Effect of parathyroid hormone administration before surgical intervention on medication-related osteonecrosis of the jaw

Abstract

The incidence of medication-related osteonecrosis of the jaw (MRONJ) caused by intravenous bisphosphonate (zoledronate) was reported to be 0.76.7%, whereas the incidence was much less (0.0040.21%) when oral bisphosphonate was administered for the treatment of osteoporosis. MRONJ is considered an intractable disease, as bisphosphonate binds to hydroxyapatite in the bone and has long-term effects. Therefore, prevention of MRONJ is critical. Invasive dental treatment, such as tooth extraction, is a risk factor for the development of MRONJ for the patient who has administered bisphsophonate. Currently, bisphosphonate is discontinued before tooth extraction, as a preventative measure against the development of MRONJ. In some cases, intermittent parathyroid hormone (iPTH) administration is recommended for the treatment of severe MRONJ. Administration of iPTH stimulates osteoblasts and has an anabolic effect. It simulates the activity of osteoclasts indirectly. This is different to the pharmacologic action of bisphosphonate, which suppresses osteoclasts and induces their apoptosis. The purpose of this study was to investigate the effect of iPTH administration before tooth extraction on bone healing in the extraction socket and MRONJ development. Forty 8-week-old female Sprague-Dawley (SD) rats were used and randomly divided into 4 groups (Groups AD). The experiments were designed with a 10-weeks pre-surgical intervention period, tooth extraction, and 8-week post-surgical intervention period. In Groups A and B, a 4-week waiting period was followed by 6 weeks of zoledronic acid (ZA, 200 μg/kg) administration, in the first 10 weeks. ZA was injected for 6 weeks and was discontinued the next 4 weeks in Group C. In Group D, iPTH (80 μg/kg) was administered during the 4 weeks after 6 weeks of ZA injection. After tooth extraction, ZA injection was continued only in Group A for 8 weeks. Clinical, histological, radiological, and histomorphometrical analysis was performed after sacrifice. The incidence of jaw necrosis was decreased in the order of A→B→C, and bony healing of the extraction socket increased in the same order. Increased number of trabeculae, decreased trabecular separation, and more osteoclasts were observed in the inter-radicular bone of M3 of Group D, as compared with that of Group C. The incidence of MRONJ was similar in both groups, but the degree of bone healing in the extraction socket was lower in group D than in group C. In conclusion, the incidence of MRONJ development was similar between the group treated with iPTH at a dose of 80μg/kg/day for 4 weeks before tooth extraction (Group D) and the group without treatment during the same period before tooth extraction (Group C). The extraction socket healing in Group D was no better than that in Group C. However, the treatment seemed to improve the trabecular pattern in the area of the bone that did not undergo extraction.

약물 관련 악골 괴사증의 발병율은 악성 종양 환자에서 정맥로를 통한 zoledronic acid 투여와 관련하여 0.7~6.7%로 보고되었으며, 골다공증 환자에서 비스포스포네이트 약제를 경구 투여시에는 0.004~0.21%로 보고되었다. 비스포스포네이트는 약물관련 악골괴사증을 일으키는 원인 약물중의 하나로 골과 결합하여 장기간 그 효과를 나타냄으로써 발생한 골괴사증의 치료를 어렵게 하고 있어, 그 예방이 무엇보다 중요하다. 비스포스포네이트 약제를 투여받는 환자에서 발치와 같은 침습적 치과치료는 약물관련 악골괴사증을 일으키는 위험 인자 중의 하나이다. 현재는 질환의 예방을 위하여 발치 전 휴약기간을 갖거나 치료적인 목적으로 골괴사증이 발생한 경우 간헐적 부갑상선호르몬의 투여를 권장하고 있다. 간헐적 부갑상선호르몬은 골모세포에 작용하여 골의 동화작용을 보이며, 파골세포의 활성을 자극할 수 있는 것으로 알려져 있다. 이는 파골세포를 억제하고 파골세포의 세포사멸 효과를 보이는 비스포스포네이트 제제의 약리작용과 차이를 보인다. 본 연구의 목적은 비스포스포네이트 제제의 약물을 투여 후 부갑상선호르몬을 간헐적으로 투여하고 발치를 시행하는 것이 약물관련 악골괴사증의 발생과 발치와의 치유에 미치는 영향에 대해 알아보고자 함이다. 8주령의 암컷 백서 40마리를 대상으로 하였으며 4군으로 나누었다. A, B군은 4주간의 waiting period 후 6주간 zoledronic acid 투여를 시행하였으며, 하악 좌측 제 1, 2 대구치 발치를 시행하였다. 이 후 A군은 8주간 약제 투여를 유지하였으며, B군은 발치 시행 후 8주간 약제투여를 시행하지 않았다. C군은 6주간의 zoledronic acid 투여 후 4주간 휴약기간을 가지고 발치를 시행하였고, D군은 휴약기간 중 간헐적 부갑상선호르몬 투여를 시행하였다. C,D군 모두 발치 후 8주간 약제투여를 시행하지 않았으며, 이 후 희생하여 육안적, 방사선학적, 조직학적 및 조직형태학적 분석을 시행하였다. 악골괴사증의 발생율은 ‘A→B→C군’의 순서로 낮아졌으며, 발치와의 골성 치유는 ‘A→B→C군’의 순서로 양호하게 이루...