Revista Cienﬁca, FCV-LUZ / Vol. XXXV Recibido: 24/09/2025 Aceptado: 26/12/2025 Publicado: 17/01/2025 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 1 of 6 Revista Cienﬁca, FCV-LUZ / Vol. XXXVI UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Histopathologic evaluaon of eﬀects of systemic Stronum Ranelate applicaon on bone healing aﬅer graﬅing bial defect Evaluación histopatológica de los efectos de la aplicación sistémica de Ranelate de Estroncio en la curación ósea tras injerto de defecto bial Burak Karabulut 1 , Murat Tanrisever 2 * , Erhan Cahit Ozcan 3 , Irem Semiha Koksaldi 3 , Burak Turgut 3 , Ozmen Istek 4 , Umit Koray Can 5 , Serkan Dundar 6α ¹Firat University, Faculty of Veterinary Medicine, Department of Pathology, Elazig, Türkiye ²Firat University, Faculty of Veterinary Medicine, Department of Surgery, Elazig, Türkiye ³Firat University, Faculty of Medicine, Department of Plasc, Reconstrucve and Aesthec Surgery, Elazig, Türkiye ⁴Mus Alparslan University, Faculty of Health Sciences, Department of Nursing, Mus, Türkiye ⁵Turkish Jockey Club Elazig Racecourse Horse Hospital, Elazig, Türkiye ⁶Firat University, Faculty of Denstry, Department of Peridontology, Elazig, Türkiye α Firat University, Instute of Sciences, Department of Stascs, Doctorate Student *Corresponding Author: mtanrisever@ﬁrat.edu.tr ABSTRACT This study evaluated the eﬀects of diﬀerent doses of stronum ranelate combined with a bovine-derived deproteinized xenogeneic bone graﬅ on bone healing in a rat defect model. Thirty-ﬁve female Sprague Dawley rats were randomly assigned to ﬁve groups (n = 7). A healthy control group received no treatment. In all other groups, a standardized 4 mm × 4 mm defect was created in the metaphyseal region of the rat bia. The defect control group received no addional treatment. In the defect–graﬅ group, the defect was ﬁlled with a bovine- derived deproteinized xenogeneic bone graﬅ. In the defect– graﬅ + stronum groups, the defect was ﬁlled with the same graﬅ and stronum ranelate was administered by oral gavage at doses of 450 mg/kg or 900 mg/kg, three mes per week for eight weeks. All rats were euthanized at the end of the eight- week experimental period. Bone ssues were harvested and processed for histological analysis. Data normality was assessed using the Shapiro–Wilk and Kolmogorov–Smirnov tests. As normality assumpons were not met, group comparisons were performed using the Kruskal–Wallis test followed by Mann– Whitney U post hoc tests. Mean horizontal defect sizes were 0 in the healthy control group, 716.86 in the defect group, 658.57 in the defect–graﬅ group, 604.57 in the defect–graﬅ dose 1 group, and 598.86 in the dose 2 group. Mean vercal values were 0 in the healthy group, 575.14 in the defect group, 596.43 in the defect–graﬅ group, 569 in the dose 1 group, and 503.29 in the dose 2 group. In conclusion, stronum ranelate had a posive eﬀect on bone healing compared to the control group, parcularly when combined with graﬅing. A signiﬁcant diﬀerence was also observed between the defect group and the high-dose group, conﬁrming its beneﬁcial eﬀect on bone healing. Key words: Stronum ranelate; bone defect; bone graﬅing; guided bone regeneraon; bia bone; rat RESUMEN Este estudio evaluó los efectos de diferentes dosis de ranelato de estroncio combinadas con un injerto óseo xenogénico desproteinizado de origen bovino sobre la cicatrización ósea en un modelo de defecto en ratas. Treinta y cinco ratas Sprague Dawley hembra fueron asignadas aleatoriamente a cinco grupos (n = 7). El grupo control sano no recibió tratamiento. En los demás grupos se creó un defecto estandarizado de 4 mm × 4 mm en la región metaﬁsaria de la bia. El grupo con defecto no recibió tratamiento adicional. En el grupo defecto–injerto, el defecto se rellenó con el injerto óseo. En los grupos defecto– injerto + estroncio, además del injerto, se administró ranelato de estroncio por vía oral a dosis de 450 mg/kg o 900 mg/kg, tres veces por semana durante ocho semanas. Al ﬁnal del período experimental, todas las ratas fueron eutanasiadas y los tejidos óseos se procesaron para análisis histológico. La normalidad de los datos se evaluó mediante las pruebas de Shapiro–Wilk y Kolmogorov–Smirnov. Dado que los datos no siguieron una distribución normal, las comparaciones entre grupos se realizaron con la prueba de Kruskal–Wallis y la prueba U de Mann–Whitney como análisis post hoc. Los valores medios del defecto horizontal fueron 0 en el grupo control sano, 716,86 en el grupo con defecto, 658,57 en el grupo defecto–injerto, 604,57 en el grupo defecto–injerto dosis 1 y 598,86 en el grupo dosis 2. Los valores medios vercales fueron 0 en el grupo sano, 575,14 en el grupo con defecto, 596,43 en el grupo defecto– injerto, 569 en el grupo dosis 1 y 503,29 en el grupo dosis 2. En conclusión, el ranelato de estroncio mostró un efecto posivo sobre la cicatrización ósea, especialmente cuando se combinó con injerto, observándose una diferencia signiﬁcava entre el grupo con defecto y el grupo de dosis alta. Palabras clave: Ranelato de estroncio; defecto óseo; injerto óseo; re- generación ósea guiada; bia; rata https://doi.org/10.52973/rcfcv-e361806

Revista Cienﬁca, FCV-LUZ / Vol. XXXVI UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico INTRODUCTION Bone augmentaon procedures have become increasingly common in individuals receiving implants. The goal of this procedure is to ensure good stability by completely anchoring the implants circumferenally to the bone aﬅer the bone healing process is complete. Surgeons have also used autogenous bone chips to enhance bone formaon [1]. The frequency of implant treatment in older paents is increasing. Systemic metabolic disorders are more common in older individuals. Therefore, appropriate treatment protocols should be deﬁned for this paent group during implant placement and bone regeneraon [2]. Bone regeneraon must allow cells with regenerave capacity to inﬁltrate the wound to facilitate regeneraon in a speciﬁc ssue. This allows guided bone regeneraon to be achieved by applying a biological concept [3],4,5]. Studies have proven the beneﬁts of guided bone regeneraon (GBR). These studies have reported similar survival rates for implants in alverolar ridges with defects and bone crests with normal structure [6]. Although both biological and synthec graﬅs have been employed in the management of bone defects, autograﬅs remain the preferred and most widely accepted opon [7]. However, owing to the limited supply of autogenous graﬅs, the risks involved in their producon, and the lower performance of synthec graﬅs, the need to develop eﬀecve and safer alternaves has emerged [8 , 9]. To address these issues, the use of osteoinducve factors and osteoprogenitor cells is recommended to migate the negave eﬀects of disrupons in the healing process and to improve osteogenesis [10 , 11 , 12]. Stronum (Sr) is an element that has a posive eﬀect on bone formaon and protects against bone resorpon. Stronum ranelate (SR) can cause cardiovascular complicaons. Therefore, cauon should be exercised in its indicaon [13 , 14 , 15] Several preclinical studies performed in both normal and osteoporoc animal models have corroborated earlier in vitro ﬁndings, demonstrang the beneﬁcial eﬀects of SR in enhancing bone structure and strength [14 , 15 , 16]. Consequently, SR has recently been integrated into various bone substute materials to promote bone regeneraon and repair. This approach seeks to achieve high local concentraons of the agent, thereby enhancing bone formaon while minimizing systemic side eﬀects and enabling safer ulizaon of its osteoanabolic and an-osteoclasc properes. However, there is a scarcity of in vivo studies, and many exisng reports lack the inclusion of appropriate control groups. The eﬃcacy and safety of SR-enriched materials remains a maer of debate, and more informaon and uniform criteria for topical SR use are needed. Studies using SR, parcularly those requiring evaluaon before clinical trials, have been conducted. As a result of these evaluaons, increases in bone structure and strength were observed in both healthy and osteoporoc animal models [16], 17 , 18]. Based on these studies, SR has been used as various bone substutes to enhance bone repair. This applicaon ensures that high doses reach the local area, reducing systemic eﬀects and improving bone formaon. It also aims to achieve osteoanabolic and an-osteoclasc acvity in a safer and more feasible manner. Discussions regarding the use of Sr-enriched materials connue. More deﬁnive data requires further study [19]. The aim of this study was to evaluate the eﬀects of administering diﬀerent doses of Stronum Ranelate to bovine deproteinized xenogeneic bone graﬅ aﬅer creang a bone defect on the bone healing process. MATERIALS AND METHODS Animals and study design Since the study will be conducted on female rats (Raus norvegicus), vaginal smears will be taken on all selected rats, and rats in the same estrus phase will be included in the study. Before starng this study, an applicaon for study approval was made to the Fırat University Animal Experimentaon Local Ethics Commiee (Protocol No: 2024-02-09, Date: 17 January 2024), and the commiee granted approval. The rats were produced by the Fırat University Experimental Research Center (Elazığ, Türkiye) and were delivered to the academics conducng the study once the speciﬁed criteria were met. This study adhered to all recommendaons of the European Declaraon of Helsinki and was conducted in Elazığ (Türkiye) within the animal experimentaon protocol of the Ministry of Agriculture of the Republic of Türkiye. No animals were subjected to pain during the experiments, and utmost aenon was paid to all ethical commiees. All recommendaons in the Declaraon of Helsinki for the protecon of experimental animals were adhered to. Thirty-ﬁve female Sprague Dawley rats, aged 6-12 months, were used in this study. The average weight of the rats used in our experimental study was between 270 and 300 g/m (WL, Shimadzu, Japan). To prevent harm to the animals during the experiment, temperature was constantly controlled, and a 12- hour (h) light/12-h dark cycle was applied. Groups of 35 rats were randomly selected. The rats were divided into 5 groups of 7 rats each. 1. Defect-Healthy Control Group: No treatment was administered to the healthy control group. 2. Defect-Control Group: In the defect study design, bone defects measuring 4 mm in diameter and 4 mm in depth were created in the corcocancellous region of the metaphyseal poron of the bia in the experimental groups. 3. Defect-Graﬅ Group: In the defect study setup, bone defects measuring 4 mm in diameter and 4 mm in height were created in the corcocancellous bone of the bial metaphysis in the experimental groups. The defect area was ﬁlled with bovine-derived deproteinized xenogeneic bone graﬅ. 4. Defect Graﬅ Stronum Dose 1 Group: In the defect study setup, bone defects of 4 mm in diameter and 4 mm in height were created in the corcocancellous bone of the bial metaphysis in the experimental groups. The defect area was ﬁlled with bovine deproteinized xenogeneic bone graﬅ. 450 mg/kg stronum ranelate was administered by oral gavage three mes per week for eight weeks. 2 of 6

Systemic Stronum Ranelate in bial graﬅing / Karabulut et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 5. Defect Graﬅ Stronum Dose 2 Group: In the defect study setup, bone defects measuring 4 mm in diameter and 4 mm in height were surgically created in the corcocancellous bone of the bial metaphysis in the experimental groups. The defect area was ﬁlled with bovine deproteinized xenogeneic bone graﬅ. 900 mg/ kg stronum ranelate was administered by oral gavage three mes per week for eight weeks. Surgical procedures Surgical procedures were performed under deep anesthesia to prevent pain in the rats. The animals were anesthezed using 50 mg/kg Ketamine (Ketasol; Richter Pharma, Wels, Austria) and 10 mg/kg Xylazine (Rompun; Bayer, Germany). A 2-cm full- thickness incision was made to access the crestal bone of the bia. The soﬅ ssues and periosteum were prepared for the operaon using a periosteum elevator. A rotary tool was used at 600 rpm under serum cooling to create the defect (NSK, Japan). Aﬅer the surgical applicaons the soﬅ ssues were aached original posions. And aﬅer suturing with 3-0 prolen sutures anbioc (Cefazolin sodium 40 mg·kg -1 , iespor 250, I.E. Ulagay, Türkiye) and analgesic (Tramadol hydrochloride 0.1 mg·kg -1 , Contramal, Abdi Ibrahim, Türkiye) were injected intramusculary. Aﬅer the procedures were completed, the experiment was terminated, and an eight-week recovery period was awaited. The rats were then euthanized. Histological analysis was then performed. Histopathological analysis procedure Histopathological analyses of the study were completed in the Pathology Department laboratory of Fırat University, Faculty of Veterinary Medicine. Aﬅer the animals were euthanized, bone samples (bias) encompassing the defect sites were preserved in 10 % neutral formalin for three days (d). All soﬅ ssues (muscle, tendon, and fascia) were then removed. They were then decalciﬁed in 10 % formic acid soluon for 1 week. Following these procedures, they were processed through alcohol, xylene, and paraﬃn series using an automac ssue processing device (Leica TP 1020, Germany). The ssues processed in these soluons were embedded longitudinally in paraﬃn (Leica EG1150 H-C, Germany). 3-micron-thick secons were cut from the paraﬃn blocks using a rotary microtome (Leica RM2125 RTS, Germany) and stained with hematoxylin- eosin (Leica Autostainer XL). Histopathological examinaon was performed using a standard light microscope (Olympus BX42, Japan). Analyses were performed by measuring the widest and deepest points of the defect areas longitudinally and the thickest part of the callus ssue transversely (cellSens Standard, Japan). Stascal analysis Stascal analyses were conducted using IBM SPSS Stascs version 23. The normality of the data was assessed using the Shapiro–Wilk and Kolmogorov–Smirnov tests. Since the data did not meet the assumpons of normality, group diﬀerences were evaluated using the Kruskal–Wallis test, followed by pairwise comparisons with the Mann–Whitney U test as a post hoc analysis. Results are expressed as mean/median, min-max, with stascal signiﬁcance deﬁned as P < 0,05. All analyses were conducted by a blinded invesgator, who was unaware of the group assignments. RESULTS AND DISCUSSION Histological analyses were performed by measuring the remaining open defects. These measurements were performed in two diﬀerent dimensions. They were evaluated separately for vercal and horizontal measurements (FIG. 1). FIGURE 1. New bone formaon and ﬁbrosis areas in the defect area of systemic Stronum Ranelate applicaon on bone healing aﬅer graﬅing bial defect in the healthy control (A) and experimental groups, B: Defect control, C: Defect graﬅ control, D: Defect graﬅ dose 1, E: Defect graﬅ dose 2, NBF: New bone formaon, F: Fibrosis. The mean horizontal defect sizes were 0 in the healthy control group, 716.86 in the defect group, 658.57 in the defect graﬅ group, and 604.57 in the defect graﬅ dose 1 group and 598.86 in the dose 2 group. In the vercal evaluaon, the mean values were 0 in the healthy group, 575.14 in the defect group, 596.43 in the defect graﬅ group, and 569 in the defect graﬅ dose 1 group and 503.29 in the dose 2 group. Signiﬁcant diﬀerences were found between the healthy group and all groups (P < 0.05). Analyses between the defect group and the graﬅ and strain ranelate groups revealed signiﬁcant diﬀerences only in the horizontal defects and in the dose 2 group. P = 0.015 (TABLE I). 3 of 6

Revista Cienﬁca, FCV-LUZ / Vol. XXXVI UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico TABLE I Horizontal and vercal defect healing of systemic Stronum Ranelate applicaon on bone healing aﬅer graﬅing bial defect Parameters Groups N Mean/Median Minimum Maximum P* Horizontal Defect-Healthy Control 7 0/0 0 0 0.001 Defect control A 7 716.86/677 612 821 Defect graﬅ A 7 658.57/644 501 756 Defect graﬅ dosage 1 A 7 604.57/661 411 771 Defect graﬅ dosage 2 A.C 7 598.86/601 524 746 Vercal Defect-Healthy Control 7 0/0 0 0 Defect control B 7 575.14/544 511.00 736 Defect graﬅ B 7 596.43/533 512.00 742 Defect graﬅ dosage 1 B 7 569/551 433.00 771 Defect graﬅ dosage 2 B 7 503.29/506 403.00 605 The Krusskall-Wallis* test was used to determine whether there was a diﬀerence between the groups. Pairwise comparisons were made with the Mann-Whitney U test. A: Stascally diﬀerent compared to Healthy (A, B: P = 0.000). C: Stascally diﬀerent compared to the defect control (C: P = 0.015). Since no defect was created in the health control group, vercal and horizontal bone defects could not be detected Among the studies conducted by Cardemil et al., [20] the study was evaluated 4 weeks aﬅer implantaon and found no diﬀerence between the groups. However, studies by some authors reported signiﬁcant improvement at 2 and 4 weeks [21]. This is thought to be related to the duraon of SR exposure. When the studies were evaluated, it was determined whether there was a signiﬁcant diﬀerence between the experimental and control groups, and there was a large similarity between the number of studies reporng a posive eﬀect and the number of studies reporng no diﬀerence. The studies evaluated new bone formaon. In this case, superiority was found in the 6-week studies. This conﬁrms the posive eﬀect of SR use on bone diﬀerenaon and osteogenesis reported in previous studies [22], 23 , 24 , 25 , 26]. In this study, similar to the studies conducted, was conducted over a longer period of 8 weeks. This is because the eﬀects are more pronounced in longer-term studies. Studies conducted with SR have not reported any adverse eﬀects on bone formaon and remodeling in healthy and paent models at any me. Posive eﬀects on osteogenesis have been observed even in osteoporoc experimental models [27]. Studies have shown that even a 0.1 % dose of SR in the compound can be eﬀecve in both bone formaon and remodeling [28 , 29]. Other studies have reported that the posive eﬀect on bone formaon increases with increasing SR dose. However, according to the studies, no deﬁnive measurement for the opmal dose has been established [30], 31]. One study on the subject observed minor changes in osteolyc acvity and bone resorpon. A decrease in the proinﬂammatory cytokine IL-6, which is involved in inﬂammaon, was observed during healing, highlighng its posive eﬀect on bone formaon and remodeling. The posive eﬀects of SR are evidenced by the observed increases in osteocalcin and bone morphogenec protein during the bone formaon process [32]. In this study, increases in bone healing were observed in the SR groups. This is thought to be due to increases in osteocalcin and bone morphogenec protein. Studies have indicated that SR administraon leads to increased bone formaon and reduced bone resorpon. Studies have observed an increase in bone mineral density, and this is aributed to an increase in bone mechanical properes. It has also been highlighted that SR promotes osteogenic bone formaon while inhibing osteoclasc resorpon [33]. SR smulates increased expression of cytokines, including alkaline phosphatase (ALP), osteocalcin (OC), and bone sialoprotein, all of which are key members of the osteoblasc gene family. This results in an increase in bone nodules and a decrease in mature osteoclasts in vitro [14], 34]. Furthermore, studies have reported increased levels of type 1 collagen, ALP, ALP, bone sialoprotein, OC, and ulmately bone matrix mineralizaon in bone marrow stromal cell cultures and immature osteoblasts. Furthermore, it has been reported that it induces pre-osteoblast proliferaon and increases osteoblast acvity [9 , 35]. Takaoka et al. [36] reported that the use of SR inhibits osteoclast-mediated bone resorpon and osteoclast acvaon, smulang osteoblast bone-forming acvity and diﬀerenaon. In a recent study, Almeida et al. [37] invesgated the use of SR and observed signiﬁcant increases in organic bone matrix. They also observed increased expression of type 1 collagen and osteoponn. A study by Pilmane et al. [38] emphasized that the use of SR promotes the formaon of bone-like nodules in osteogenic cultures and increases osteoblasc acvity, suggesng that it may help reduce fractures due to bone hardening, parcularly in postmenopausal women. CONCLUSION In this study, SR was administered in two doses (450 mg/ kg and 900 mg/kg). Compared to the control group, it was found to have posive eﬀects on bone healing, especially when 4 of 6

Systemic Stronum Ranelate in bial graﬅing / Karabulut et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico administered in conjuncon with graﬅ. Stascally signiﬁcant diﬀerences were obtained between the defect group and the dose 2 group. This demonstrates the posive eﬀect of SR on bone healing. When compared with similar studies, the results support these ﬁndings. This is thought to be primarily due to its eﬀect on osteoblast acvity. However, dose adjustments should be made more carefully, and the opmal dose should be precisely determined; therefore, further studies are needed. Conﬂict of interest All authors have declared no conﬂicts of interest. BIBLIOGRAFIC REFERENCES [1] Nayak VV, Goncalves JAKQ, Mirsky NA, Arakelians ARL, Bergamo ETP, Torroni A, Boczar D, Coelho PG, Witek L. 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