Changes in cortical bone channels network and osteocyte organization after the use of zoledronic acid

Objective The aim of this study was to evaluate the effects of zoledronic acid (ZA) on the cortical bone channels network (CBCN) and osteocyte organization in relation to the bone channels. Materials and methods Eighteen male Wistar rats were divided into control (CG) and test groups (TG). Twelve animals from TG received 3 ZA doses (7.5 µg/kg), and 6 animals from CG did not receive any medication. TG animals were euthanized at 14 (n = 6) and 75 (n = 6) dadys after drug injection. CBCN was analyzed in mandibles and tibias using computational routines. The osteocyte organization was qualitatively evaluated in tibias using a three-dimensional reconstruction of images from serial histological sections. Results Significant differences in CBCN of tibia were found between the treated and untreated rats, with a wider range of sizes and shapes of the channels after the use of ZA (channels area p = 0.0063, channels area SD p = 0.0276) and less bone matrix (bone volume p = 0.0388). The alterations in the channels’ morphology were more evident at 75 days after the drug injection (channels perimeter p = 0.0286). No differences were found in mandibles CBCN. The osteocyte distribution revealed more variable patterns of cell distribution in ZA groups, with non-homogeneous distribution of cells in relation to the bone channels. Conclusion Zoledronic acid induces structural changes in CBCN and modifies the osteocyte arrangement in cortical bone in the tibia; also, the variability in the morphology of bone channels became more evident after a certain time of the use of the drug.

Análise histológica e histomorfométrica da osseointegração de implantes de titânio inseridos na tíbia de ratos Wistar induzidos por ácido zoledrônico e dexametasona / Histologic and histomorphometric analysis of the osseointegration of endosseous implants placed on the tibiae of Wistar rats treated with zoledronic acid and dexamethasone

A terapia com bisfosfonatos tem sido frequentemente empregada no tratamento de doenças metabólicas do osso e neoplasias malignas. O objetivo deste estudo foi avaliar através de análise histológica e histomorfométrica em cortes não descalcificados, a influência dos bisfosfonatos nitrogenados endovenosos associados ou não a dexametasona sobre a osseointegração de implantes instalados em tíbias de 27 ratos Wistar. Ácido zoledrônico e dexametasona foram administrados por via subcutânea nos animais dos grupos experimentais. Os animais foram acompanhados por 7, 14 e 28 dias. Nossos resultados mostraram que não houve falha na osseointegração em nenhum animal avaliado e que não foram observadas diferenças estatisticamente significantes entre os 3 grupos com relação à quantidade de contato entre osso e implante e presença de osso em áreas pré determinadas, nos tempos observados. No entanto nossas observações histológicas revelaram que nos animais tratados com bisfosfonatos associados ou não com dexametasona, aos 14 e 28 dias após a colocação do implante não ocorreu o fenômeno de remodelação da cortical óssea, ao contrário do grupo controle. Concluímos que a terapia com bisfosfonatos associada ou não com dexametasona não impediu a osseointegração do implante com o osso mas inibiu severamente a remodelação da cortical óssea pré existente.

Bisphosphonate therapy has been often employed in the treatment of metabolic bone diseases and malignancies. The aim of this study was to evaluate through histological and histomorphometric analysis the influence of intravenous nitrogen-containing bisphosphonates alone or combined with dexamethasone on the osseointegration of implants placed in the tibia of 27 male Wistar rats in non decalcified samples. Zoledronic acid and dexamethasone were administered through sub cutaneous injections. The animals were followed through 7, 14, and 28 days. Our results showed that there was no failure in osseointegration in any animal, and that there were no statistically significant differences among the 3 groups regarding the amount of bone-implant contact and peri-implant bone density in predetermined areas. However our histological observations revealed that animals treated with bisphosphonates, associated or not with dexamethasone, at 14 and 28 days after implant placement has not occurred the phenomenon of cortical bone remodeling, unlike control group. We conclude that bisphosphonate therapy associated or not with dexamethasone did not prevent osseointegration of the implants but severely inhibited the remodeling of pre-existing cortical bone.

Osteonecrose maxilofacial induzida por bisfosfonatos em indivíduos com osteoporose / Bisphosphonate-induced maxillofacial osteonecrosis in osteoporotic individuals

Osteonecrose dos maxilares relacionada aos bisfosfonatos pode ser uma complicação importante do tratamento da osteoporose a longo prazo. A possibilidade de osteonecrose dos maxilares em pacientes expostos a bisfosfonatos nitrogenados foi descrita pela primeira vez em 2003. Desde então, relatos de casos e estudos retrospectivos demonstraram maiores percentuais de ocorrência de osteonecrose em pacientes que fizeram ou fazem uso de bisfosfonatos. Embora esta complicação possa ser espontânea, os procedimentos invasivos orais têm um papel como fatores de risco associados aos procedimentos odontológicos, tais como as extrações dentárias e cirurgias de outros ossos. Além disso, infecções dentárias e doença periodontal são relatadas como principais fatores de risco para o desenvolvimento de osteonecrose dos maxilares induzida por bisfosfonatos. Por isso, dentistas, clínicos gerais, ortopedistas, geriatras e cirurgiões bucomaxilofaciais precisam estar cientes do problema e trabalhar em um ambiente multidisciplinar, incentivando o diagnóstico precoce e a prevenção de novos casos potenciais.

Bisphosphonate-related osteonecrosis of the maxillae may be an important complication of long-term osteoporosis treatment. The possibility of osteonecrosis of the maxillae in patients exposed to nitrogenated bisphosphonates was first described in 2003. Since then, case reports and retrospective studies have demonstrated higher percentages of occurrence of osteonecrosis in patients who have used or are using bisphosphonates. Although this complication may be spontaneous, invasive oral procedures have a role as risk factors associated with dental procedures such as tooth extractions and other bone operations. In addition, tooth infections and periodontal disease have been reported to be the main risk factors for development of bisphosphonate-induced osteonecrosis of the maxillae. For this reason, dentists, general clinicians, orthopedists, geriatricians and oral-maxillofacial surgeons need to be aware of this problem and work in a multidisciplinary environment, thereby stimulating early diagnosis and prevention of further potential cases.