Ludzkie koronawirusy - autor: Krzysztof Pyrć z Zakładu Mikrobiologii, Wydział Biochemii, Biofizyki i Biotechnologii, Uniwersytet Jagielloński, Kraków

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© Borgis - Postępy Nauk Medycznych 1/2017, s. 43-48
*Michał Wąsowski, Marek Tałałaj
Osteonecrosis of the jaw and atypical femoral fractures as complications of antiresorptive therapy
Martwica żuchwy i atypowe złamania kości udowej jako powikłania terapii antyresorpcyjnej
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Associate Professor Marek Tałałaj, MD, PhD
Streszczenie
Bisfosfoniany (BPs) i denosumab (DSB) istotnie ograniczają ryzyko złamań kręgosłupa i złamań pozakręgowych u pacjentów z osteoporozą oraz zmniejszają ryzyko wystąpienia powikłań kostnych u pacjentów z chorobą nowotworową i przerzutami do układu kostnego. Martwica kości szczęki/żuchwy (ONJ) oraz atypowe złamania kości udowej (AFFs) są rzadkimi, ale potencjalnie poważnymi, niepożądanymi objawami terapii antyresorpcyjnej z wykorzystaniem silnych bisfosfonianów i denosumabu. Wyższe dawki leków antyresorpcyjnych stosowane u pacjentów z chorobami nowotworowymi narażają ich na większe ryzyko obu powikłań niż pacjentów z osteoporozą lub chorobą Pageta. Przyczyny i patofizjologia ONJ i AFFs pozostają wciąż niedostatecznie poznane.
Atypowe złamania kości udowej zlokalizowane w regionie podkrętarzowym i trzonie kości udowej były rejestrowane zarówno u pacjentów przyjmujących BPs, jak i DSB, ale występują one także u osób nienarażonych na działanie tych leków.
Summary
Bisphosphonates (BPs) and denosumab (DSB) significantly reduce the risk of vertebral and nonvertebral fractures in patients with osteoporosis and decrease the risk of skeletal-related events in patients with cancer and metastatic bone disease. Osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFFs) are rare but potentially serious side effects of antiresorptive treatment with high potency bisphosphonates and denosumab. Higher doses of antiresorptive drugs given to patients with neoplastic diseases expose them to higher risk of both complications than patients with osteoporosis or Paget’s disease of bone. The causes and pathophysiology of ONJ and AFFs remain not well understood.
Atypical femoral fractures located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on DSB, but they also occur in persons not exposed to these drugs.
INTRODUCTION
Osteoporosis-related fractures result in increased mortality, morbidity, and huge social costs worldwide. After the age of 50, one in three older women and one in five older men will experience a fragility fracture, mainly of the spine, hip, and forearm (1-3).
The landscape of anti-osteoporotic therapies, for the last two decades, have been dominated by bisphosphonates (BPs). The results of randomized placebo-controlled trials of at least 3-4 years duration supported the efficacy of nitrogen-containing BPs in decreasing the risk of vertebral fractures (by 40-70%), hip fractures (by 20-50%) and non-vertebral fractures (by 15-39%), depending on the drug used, skeletal site, and individual risk profile. BPs have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of postmenopausal, glucocorticoid-induced, and male osteoporosis (1).
Within the last several years, however, reports on serious complications, potentially related to the long-term therapy with BPs, have been published. The most alarming of them are osteonecrosis of the jaw (ONJ), first reported by dentists and oral surgeons in 2003, and atypical femoral fractures (AFFs), first described in 2007. Many subsequent publications, including 3 major reports of American Society for Bone and Mineral Research (ASBMR) Task Forces paid attention to the possible correlations between long-term BP therapy and morbidities mediated by decreased bone turnover due to reduced osteoclast function (1, 4-6). It has been noticed, however, that AFFs could occur in patients not receiving any antiresorptive therapy (1, 7-9). Growing number of incidents of AFFs in patients on long-term treatment with BPs induced FDA in 2010 to review available data and release “Warnings and Precautions”, suggesting that information on the risk of AFFs should be added to the labels of all BP products approved for the prevention and/or treatment of osteoporosis (6, 10). In 2011 FDA re-reviewed long-term safety and efficacy of BPs and recommended physicians to verify indications for continuation of long-term therapy with BPs beyond the period of 3-5 years (1, 11).
DRUG HOLIDAY CONCEPT
The concept of “drug holiday” has been suggested to minimize side effects and maximize benefits of long-term treatments of chronic diseases (1, 12). Two clinical trials provided data on benefits and risks of long-term use of BPs in patients with osteoporosis. Fracture Intervention Trial Long-Term Extension (FLEX) revealed that postmenopausal women treated with alendronate for as long as 10 years experienced fewer clinical vertebral fractures than patients switched to placebo after 5 years of active therapy. In the HORIZON extension trial, women given 6 annual infusions of zoledronic acid had less morphometric vertebral fractures compared with those switched to placebo after 3rd dose of the drug. Beneficial response to continued therapy was observed, however, only in women with low bone mineral density (BMD): T-score at femoral neck between -2 and -2.5 in FLEX trial and below -2.5 in HORIZON extension study. Considering these results the ASBMR Task Force have suggested to reassess risk-benefit ratio after 5 years of oral or 3 years of intravenous therapy with BPs. Continuation of oral treatment for up to 10 years or intravenous therapy up to 6 years, with its periodic evaluation, should be considered in patients at high risk for fracture, with low BMD, previous major osteoporotic fracture, or in women who experienced fracture on therapy. In other patients 3-5 years of treatment with BPs should be followed by a period of “drug holiday” lasting 2-3 years. Suggested approach could be applicable, with some adaptations, to men and patients with glucocorticoid-induced osteoporosis (1).
The American Association of Clinical Endocrinologists (AACE) guidelines have suggested a “drug holiday” after 4-5 years of BP treatment in patients at moderate risk of fractures, and after 10 years of active therapy for high-risk patients, but terms “high” and “moderate” risks have not been defined (1, 13).
OSTEONECROSIS OF THE JAW
Osteonecrosis of the jaw (ONJ) as a possible complication of bisphosphonate therapy was first reported in 2003, in patients with metastatic cancer treated with high doses of intravenous BPs. The incidence of ONJ in patients with osteoporosis was estimated to be between 1/10,000 and 1/100,000, only slightly higher than the incidence of the disease in general population (1, 14).
Definition
Osteonecrosis of the jaw is characterized by:
– an exposed necrotic bone in the maxillofacial region persisting for at least 8 weeks in spite of appropriate therapy,
– exposure to potent anti-resorptive or anti-angiogenic agents,
– no history of radiation therapy on the jaw (15).
The clinical course of the disease was originally grouped into three stages: the presence of exposed bone without pain or signs of infection (stage 1), with pain and signs of infection (stage 2) and with the appearance of fistulas, fractures and osteolysis (stage 3). Recently stage 0 characterized by certain symptoms and radiological changes in the absence of exposed bone has been additionally proposed. The majority of cases of ONJ in patients with osteoporosis are at stages 0-1, whilst in cancer patients at stages 2-3.
The pathogenesis and risk factors
The pathogenesis of ONJ remains unclear, but several potential mechanisms have been proposed. These include long-term suppression of bone remodeling, reduced blood supply due to inhibition of angiogenesis, recurrent microtraumas, infection/inflammation and immune dysfunction. Higher incidence of ONJ in Asian populations suggests genetic predisposition to the disease (16). The cases of ONJ in cancer patients treated with high doses of potent BPs or denosumab (DSB) strongly suggest that profound and prolonged inhibition of bone remodeling may be the primary cause. Significant suppression of the bone turnover with BPs in the jaw bones, observed in animal studies, may explain predisposition of this region to ONJ compared with other parts of the skeleton (16-18).
Inhibition of angiogenesis can be another important mechanism as ONJ is a form of avascular necrosis. It was found that zoledronic acid in vitro inhibited angiogenesis and in cancer patients decreased serum vascular endothelial growth factor (VEGF) concentration. The results of clinical studies has combined ONJ and treatment with antiangiogenic drugs, such as bevacizumab and tyrosine kinase inhibitors. On the other hand it was found that treatment with DSB did not result in inhibition of angiogenesis (19-21).
The main localization of ONJ is mandible and only one-third of cases occur in the maxillary bone. It suggests that frequent, recurrent microdamages inflicted upon the lower jaw bones with mastication might play role in pathogenesis of the disease (18, 21). Other potential risk factors of ONJ in patients treated with antiresorptive drugs include poor oral hygiene, cigarette smoking, diabetes mellitus, concomitant glucocorticoid- and/or chemotherapy, and invasive dental procedures, such as dental extractions or implants, especially in patients with preexisting periodontal or periapical disease. Complex biofilms have been found on the bone/tooth and mucosal surfaces around BP-related ONJ, composed of Actinomyces and other organisms including fungi and viruses. It is still unknown whether BP-related ONJ is the result of direct drug toxicity to the bone and/or soft tissues that become secondarily infected or a primary infection is subsequently exacerbated by the treatment with antiresorptive agents (17-24).
Treatment and prevention of ONJ
Over the last years treatment of ONJ has generally shifted away from aggressive surgical interventions to conservative therapy with limited debridement, antibiotics and oral rinses with chlorhexidine or hydrogen peroxide. In the majority of patients with osteoporosis treated with BPs the clinical course of ONJ is mild and self-limited (18, 25). In most such cases conservative management may be sufficient, resulting in healing 30-60% of patients, although some cases become chronic and develop complications (26-28). Microbial cultures from areas of exposed bones usually isolate normal oral microbes although sometimes they can help to define comorbid oral infections and to select appropriate antibiotic regimen, especially when there is extensive soft tissue involvement (18, 29). The areas of necrotic bone, being a source of chronic soft tissue irritation, and loose bony sequestra need to be removed or recontoured to optimize soft tissue healing (18, 30). The extraction of symptomatic teeth within exposed, necrotic bone should be considered as it appears unlikely that extraction will worsen the established necrotic process. Surgical resection of necrotic bone should be reserved for refractory or advanced cases and performed by experienced oral and maxillofacial surgeons as it may occasionally result in larger areas of exposed and painful, infected bone (30-34).
There are no prospective data to stop antiresorptive or antiangiogenic therapy in patients with ONJ. Discontinuation of antiresorptive therapy might stabilize ONJ, reduce the risk of developing new sites, and help to control clinical symptoms but, especially in cancer patients, it could result in recurrence of bone pain and increase skeletal-related events. The decision must be made individually, on a case-by-case basis, taking into account the estimated risks and benefits. Some authors reported better outcomes of ONJ with discontinuation of treatment with BPs for a period of 1-6 months, but it could result in recurrence of bone pain and progression of bone metastases in oncological patients (18, 35). As bisphosphonates accumulate in bone tissue for months or years, the rationale for discontinuation of therapy in patients with ONJ is the interruption of their effects on oral soft tissues, especially epithelial cells and fibroblasts surrounding ONJ. Few reports describe healing or complete resolution of ONJ in patients given iv therapy with BPs within several months of cessation of these agents. On the other hand there are publications on spontaneous resolution of ONJ with continued therapy. The American Dental Association as well as the American Association of Oral and Maxillofacial Surgeons do not recommend routine discontinuation of BP treatment in osteoporotic patients prior invasive dental procedures (18, 36, 37).

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Piśmiennictwo
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otrzymano: 2016-12-07
zaakceptowano do druku: 2016-12-28

Adres do korespondencji:
*Michał Wąsowski
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases Centre of Postgraduate Medical Education
Czerniakowska 231, 00-416 Warszawa
tel. +48 (22) 584-11-47
kl.geriatrii@szpital-orlowskiego.pl

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