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. 2023 Apr 14;24(3):e35. doi: 10.4142/jvs.23023

Radioprotective role of amifostine on osteointegration of titanium implants in the tibia of rats

Nevra Aydemir Celep 1,2, Hülya Kara 3, Elif Erbaş 2,✉, Elif Doğan 4
PMCID: PMC10244126  PMID: 37271503

Abstract

Background

Titanium is the most widely used metal for bone integration, especially for cancer patients receiving ionizing radiation. This study aimed to investigate the amifostine administration that would reduce the effects of radiation on bone healing and osseointegration in rat models.

Objectives

It is aimed that the application of amifostine in rats receiving radiotherapy treatment will reduce the negative effects of ionizing radiation on the bone.

Methods

Thirty-five adult male Wistar rats were randomly divided into one healthy and four experimental groups. In three consecutive days, two experimental groups of rats (AMF-RT-IMP and RT-IMP) were exposed to radiation (15 Gy/3 fractions of 5 Gy each). Then the titanium implants were inserted into the left tibia. Before the radiotherapy process, a 200 mg/kg dose of amifostine (AMF) was administered to the rats in the AMF-IMP and AMF-RT-IMP groups. Twenty-eight days after the screw implant, all rats were sacrificed, and their blood samples and tibia bones were collected for analysis.

Results

The results indicated an accelerated bone formation and a more rapid healing process in the screw implants in the AMF-IMP, AMF-RT-IMP, and AMF-RT groups than in the RT-IMP group. Also, bone-implant contact area measurement and inflammation decreased with amifostine treatment in the implants subjected to irradiation (p < 0.05).

Conclusions

The results obtained in the present study suggested that amifostine prevents the losses of bone minerals, bone integrity, and implant position from ionizing-radiation when given before exposure.

Keywords: Ionizing radiation; amifostine; implants, artificial; osseointegration; osseo-integrated implants

INTRODUCTION

Therapeutic approaches for cancer patients generally consist of surgical tumor extirpation and subsequent reconstructive procedures. In addition to the surgical intervention, radiotherapy is also often a part of the cancer treatment. Radiation therapy is an essential, definitive and adjuvant therapy for many cancer patients [1]. Nevertheless, pathological fracture and osteoradionecrosis may occur in nearly one in four patients as the consequences of long-term radiation therapy [2,3].

Amifostine may be useful to protect injured bone from the destructive effects of ionizing radiation. Amifostine administration before irradiation may preserve the biomechanical properties of the bone [2]. Amifostine or AMF, S-2-[3-aminopropylamino] ethylphosphothioic acid or WR-2721 was investigated by the Walter Reed Army Institute of Research among thousands (over 4000) of sulfhydryl-containing drugs with varying degrees of superior radioprotective properties [4,5]. The use of amifostine as a radioprotectant may decrease dangerous complications of radiation-induced damages of bones. This benefit would potentially affect the approach and use of any radiation protocol [2]. Also, amifostine can prevent both distraction osteogenesis and inhibition of fracture repair [6,7]. Tchanque-Fossuo et al. [8] and Gong et al. [9] suggested that amifostine can protect the bone structure against ionizing radiation therapy.

We hypothesized that amifostine administration would reduce the effects of ionized radiation on bone healing and osteointegration in the rats undergoing a treatment with radiotherapy.

MATERIALS AND METHODS

Animals

Thirty-five male Wistar rats (300–350 g and 24 weeks old) were housed in an air-conditioned room (24oC). Animals were treated with humane care according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the U.S. National Institutes of Health. All rats were fed with tap water ad libitum and standard rat pellets.

Experimental grouping

All rats (300–350 g) were randomly allocated to one control and four treatment groups: healthy group (control, n = 7), implant group (IMP, n = 7), radiotherapy + implant group (RT-IMP, n = 7), amifostine + implant group (AMF-IMP, n = 7), amifostine + radiotherapy + implant group (AMF-RT-IMP, n = 7). Control specimens received neither radiation nor amifostine pretreatment.

Drug administration

Amifostine (Ethyol 500 mg) was administered by i.p. injection (200 mg/kg in sterile normal saline) to animals in the AMF-IMP and AMF-RT-IMP group 20 min before each dose of radiation.

Irradiation procedure

The radiation dose applied to the RT-IMP and AMF-RT-IMP groups were 15 Gy at three fractions in three consecutive days using a radiotherapy machine (Siemens Linear accelerator, German). A total of 15 Gy in three fractions of five Gy of each dose was applied to the rats in the study. The reason we applied the irradiation in three fractions is because the previous studies [10,11] indicated that this approach was less harmful compared to giving the total dose at once. The distance from the source to the skin was 12 cm. The rats received tibial irradiation with a three consecutive 5 Gy dose of gamma irradiation. For radiotherapy, the animals were anesthetized using xylazine HCl and Ketamine HCl before irradiation, then immobilized. Using beam collimation and lead shields, only the fore extremities were exposed to radiation.

Surgical procedure

One-day after the last radiotherapy, all animals were anesthetized using xylazine HCl and Ketamine HCl (8 mg/kg, Xylazinbio %2, Bioveta, Czech Republic and 60 mg/kg, Ketasol %10, Richter Pharma ag, Austria). The area of operation was shaved, and the skin was cleaned with 70% ethanol. Then machined-flat surface titanium mini screw implants (1.2 mm × 4mm, MCT Titanium Mini Screw Master Kit, MCT BIO, Korea) were placed 3–4 mm the proximal extremity of the tibia and distal to the proximal metaphysis using 1.2 mm sharp drills and a physiodispenser (Surgic Pro, NSK Corp., USA) at 25–-30 newton meters torque as suggested in the previous studies [12,13]. After a 28-day consolidation period, the animals were euthanized and their left tibia was harvested.

Biochemical analysis

At the end of the study, under anesthesia, blood samples were individually collected from the heart of each rat, which was then decapitated. The blood samples were centrifuged at 1,500 rpm for 10 min, and the serum samples were stored in the −80°C freezer until analysis. Serum Bone-Alkaline phosphatase (B-ALP) enzyme concentration and Calcium (Ca), Magnesium (Mg) and Phosphorus (P) levels were determined using specific diagnostic kits (Beckman Coulter; DXI 800 USA). Bone-specific alkaline phosphatase (B-ALP) level was measured using a thermo-activation method [14].

Histological analysis

The tibia tissues were fixed in 10% formalin for 24 h, and decalcified with 5% nitric acid solution for eight days (each day the solution was renewed). There are multiple decalcification methods, but nitric acid is a well-balanced option that quickly produces high-quality histological specimens and microscopic slides [15]. Following the decalcification process, the specimens were taken to the neutralization process with sodium bicarbonate for 3h and then subjected to histological processing. The tissues were dehydrated with a series of alcohol, cleared with xylene, and then embedded in paraffin. Histological sections of 7-µm thicknesses were serially taken from paraffin blocks using a Leica RM2125RT microtome (Leica Microsystems, Germany), and six serial sections were obtained for each block. The serial sections were stained with hematoxylin - eosin for histopathologic assessment. The stained sections were visualized and examined under a trinocular light microscope (Nikon Eclipse 50i). Histomorphometric measurement was performed using a trinocular light microscope attached to an image analysis software (Kameram SLR, Turkey).

Histological scoring

Osteointegration of titanium screws to the bone surface was measured histomorphometrically on the body and within the recesses. The percentage of bone-to-implant contact (BIC) without apical surface at the lateral sides of the implants was estimated using an image analysis software (Kameram S.L, Turkey). The corresponding screw circumference without apical surface was measured in such a way that it allowed the calculation of the percentage of the bone and connective tissue contact area and implant surface area or the surrounding gap, according to the methods described in a previous study [16].

Additionally, an inflammatory score was used to determine the implant loosening caused by infection. Inflammatory (osteoclast) cells were counted under a light microscope in eight histological sections for all groups by a histology expert as described by a previous study [14]. Inflammatory cell score for intensity per unit area (mm2):

Non-existent: or few inflammatory cells = 1,
Slight: the average number of inflammatory cells < 10 = 2,
Moderate: the average number of inflammatory cells: 10–25 = 3,
Severe: the average number of inflammatory cells > 25 = 4.

Radiologic analysis

For radiographic examination, after the animals were sacrificed, all tibia bones were removed, and their radiographs were taken in the mediolateral position. The radiographs were evaluated according to the location of the implant, fracture, absence of continuous radiolucency around the implant, cortical integrity and thickness, and trabecular bone density.

Statistical analysis

The obtained data were statistically analyzed for a normal distribution with one-way analysis of variation (ANOVA), and then, the post hoc Duncan test was applied using SPSS 17.0 software (SPSS Inc., USA). All data were expressed as mean ± standard deviation. The p-value less than 0.05 was considered significant.

RESULTS

In the biochemical analysis, serum calcium (Ca) levels were found to be significantly higher in RT-IMP group than all other groups (p < 0.05). Also, serum calcium level was lowest in the control group and significantly lower than the RT-IMP and AMF-RT-IMP groups (p < 0.05). The serum magnesium level was considerably higher in the RT-IMP and AMF-RT-IMP groups than in the other groups. Meanwhile, there was a significant difference between the RT-IMP and AMF-RT-IMP groups in terms of magnesium levels (p < 0.05). The serum concentration of phosphorus (P) in the RT-IMP group was significantly higher than in the other groups (p < 0.05). Also, there were no significant differences among the control, IMP, RT-IMP, and AMF-IMP groups in terms of phosphorus levels (p > 0.05). Additionally, the B-ALP enzyme levels of the AMF-RT-IMP and RT-IMP groups were significantly higher than the other groups (p < 0.05). The serum levels of Ca, Mg, P, and B-ALP are presented in Fig. 1.

Fig. 1. Serum biochemical calcium (Ca), magnesium (Mg) and phosphor (P), and B-ALP enzyme levels for all groups; the letters indicate the statistical differences among groups. A p value of < 0.05 was considered statistically significant.

Fig. 1

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U/l, units per liter; B-ALP, bone-alkaline phosphatase.

In the histological analysis, there were some new bone formation, bone trabeculae, osteoid tissue, and osteoblast in the surrounding screw area of the tibia. However, there was a decrease in bone trabeculae, new bone formation, osteoid tissue, and active osteoblast cells in the IMP, AMF-IMP, and RT-IMP groups compared to in the AMF-RT-IMP group. Additionally, there was little bone formation in screw-surrounded areas compared to the AMF-RT-IMP group sections.

In the inflammatory cell analysis, the inflammatory cell density and the score of the RT-IMP groups were significantly higher than the other groups (p < 0.05). However, there was no significant difference among the IMP, AMF-IMP, and AMF-RT-IMP groups regarding to inflammatory cell score (p > 0.5). The inflammatory scores of all groups are presented in Table 1.

Table 1. The percentage of histomorphometric measurement of bone-to-implant contact and inflammatory cell scores for rats from 4 treatment groups.

Groups (n = 7) BIC (%, mean ± SD) Inflammatory score (mean ± SD)
IMP 33.42 ± 6.11a 2.71 ± 0.75a
AMF-IMF 32.14 ± 5.78a 2.65 ± 0.64a
RT-IMP 21.53 ± 4.76b 3.71 ± 0.48b
AMF-RT-IMP 41.61 ± 7.23c 2 ± 0.81a
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The letters (a,b,c) indicated the statistical differences between groups, the data were analyzed by ANOVA followed Duncan Post-hoc test. A p value of < 0.05 was considered statistically significant.

IMP, implant group; RT-IMP, radiotherapy + implant group; AMP-IMP, amifostine + implant group; AMP-RT-IMP, amifostine + radiotherapy + implant group.

In the analysis of osteointegration, the percentage of BIC tissue was found significantly higher in the AMF-RT-IMP group than in the other groups (p < 0.05). Also, the percentage of BIC was found to be lower in the RT-IMP group than the IMP group (p < 0.05) (Fig. 2, Table 1).

Fig. 2. Hematoxylin-eosin staining of screw implanted tibia bones belonging to the 4 groups of rats, IMP, RT-IMP, AMF-IMP and AMF-RT-IMP. 'Screw' indicates the screw placed areas. Lower panels are the magnified view of the black framed areas. Black arrows indicate the bone-to-implant contact faces and blue arrows osteoclast cells.

Fig. 2

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screw, screw placed areas; black frame, magnified areas; open arrows, bone-to-implant contact faces; blue arrows, osteoclast cells; SC, subperiosteal callus; CB, cortical bone.

The radiographs presented that the titanium implants remained in their original location in the bone tissues, and there was no loosening or dislocation after implantation. There was no fracture in the operated bone. Also, radiolucent areas around the implant were not detected in the radiographs. When cortical integrity and thickness in the tibial bone and trabecular bone density were evaluated, no abnormality was observed (Fig. 3).

Fig. 3. Radiologic view of the screw implanted into the rat tibia at the end of the study.

Fig. 3

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IMP, implant group; RT-IMP, radiotherapy + implant group; AMP-IMP, amifostine + implant group; AMP-RT-IMP, amifostine + radiotherapy + implant group.

DISCUSSION

The use of radiation therapy, which has been found to cause numerous pathological problems such as bone fractures, is common for cancer patients [17,18]. To date, studies on ionizing radiation damages to the axial skeleton and long endochondral bones are limited in the literature. After radiotherapy treatment, long bone fracture complication can frequently be seen due to the high doses of radiation given in the treatment of extremity sarcoma [19,20]. Existing studies on limb-sparing therapy of soft tissue sarcoma of the extremities suggest a post-radiotherapy fracture incidence ranging from 4 to 8.6%.

There is a continued interest and need to identify and develop non-toxic radioprotective compounds. The present study examined the radioprotective effect of amifostine, which can block the level of gamma irradiation-induced pathologic alterations on bone structure. The amifostine dose (200 mg/kg) used in our study was determined according to the previous studies [6,7,21]. Amifostine is usually a well-tolerated drug; however, it may have some adverse effects, including hypotension, nausea, vomiting, and allergic reactions that may be related to dose management [19]. Additionally, a radioprotective effect of amifostine has been investigated by many previous studies [22,23].

Laboratory animal models are commonly used to assess pathophysiology of diseases and new treatment strategies. Mice and rats are most commonly used laboratory animals due to their low cost, easy handling, and the ease of increasing their number in trials. The animals are usually used to model bone fixation models, diseases, and biomedical researches that are often clinically observed in unhealthy, aged, or healing-compromised humans [24]. In the study, we used rat models to assess the radioprotective effect of amifostine on titanium screw implanted bone osseointegration that was subjected to irradiation.

Our results demonstrate that the amifostine provides significant protection to rat’s bone against the osteoclastogenic effects of gamma irradiation. Although the majority of in vitro studies with radioprotectants focused on the prevention of cellular viability, our research addresses not only the impact of amifostine and fractionation on cellular regeneration but also osteoblastic capacity osteointegration. We measured the radiation-induced bone destruction and mineral loss. In this study, we assessed the effect of amifostine pretreatment on osteointegration and bone renewal. Although amifostine has been shown to have radioprotective effects on skin and salivary glands, and previous studies also suggested that the radioprotective role of amifostine to other cell types such as endothelial cells and mesenchymal progenitor cells, its efficacy as a radioprotective agent has not been tested in osteointegration [24,25,26]. Both previous in vitro and in vivo pharmacokinetic analyses and our study revealed that the radioprotective role of amifostine is acute and dependent on time of administration, dose and alkaline phosphatase activity [25,26,27].

These reports highlight once again the preventive role of amifostine against radiation-induced mineral loss in tibia [25,26,27]. However, amifostine does not result in a complete rescue. Our biochemical results indicate both the strengths and limitations of amifostine treatment and reveal the effects of the metabolic pathway that inhibits the bone healing and regeneration. Amifostine seems to specifically prevent the bone mineral loss. It diminishes the effect of radiation on bone alkaline phosphatase enzyme activity and the serum levels of calcium, magnesium, and phosphorus. Therefore, it significantly protects the bone quality through preserving osseous regeneration and repair capacity. Similarly, the radioprotective effect of amifostine on bone-forming cells has been previously shown to increase bone regeneration capacity [28]. Besides, a prior study has determined the effects of radiation treatment on the mineral composition of the mandible [8]. On the other hand, the present study demonstrated that AMF has a protective role on the mineral composition of the irradiated bone.

The histological and radiological findings revealed the biocompatible and osteoconductive implant surfaces in all groups, with different rates of BIC surfaces. The preservation of bone integrity and implant position observed on the radiographs suggested the existence of a mechanical support in the bone.

The results demonstrated an enhanced growth of bone around the implant in radiotherapy groups that received amifostine treatment. The osteointegration of the bone to implants by an inflammatory reaction played a major role in integrating the implant in the early healing process. The histomorphometric analysis we obtained revealed that the regenerative capacity of the tibia significantly reduced inflammatory cell counts and contributed to the osseointegration of implants after radiotherapy. Furthermore, there was a positive effect of amifostine administration on bone cell adhesion and inflammatory cell inhibition. Also, this may be attributed to the significant radioprotective effect of amifostine. The radioprotective role of amifostine against radiation-induced mucositis, dermatitis, and alopecia was reported by Kopjar et al. [21] and Kouloulias et al. [22] reported the radioprotective effect of amifostine on lymphocytes when administered before radiotherapy. From the results presented in our study, it could be suggested that amifostine can be a good candidate as a radioprotective agent for osteointegration. Also, amifostine is a radioprotective agent used to prevent or reduce healthy tissue toxicity. In this study, we present an experimental data focusing on the toxicity of ionizing radiation in bones with implants or titanium mini screws. On the other hand, for a better understanding of the radiobiologic role of amifostine, further studies are needed.

Within the limits, the present study exhibited that although radiation negatively affected the osteointegration via the bone mineral loss and maintenance of bone mass, amifostine contributes to the stability of the implant osteointegration during radiation therapy. Future research should confirm the present results of the histomorphometric and biochemical parameters.

Footnotes

Conflict of Interest: The authors declare no conflicts of interest.

Author Contributions:
  • Conceptualization: Doğan E, Kara H.
  • Data curation: Erbaş E, Hülya Kara.
  • Formal analysis: Aydemir Celep N, Erbaş E.
  • Funding acquisition: Kara H.
  • Investigation: Erbaş E.
  • Methodology: Aydemir Celep N.
  • Project administration: Erbaş E.
  • Resources: Aydemir Celep N.
  • Software: Aydemir Celep N.
  • Supervision: Kara H.
  • Validation: Doğan E.
  • Visualization: Erbaş E.
  • Writing - original draft: Erbaş E, Doğan E, Kara H.
  • Writing - review & editing: Erbaş E, Aydemir Celep N.

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