In this study, the effect of systemic administration of different omeprazole doses on the osseointegration of titanium implants on rat tibia was evaluated by both biochemical and biomechanical analyses. No effect was observed.
Al Subaie et al. used 24 Sprague-Dawley rats in their experimental study, a titanium implant was placed in the left tibia . During the 2 weeks following surgery, 12 rats were treated with omeprazole (5 mg/kg, daily) and the other 12 with saline. They reported that omeprazole impaired the bone implant connection histologically. Due to this reason, we prefered 5 mg/kg and 10 mg/kg oral doses in experimental period according to Armah et al.’s and Al Subaie et al.’s research [15, 17].
In an animal study evaluating omeprazole’s osteogenic activity, Cottrell et al.  found no significant effect on bone formation. In another animal study, Hasanin et al.  reported that omeprazole had both negative and positive effects on bone remodeling, on the one hand reducing calcium absorption and bone formation, and on the other hand potentially inhibiting bone resorption by supressing the vacuolar osteoclastic H+-ATPase enzyme. Bodde et al.  reported that omeprazole treatment had no significant effect on bone formation. Joo et al.  evaluated the effects of long-term OME therapy on bone turnover in their in vivo study. They examined the signaling pathway involved in osteoclast differentiation and bone resorption/formation parameters experimentally in osteporosis model after the ovariectomy in female rats. Joo et al.  reported that there was no statistically significant difference in serum calcium levels among all groups. In general, it can be seen that serum calcium levels do not change substantially beyond the normal range in rats even though ovaries have been removed. As in our work, they thought that this result was similar to previous data showing that serum calcium can remain unchanged even under internal or external experimental conditions. Huang et al.  In their studies investigating the effects of calcitriol on bone mineral density in patients treated with esomeprazole, an isomer of omeprazole, they reported that serum ALP values did not make a statistical difference between the treatment and control groups. Our results-ALP are consistent with Huang et al's research. Serfaty-Lacrosniere et al.  investigated whether hypochlorhydria associated with treatment with omeprazole could affect intestinal absorption of calcium, phosphorus, magnesium, or zinc in their research in humans and they reported that no change in the intestinal absorption of phosphorus. But Al Subaie et al. reported that omeprazole-5 mg/kg with intraperitoneal injection daily negatively affected bone implant connection in a 2-week experimental protocol histologically . But two different doses of omeprazole-5 mg/kg and 10 mg/kg with oral gavage, did not produce a significant effect on the osseointegration of titanium implants in our study.
Clinical studies have been conducted on the effect of PPIs on osseointegration. Altay et al. , retrospectively analyzing 1918 dental implants in 592 patients, found that the use of PPIs increased the risk of premature dental implant loss. Similarly, in a retrospective cohort study, Wu et al.  reported that PPIs increased the risk of failure of osseointegrated dental implants. In another retrospective cohort study involving 3559 dental implants and 999 patients, Chrcanovic et al.  reported that implant loss rates were 12% in PPI users and 4.5% in non-PPI users, concluding that PPI use had a negative effect. Aghaloo et al.  also found that PPIs had a negative effect on implant osseointegration. Mester et al.  reported a link between the use of PPIs and bone regeneration and osseointegration; however, factors such as recipient bone, surgical trauma, titanium surface limitations, comorbidities, and interaction with other pharmacological agents should be considered together. Although the overall effect of omeprazole on bone metabolism was similar in this study, only the tibial bone was evaluated. Bone healing and implant osseointegration are difficult to simulate in vitro, as they depend on cells, hormones, and systems. A rat tibia model was chosen for ease of application for implant integration; however, its structure is not similar to that of the mandible or the maxilla. Although the tibial bone is surrounded by thick and well-perfused muscles, it cannot fully imitate intraoral conditions. In addition, experimental rat model studies differ from human studies in terms of skeletal change and maturity and bone turnover and healing behavior [15, 16, 18, 22].
Reverse-torque analysis is used in animal and laboratory studies—but not clinically—to evaluate primary implant stability and osseointegration. Reverse-torquing the implant in the bone provides an indirect measurement of the force required to separate the bone–implant interface. It is an objective evaluation criterion for implants with different designs and surface features and for different bone healing conditions [23,24,25]. Reverse torque analysis is an application that allows the evaluation of the entire bone around the implant. Histological analysis, on the other hand, allows evaluation only on a specific and very thin section. In our study, the reverse-torque test was used to evaluate the effect of different postoperative doses of omeprazole on osseointegration according the literature [24, 25]. No difference was found between the doses.
Serum calcium and phosphorus levels are direct measures of the degree of mineralization during bone healing. In this study, there were no statistically significant differences in serum calcium and phosphorus levels between the control and the omeprazole groups. However, it should be remembered that bone density and mineralization degree alone are not sufficient for bone quality evaluation. Serum alkaline phosphatase is an important biochemical bone-building marker [10, 21]. Although the difference between the three groups was not statistically significant, a numerical increase in alkaline phosphatase levels was observed in the groups treated with omeprazole compared to the control group.
Although the biomechanical osseointegration levels and biochemical markers make a numerical difference between the groups, it is seen that there is no statistically significant difference between the groups. This result contradicts with the work of Al Subaie et al. . In additon the histological examination can examining a specific cross section but biomechanic evaluation can evaluate the 3-dimensional response of the entire bone tissue around the implant. For this purpose, we preferred biomechanical analysis in our study.
This study has some limitations. First, the molecular mechanisms underlying the relationship between systemic omeprazole and osseointegration and bone tissue are not fully explained due to the method used in this study. Second, although experimental animal studies are necessary to explain the relationship between systemic omeprazole and bone tissue, the data from the results of these studies can only be used to predict the corresponding pathways in humans. Third, the survival rate or long-term success of implants could not be evaluated in this study. Fourth, in our skeletal system, long bones such as tibia-femur and craniofacial bones (mandible-maxilla) have different osteogenic potential and therefore may respond differently to systemic administration of omeprazole [26, 27].