Effects of single-dose versus fractionated irradiation on the suppression of heterotopic bone formation - an animal model-based follow-up study in rats

Abstract

The histological and enzymatic effects of single-dose irradiation of 7 Gray (Gy) versus fractionated irradiation of 5 x 2 Gy on the suppression of heterotopic ossification were examined over a period of 60 days in adult male Wistar rats (n = 57). The standardized osteogenesis model system in rats 19, 10, 11, 16, 19] was used for this purpose. The course of developing ossifications was documented quantitatively and qualitatively by means of quantitative computed tomography/osteodensitometry and digital luminescence radiography. Assessment of the activities of the enzymes alkaline and acid phosphatase throughout the experiment as well as characterization of the isoenzyme of alkaline phosphatase (AP) in connection with histological observations displayed a metaplasia of the ingrowing connective tissue into bone-typical cells during osteoinduction. Thus, the increase of AP is the first sign of a functional transformation of mesenchymal stem cells into chondroid bone cells. The increase in the acid phosphatase level with a maximum of activity between the 15th and 30th day (according to the respective treatment group) is highly suggestive of a remodeling process paralleling incipient chondroclast and osteoclast activity. In the animal groups undergoing irradiation, the above-mentioned increase of enzymes occurred after a delay. Furthermore, the maximum values observed were lower than those in the group not undergoing irradiation. Both findings were more manifest in the animal group which underwent 5 x 2 Gy of radiation than in the group which underwent single-dose irradiation of 7 Gy. Radiation suppresses matrix-induced osteogenesis. The histological and enzymatic course of this process was unchanged in the animals which did not undergo irradiation. However, it was quantitatively reduced and accompanied by a retardation of osteogenesis. Both effects were again reduced with fractionated irradiation of 5 x 2 Gy, which is theoretically dose-equivalent to a 1 x 7 Gy application. Histological examinations revealed damage to the migratory, proliferating mesenchymal stem cell population by irradiation doses which had relatively small effects on preosteoblasts, osteoblasts, chondroblasts and other specialized cell forms. Therefore, it may be concluded that the smaller degree of heterotopic ossification in the irradiated groups was due to damage of and a decrease in the number of mesenchymal stem cells at the implant site. Our results stress the necessity of instituting postoperative irradiation therapy as early as possible to prevent heterotopic ossification. In view of experimentally proven better effects, fractionated irradiation has to be preferred to a dose-equivalent single-dose radiation, especially considering the fewer side-effects noted with fractionated irradiation.

Early Excision and Late Excision of Heterotopic Ossification after Traumatic Brain Injury Are Equivalent: A Systematic Review of the Literature

“…In addition, no significant difference was observed between single-dose and fractionated administration. On the contrary, Esenwein et al (Esenwein et al, 2000) obtained a markedly better effect after fractionated irradiation, at equivalent doses, in rats following the induction of HO. Again, no conclusive inferences on the effectiveness of radiation in preventing HO after brain injury could be drawn from the published data.…”

Dysregulation of Local Stem/Progenitor Cells as a Common Cellular Mechanism for Heterotopic Ossification

“…Our unpublished data indicated that bone marrow‐derived MSC are capable of contributing to HO formation from early to later stages (data not shown), which suggests that local populations of MSC‐like cells could be the receptive cell population in this model. Consistent with this hypothesis, radiation therapy, which would reduce or eliminate local MSC, has been successfully used to prevent HO after traumatic events [41]. Unfortunately, radiation therapy is not commonly used in FOP patients due to potentially severe side effects [42].…”

Munchmeyer's disease—a rare case report and review of literature

“…They include local blisters, iodine, mercury, colchicum, local bleeding, sarsaparilla, nitric acid, lactic acid, phosphoric acid, thyroid extract, thiosamine, sodium citrate parathyroid extract, low calcium diet, vitamin B1, vitamin E, disodium hydrogen phosphate, beryllium, androgens, ethylenediaminetetraacetic acid, ketogenic diet, ultrasound, antimitotic agents, oestrogens, thymectomy, radiotherapy, radium implants and surgical removal of plaques. 5,[19][20][21][22] Ethane-1-hydroxy 1, 1-diphosphate showed beneficial effects on two acute cases of this disease. 23 The role of corticosteroids is uncertain.…”