Revista Cienfica, FCV-LUZ / Vol. XXXV Recibido: 20/01/2025 Aceptado:03/04/2025 Publicado: 20/05/2025 hps://doi.org/10.52973/rcfcv-e35624 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 1 of 6 Histopathological evaluaon of effects of high fructose diet on bone healing in bial defects: An Experimental study Evaluación histopatológica de los efectos de una dieta alta en fructosa sobre la curación ósea en defectos biales: un estudio experimental * ¹Diyarbakir Agriculture Vocational School, Department of Plant and Animal Production, Dicle University, Diyarbakir, Turkiye. ²Bursa Duacinari Oral and Dental Health Center, Ministry of Health, Bursa, Turkiye. ³Department of Surgery, Faculty of Veterinary Medicine, Firat University, Elazig, Türkiye. ⁴Department of Pathology, Faculty of Medicine, Firat University, Elazig, Türkiye. ⁵Department of Peridontology, Faculty of Denstry, Firat University, Elazig, Türkiye. ⁶Department of Stascs, Instute of Science, Firat University, Elazig, Türkiye. *Corresponding author: sdundar@firat.edu.tr ABSTRACT The purpose of this study was to examine the impact of a high- fructose diet on bone regeneraon in defects created in rat bias. The experimental setup was performed with 24 female Sprague-Dawley rats in the same estrus period; the rats were divided into two groups as control and experimental groups. In the control defect group (n=12), a cylindrical defect of 4 mm in diameter and 4 mm in depth was surgically created in the corcocancellous bone of the metaphyseal part of the right bia of each rat. No other applicaon was made in this group during the experimental setup. For each rat in the high- fructose-fed defect group (n=12), cylindrical defects of 4 mm in diameter and 4 mm in depth were surgically created in the corcocancellous bone of the metaphyseal part of the right bia. Fructose supplements of the groups were added to the drinking water at a rate of 20% (w/v). All rats were sacrificed at the end of the 12th week of the surgical applicaon. The histological samples were evaluated under a light microscope. There was no significant differences in the bone regeneraon between control animals and high fructose diet consumpon group.52.2 ± 9 % for Controls, versus 49.8 ± 7.67 % for HFD (P>0,05). Further research is needed to determine the mechanisms responsible for these changes in bone structure and how these changes affect bone quality and strength with age. Key words: Fructose; high fructose diet; bone healing; bone metabolism; bone formaon RESUMEN El objevo de este estudio fue invesgar el efecto de la alimentación con dieta alta en fructosa sobre la regeneración ósea en defectos creados en bias de ratas. El experimento se realizó con 24 ratas Sprague-Dawley hembras en el mismo período de celo; las ratas se dividieron en dos grupos: grupo control y grupo experimental. En el grupo control con defecto (n=12), se creó quirúrgicamente un defecto cilíndrico de 4 mm de diámetro y 4 mm de profundidad en el hueso corcoesponjoso de la parte metafisaria de la bia derecha de cada rata. No se realizó ninguna otra aplicación en este grupo durante el experimento. Para cada rata del grupo con defecto alimentado con alta fructosa (n=12), se crearon quirúrgicamente defectos cilíndricos de 4 mm de diámetro y 4 mm de profundidad en el hueso corcoesponjoso de la parte metafisaria de la bia derecha. Los suplementos de fructosa de los grupos se agregaron al agua potable a una tasa del 20% (p/v). Todas las ratas fueron sacrificadas al final de la semana 12 de la aplicación quirúrgica. Las muestras histológicas fueron evaluadas bajo un microscopio ópco. No hubo diferencias significavas en el caso de la regeneración ósea entre los grupos control y dieta alta en fructosa 52,2 ± 9 % para animales en la dieta control, versus 49,8 ± 7,67 % para HFD. (P>0,05). Se requieren más invesgaciones para idenficar los mecanismos responsables de estas alteraciones en la estructura ósea y determinar si los cambios afectan en úlma instancia la calidad y la resistencia ósea con la edad. Palabras clave: Fructosa; dieta alta en fructosa; curación ósea; metabolismo óseo; formación ósea Can Ayhan Kaya 1 , Aslı Sagsoz 2 , Murat Tanrisever 3 , Turker Gelic 3 , Ibrahim Hanifi Ozercan 4 , Serkan Dundar 5 6 *
Bone healing in high fructose diet / Kaya et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico INTRODUCTION Recently, many changes were detected in the human diet. Commonly consumed foods and beverages such as beverages, cookies, bread, processed snacks, fermented milk products and chocolate products contain large amounts of sweeteners. Sucrose, high fructose syrups, glucose syrup, fruit juices, honey and molasses, which are frequently used in the chocolate, cake and biscuit industry, can be included in these sweeteners [1]. In humans it was reported that fructose consumpon significantly increases de novo lipogenesis, whereas eucaloric glucose intake does not [2 , 3]. It can be said that fructose has a more lipogenic property compared to glucose. Additonally, it can be said that this lipogenic effect is more pronounced in individuals with insulin resistance or type 2 diabetes [4 , 5]. Fructose does not induce the producon of insulin or lepn, hormones. These hormones are important and necessary for long-term energy regulaon. Long-term fructose consumpon, which reduces insulin responsiveness and lepn producon, may have harmful effects on energy regulaon and body fat metabolism [6]. Recently, excessive fructose consumpon has been associated with obesity and metabolic syndrome [7]. And high fructose consumpon in rats has been reported to cause hypertension, and increasing blood triglyceride, insulin, and insulin resistance [8]. Fructose is more lipogenic when compared with glucose and leads to higher triglyceride levels [9]. The increase in triglycerides increases the intramyocellular triglyceride content in skeletal muscle, due to this mechanisms insulin resistance develops in the individual [10 , 11]. High-fructose diets contribute both directly and indirectly to metabolic syndrome, insulin resistance, and cardiovascular disease. The direct effect occurs when fructose consumpon disrupts lipid and carbohydrate metabolism, and the indirect effect occurs when sugar creates a posive energy balance that leads to fat accumulaon and weight gain [12 , 13 , 14 , 15]. Studies in rats fed 10% fructose and 20% high-fructose syrup have also seen endothelial and liver dysfuncon [12 , 13]. In the bone, osteoblasts and fat cells originate from the same mesenchymal stem cells. Local and systemic condions can affect osteoblasts and fat cells [16]. Notably, diet-related negave impacts on trabecular bone structure may change by sex, with male mice showing greater changes compared to female mice [17]. Studies examining the relaonship between bone microarchitecture and nutrion in female rodent models may help to exhibit the relaonship between nutrion and bone metabolism in humans. In addion, studies on rodents regarding effects of the diets on bone metabolism in long-term may also be valuable in revealing the long-term relaonship between nutrion and bone ssue in humans. Histomorphometric examinaons have shown that bone microarchitecture deteriorates in animals fed a fay diet. It may also be of interest to examine diet-induced changes in osteoblast funcon [18]. Dietary habits can affect bone metabolism and bone remodeling processes. It was stated that high-saturated fat diet increases osteoclast acvity, which is the main cells of trabecular bone destrucon, and increases the level of fat in the bone marrow in rodent models [19 , 20 , 21 , 22]. Ex vivo examinaon of fructose-rich diets, which are converted to triglycerides in the liver and are directly linked to insulin resistance, has shown that their osteogenic properes are reduced and the adipogenic properes of bone marrow stromal cells are increased [6 , 23]. It has been reported that the combinaon of high-fat and high- fructose diets disrupts the physiological balance between bone formaon and bone destrucon, called remodeling, and leads to a decrease in trabecular bone volume [24]. In addion, it has been reported in studies conducted on both minipigs and mice that a high-fat diet also negavely affects the osseointegraon process, where bone metabolism is extremely important [25 , 26]. The areas of interest of reconstrucve bone surgery include congenital bone disorders, bone losses due to trauma, tumoral formaons and bone losses due to severe infecons. Bone defects in a small size may heal spontaneously, while bone defects in a large size may require various materials. The aim of bone defect treatment in surgical applicaons is to repair and renew bone ssue [27 , 28]. The aim of this study is to examined the healing levels of bone defects created in the bias of rats (Raus norvegicus) fed a high-fructose diet for 12 weeks using histopathological methods. MATERIALS AND METHODS Animals and study design All experimental processes of this study were performed at Fırat University Experimental Research Center (Elazig, Turkiye) aſter receiving approval from Fırat University Animal Experiments Local Ethics Commiee (Elazig, Turkiye) (Protocol No: 30 December 2022-13363). All rats included in this study were obtained from rats produced at Fırat University Experimental Research Center. During all experimental phases, the Declaraon of Helsinki for the care and welfare of animals was strictly followed. The experimental setup was performed with 24 female Sprague-Dawley rats in the same estrus period by using vaginal smear method; the rats were divided into two groups as control and experimental groups. A cylindrical defect of 4 mm in diameter and 4 mm in depth was surgically created in the corcocancellous bone of the metaphyseal part of the right bia of each rat in both of the groups [27 , 28]. No other applicaon was made in the control group during the experimental protocol. The high-fructose-fed defect group was supplemented with 20% fructose in their drinking water (w/v) [12]. All rats were euthanized at the end of the 12th week aſter surgery [22]. Surgical procedure All rats were leſt without food for 8 hours (h) before the creaon of the defects. All surgical procedures performed on the subjects were developed under general anesthesia. Xylazine hydrochloride (Rompun®, Bayer, Germany) (10 mg/kg) and Ketamine hydrochloride (Ketasol®, Richter Pharma, Austria (40 mg/kg) were used to provide anesthesia. Aſter the operaon area was shaved, ansepsis was provided using povidone iodine soluon. A 1.5 cm surgical incision was made on the bial crest in the surgical area and a periosteal elevator was used to scrape the soſt ssue in the corcocancellous bone area where the defect would be created. 2 of 6
Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico In all rats included in the study, monocorcal bone defects of 4 mm in diameter and 4 mm in depth were created in the corcocancellous bone layer in the metaphyseal parts of the right bia bones using a surgical drill (WH Physiodispenser, Austria) under sterile saline cooling. Aſter surgery, all soſt ssues and skin were sutured to their original posions (5/0 vicryl, Ethican, Inc. USA). Intramuscularly anbioc (Penicillin, 50 mg/kg) and analgesic (Tramadol hydrochloride, 0.1 mg/kg) were administrated for infecon and pain control for 3 day (d) aſter surgery. All rats in the control group fed with a normal diet and in the experimental group fed with a high-fructose diet were euthanized in the 12th week of the study. Bone blocks containing defects in the right bia bones of the rats were removed, decalcified by using %10 formic acid soluon and subjected to histopathological analysis. Applicaon of fructose diet Fructose supplements of the groups was added to the drinking water at a rate of 20% (w/v) [12]. The rats access to water and food was (will be) provided with ad ad libitum. Histopathological analyses Histopathological analyses were performed at the Department of Pathology, Faculty of Medicine, Fırat University (Elazig, Turkiye). Aſter hematoxylin and eosin staining, histological samples were evaluated under a light microscope (Olympus BX43, Tokyo, Japan). Histopathological analysis was performed by measuring the rao (%) of new bone formaon in the healing bone defect area to the defect area [27 , 28] Images of all histological secons were captured with a digital camera (Olympus Bx51; Olympus Corporaon, Tokyo, Japan) connected to a light microscope and recorded on a computer. Imaging soſtware (Olympus DP71; Olympus Corporaon, Tokyo, Japan) was used to perform histomorphometric analyses [27 , 28]. Stascal analysis IBM SPSS Stascs version 22 was used to evaluate the data obtained in this study. The Kolmogorov-Smirnov test was used to evaluate whether the data were normally distributed. Student’s T test was used to compare between groups in the evaluaon of normally distributed data. Data are given using mean and standard deviaon. Significance was assessed at P<0.05. RESULTS AND DISCUSSION As seen in the TABLE I, no significant difference was detected between control rats and high fructose diet rats in histological newly regenerated bone raos (%) (P>0,05 P:0,529 ) (52,2± 9 % for Controls, versus 49,8 ± 7,67 % for HFD) (FIG. 1 A,B). TABLE I. Newly regenerated bone (NRB) of the groups. *Student T Test. GROUPS MEAN (%) (NRB) ST. DEV. P* CONTROL (n=12) 52.2 9.00 0.529 HIG FRUCTOSE DIET (n=12) 49.8 7.67 FIGURE 1. Decalcified histologic images of the groups; A: Control Group, B: High Fructose Diet Group. Newly reegenerated bone (NRB) ssues in defect site and are surrounded by fay bone marrow. Bone filling and maturaon of the defects in the experimental group; high fructose diet, were not stascally significantly different compared with controls (P>0.05). (Hematoxylin-Eosin). *Newly regenerated bone Diet can directly affect the bone remodeling process and bone metabolism, which is an important parameter of healing in bone defects. It has been reported that saturated high-fat diets negavely affect the trabecular bone microstructure in rodents, disrupt the microstructure, increase osteoclast acvity and funcon, and increase the fay part in the bone marrow. Fructose-rich diets are directly metabolized to triglycerides in the liver, which directly causes insulin resistance. In ex vivo studies examining the relaonships between fructose diets and bone ssue, it has been shown that fructose diets reduce the osteogenic potenal in stromal cells in the bone marrow and suppress osteogenic properes by increasing the adipogenic potenal. In addion to their use alone, it has been stated that high-fat and high-fructose diet combinaons also disrupt bone metabolism and lead to a decrease in trabecular bone volume [12]. When examining the link between diet and bone metabolism, it is seen that both osteoblasts and adipocytes originate from common mesenchymal stem cells in the bone marrow. Both adipocytes and osteoblasts can be affected by local and systemic condions and changes [29 , 30]. Alteraons in bone microstructure may lead to funconal alteraons, which can be assessed using dynamic histomorphometry-a quantave method for evaluang bone formaon over me. Studies have shown reduced bone formaon in animals fed a high-fat diet [18]. Preclinical animal models offer valuable insights into how modifiable factors, such as diet, may impact bone metabolism. When the literature is examined, it is seen that there are studies examining the effects of sugar diet on bone ssue parameters; bone morphometry-microstructure, bone mineral content-density and biyomechanical strength. It was stated that consumpon of high-fat sucrose (HFS) diet has negave effects on bone strength and morphological structure in female rats during growth and development [20 , 31]. According to the data obtained from the Lorincz et al. study [32], mice fed high fructose syrup were 40% heavier than mice on the low- fat complex carbohydrate diet and when assessed for body fat, mice fed high fructose syrup had 14.9% more body fat. Addionally, these study when examined at the molecular level, mice fed high fat sucrose diet had increased expression of cyclooxygenase-2 mRNA in the bia bones compared to control subjects [32]. To uncover the mechanism behind these situaon, changes in molecular and endocrine markers of bone turnover were examined; serum tartrate-resistant acid phosphatase, osteocalcin, Receptor acvator of nuclear factor kappabeta ligand (RANKL), osteoprotegerin/RANKL and cyclooxygenase-2. Lorincz et al. [32] suggested that the difference between the two groups may be due to the triggering of osteoclast cells by chronic inflammaon caused by obesity. According to the 3 of 6
Bone healing in high fructose diet / Kaya et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico data obtained from the Lorincz et al. [32] study, HFS mice were 40% heavier and had 14.9% more body fat than low-fat complex carbonhydrate mice. Addionally, increased expression of cyclooxygenase-2 mRNA was detected in the bias of HFS- fed mice compared to controls [32]. Histopathological data obtained from this study revealed that there was no difference in bone healing in subjects fed a high fructose diet for 12 weeks compared to controls. Within the limitaons of this study it can be stated that this result may also be due to the difference in method. In another study, Douard et al. [33] reported that fructose consumpon reduces calcium transport in both the intesnes and the kidneys. Pregnant and virgin female rats were each randomly assigned to 3 groups fed a 63% glucose, a 63% fructose, or a 63% starch diet modified from a standard, published American Instuteof Nutrion (AIN)-93G formula containing normal Ca 2+ and P i levels.They stated that the relaonship between fructose consumpon and decreased calcium transport is an effect related to the decrease in 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) levels. It is thought that the increased expression of 24-hydroxylase (CYP24A1), which promotes renal catabolism of 1,25-(OH)2D3, and the decreased expression of 1α-hydroxylase, which impairs 1,25-(OH)2D3 synthesis, are related to this mechanism. As a result of the above menoned mechanism it was suggested that fructose negavely affects calcium metabolism by altering vitamin D regulaon [33]. Tsanzi et al. [34], in their experimental animal studies examining the effects of different types of sugary drinks on bone mass and biomechanical strength, could not detect any difference in the biomechanical strength of the bia between the experimental groups. The researchers suggested that this result may have been due to the short duraon of the experimental setup. In contrast, Tjäderhane and Larmas [35] stated that they found changes in the bending strength of the bia aſter only 5 weeks of feeding in their studies on subjects fed a high sucrose diet [35]. Tsanzi et al. [34] also reported that serum osteocalcin, serum alkaline phosphatase and urine deoxypyridinoline, which are considered to be the main markers of bone metabolism, did not create a significant difference between the groups. The authors reported that these results obtained may be due to the fact that the changes in bone turnover are region-specific. In addion, they stated that their measurements may have shown the bone formaon and resorpon acvity of the enre skeletal system rather than regional changes [34]. This study was conducted on the bial bones of rats. The data obtained from this study may not be valid for the enre skeletal system of the rats included in the study. Nuche-Berenguer et al. [36] studied the changes in bone structure associated with insulin resistance induced by fructose consumpon in male rats by feeding them 20% fructose containing drinking water for 8 weeks. The researchers reported that bone trabeculaon was higher and bone filling was lower in fructose-fed rats compared to normal water-drinking controls. The researchers also suggested that a higher degree of structural irregularies in trabecular bone was detected in subjects consuming fructose containing water [36]. In nutrional studies, the deterioraon in mineral balance caused by sugar consumpon has been explained by referring to previous studies [37 , 38]. However, the negave relaonship between sugar consumpon and mineral balance has not been fully clarified due to uncertaines in the studies, inconsistencies between studies, and lack of bone measurements. More advanced studies are needed on other potenal mechanisms to beer understand the negave relaonship between sugar consumpon and bone health. In a study conducted by Tjaderhane and Larmas in male and female weaned rats they noted that the strength in the bia and femurs of rats fed a low-fat diet was lower, high sucrose diet when compared to those fed a starch-based diet [35]. In addion, the bia and femur calcium levels of the subjects were significantly lower in female rats fed a sucrose diet. The researchers reported that possible mechanism could be due to increased urinary calcium excreon resulng from hyperinsulinemia following sucrose consumpon, and that this mechanism may account for the differences in bone calcium content and mechanical strength observed between the groups. It was stated that sucrose consumpon negavely affects bone health independently of fat consumpon [36]. Felice et al. [23] reported in their studies on rats that fructose diet causes metabolic syndrome, fructose feeding has negave effects on bone microarchitecture and this harmful effect is related to the disrupon of bone formaon mechanism. They also reported that these changes may be due to deflecon in adipogenic/ osteogenic potenal of mesenchymal stem cells affected by modulaon in Runx2/PPARγ rao [23]. In another study, Yarrow et al. [22] invesgated the effects of 12 weeks of standard diet (Control), 30% moderate high fat/ no sugar diet, or 30%/40% high fat/no sugar diet/high fructose diet on trabecular cancellous and corcal bone development in 8-week-old male Sprague-Dawley rats. Yarrow et al. reported that feeding “western” high-fat diet in skeletally immature male rats disrupted the architecture of cancellous bone ssue but not corcal bone, and bone loss was not exacerbated when fructose was consumed along with the high-fat diet [22]. In another study, Bass et al. [39] invesgated the effects of glucose and fructose diets on bone formaon, bone microstructure and architecture, and biomechanical strength of bone ssue. The researchers emphasized that glucose and fructose may also have different effects on bone ssue due to their different metabolic and structural properes. The researchers first randomly divided the two-month-old rats they included in their study into two groups: one group was given a high-fructose diet for 12 weeks, while the other group was given a high-glucose diet for 12 weeks. According to the data obtained at the end of the study, the researchers determined that the subjects who were given a high- fructose diet had beer bone microstructure and architecture than the subjects who were given a high-glucose diet. In another study Khan et al. studied the effects of moderate fat/high sugar and high fat/high fructose diets on femur bones in weaned male Wistar rats [40]. The researchers evaluated the mineral content and density of the rats right femur bones, corcal and cancellous bone architecture, and cell populaons within the bone. The experimental phase was completed by dividing the rats into three feeding groups: control, high fat/high fructose, and moderate fat/high sugar during the 17-week experimental setup. At the end of the study, bone mineral content and bone mineral density in the rats’ femur bones were examined by densitometric method. Microcomputed tomography was used to evaluate the microstructural features of corcal and cancellous bone. Osteoblast, osteoclast, fat cell, and chondrocyte numbers were evaluated using histomorphometric methods. At the end of the study, the researchers reported that the moderate fat/high sugar diet was largely beneficial for bone, while the high fat/high fructose diet had negave effects on bone mineral content, bone mineral density, bone microstructure and bone cell populaons [40]. In this study, no difference was found in bone healing in the rats given a high-fructose diet compared to the control group rats fed a normal diet. These results do not contradict the 4 of 6
Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico study of Bass et al., who reported that the applicaon of a high- fructose diet did not worsen bone microstructure [39]. CONCLUSION Within the limitaons of this study, it can be stated that high fructose diet applicaon does not have a suppressive effect on the healing of bone defects. Further research is required to determine the mechanisms responsible for the changes in bone structure caused by diet and to determine the methods of protecon against these changes caused by diet. Conflicts of interest The author declares that I have no conflict of interest. BIBLIOGRAFIC REFERENCES [1] Nakagawa T, Tule KR, Short RA, Johnson RJ. Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndrome. Nat. Rev. Nephrol. 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