a selective COX-1 inhibitor (resveratrol, 1 and 10 μM), and a selective COX-2 inhibitor (NS-398, 1 and 10 μM) did not have a significant effect on the number of cells derived from human osteosarcomas [20]. Furthermore, Boyan et al. demonstrated that the NSAIDs reduced prostaglandin E₂ (PGE2) production of cells attached to a rough titanium surface. Their results indicated that both COX-1 and COX-2 are involved in the production of osteocalcin, PGE2, and TGF-β1 by osteoblasts [20]. They also demonstrated that osteoblasts produced increased levels of PGE2 on rough titanium surfaces and that this was correlated with increased alkaline phosphatase activity and osteocalcin production [20]. This suggests that PGE2 may have a role in osteoblast proliferation and differentiation on titanium surfaces, and that this favourable effect of PGE2 was inhibited when a NSAID was present [20]. Arpommaeklong et al. found that a non-selective COXinhibitor (indomethacin, 0.1 μM) and a selective COX-2 inhibitor (celecoxib, 1.5, 3.0, and 9.0 μM) inhibited the growth of cell cultures derived from rat calvarias, where the effect was dose-dependent in the cultures treated with celecoxib [19]. Furthermore, Arpommaeklong et al. demonstrated that PGE2 levels were significantly lower in the groups that were treated with a NSAID, and have postulated that PGE2, consistent with Boyan et al., may have a role in osteoblast growth and differentiation [19, 20].

The clinical evidence demonstrating the effects of NSAIDs on the osseointegration of titanium dental implants is limited with only two clinical trials and one retrospective study identified in the database searches (Table 7). In the clinical trial conducted by Alissa et al., the effect of a 7-day post-operative course of ibuprofen (600 mg, taken four times daily) on the marginal bone level around dental implants was investigated [21]. They found that there were no statistically significant differences between the treated and placebo groups in the mean marginal bone level around dental implants at 3 and 6 months after implant placement [21]. In a similar clinical trial conducted by Sakka et al., the effect of a 7-day course of ibuprofen (600 mg, taken four times daily) on the marginal bone level around dental implants was also investigated [24]. They found that there were no significant differences between the ibuprofen and non-ibuprofen groups, consistent with the findings of Alissa et al., when comparing the changes in marginal bone level around dental implants [24]. However, a retrospective study conducted by Winnett et al. postulated that the adverse biological events following dental implant placement were associated with perioperative use of NSAIDs [25]. Winnett et al. reported a total loss of 197 dental implants due to failed osseointegration from patients with failing implant/s (468 implants in 104 patients) treated in a postgraduate dental clinic (between 1979 and 2012). The patients (n = 60) that used NSAIDs peri-operatively experienced a total of 119 failed implants, whilst the non-NSAID cohort (n = 44) experienced a total of 78 failed implants. Winnett et al. identified that ibuprofen (600 mg, taken four times daily) was the most commonly prescribed; however, other prescribed NSAIDs included Ketorolac, Vioxx, Celebrex, Diflunisal, Meloxicam, and Naproxen [25]. Despite the clinical trials conducted by Alissa et al. and Sakka et al., both of whom have demonstrated that a 7-day post-operative course of ibuprofen (600 mg, taken four times daily) did not significantly affect bone levels around dental implants at 3 and 6 months after placement, the data gathered by Winnett et al. indicates that NSAIDs may have detrimental effect on osseointegration [25].