© 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
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.
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.
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).
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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1. Adler RA, Fuleihan GE-H, Bauer DC et al.: Managing osteoporosis in patients on long-term bisphosphonate treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2016; 31(1): 16-35.
2. Johnell O, Kanis JA: An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 7(12): 1726-1733.
3. Eisman JA, Bogoch ER, Dell R et al.: ASBMR Task Force on Secondary Fracture Prevention. Making the first fracture the last fracture: ASBMR task force report on secondary fracture prevention. J Bone Miner Res 2012; 27(10): 2039-2046.
4. Shane E, Burr D, Abrahamsen B et al.: Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014; 29: 1-23.
5. Khosla S, Burr D, Cauley J et al.: Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22(10): 1479-1491.
6. Shane E, Burr D, Ebeling PR et al.: Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010; 25(11): 2267-2297.
7. Dell RM, Adams AL, Greene DF et al.: Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012; 27(12): 2544-2550.
8. Schilcher J, Michaëlsson K, Aspenberg P: Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011; 364(18): 1728-1737.
9. Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K: Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med 2014; 371(10): 974-976.
10. FDA. Background Document for Meeting of Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee. 9/09/2011 Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ucm270958.pdf.
11. Whitaker M, Guo J, Kehoe T, Benson G: Bisphosphonates for osteoporosis – where do we go from here? N Engl J Med 2012; 366(22): 2048-2051.
12. Tanaka Y: Intensive treatment and treatment holiday of TNF-inhibitors in rheumatoid arthritis. Curr Opin Rheumatol 2012; 24(3): 319-326.
13. Watts NB, Bilezikian JP, Camacho PM et al.: American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis: executive summary of recommendations. Endocr Pract 2010; 16(6): 1016-1019.
14. Ruggiero SL, Dodson TB, Fantasia J et al.American Association of Oral and Maxillofacial Surgeons Position Paper on Medication-Related Osteonecrosis of the Jaw – 2014 Update. Journal of Oral and Maxillofacial Surgery 2014; 72(10): 1938-1956.
15. Ruggiero SL, Dodson TB, Assael LA et al.: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws – 2009 update. J Oral Maxillofac Surg 2009; 67: 2-12.
16. Allen MR, Kubek DJ, Burr DB: Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs. J Bone Miner Res 2010; 25: 98.
17. Ristow O, Gerngroß C, Schwaiger M et al.: Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis? J Oral Maxillofac Surg 2014; 72: 903.
18. Hellstein JW, Adler RA, Edwards B et al.: Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2011; 142(11): 1243-1251.
19. Chiu WY, Chien JY, Yang WS et al.: The risk of osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene. J Clin Endocrinol Metab 2014; 99(8): 2729-2735.
20. Santini D, Vincenzi B, Dicuonzo G et al.: Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 2003; 9: 2893.
21. Hoefert S, Schmitz I, Tannapfel A et al.: Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings. Clin Oral Investig 2010; 14: 271.
22. Wood J, Bonjean K, Ruetz S et al.: Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302: 1055.
23. Allen MR, Burr DB: The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 2009; 67: 61.
24. Kos M, Junka A, Smutnicka D et al.: Pamidronate enhances bacterial adhesion to bone hydroxyapatite. Another puzzle in the pathology of bisphosphonate-related osteonecrosis of the jaw? J Oral Maxillofac Surg 2013; 71: 101.
25. Naik NH, Russo TA: Bisphosphonate-related osteonecrosis of the jaw: the role of actinomyces. Clin Infect Dis 2009; 49: 1729.
26. Saad F, Brown JE, Van Poznak C et al.: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012; 23: 1341.
27. Bilezikian JP: Osteonecrosis of the jaw – do bisphosphonates pose a risk? N Engl J Med 2006; 355: 2278.
28. Allen MR, Ruggiero SL: A review of pharmaceutical agents and oral bone health: how osteonecrosis of the jaw has affected the field. Int J Oral Maxillofac Implants 2014; 29: 45.
29. Kademani D, Koka S, Lacy MQ, Rajkumar SV: Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 2006; 81: 1100.
30. Migliorati CA, Schubert MM, Peterson DE, Seneda LM: Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005; 104: 83.
31. Farrugia MC, Summerlin DJ, Krowiak E et al.: Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope 2006; 116: 115.
32. Tirelli G, Biasotto M, Chiandussi S et al.: Bisphosphonate-associated osteonecrosis of the jaws: the limits of a conservative approach. Head Neck 2009; 31: 1249.
33. Seth R, Futran ND, Alam DS et al.: Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope 2010; 120: 2165.
34. Ferlito S, Puzzo S, Palermo F et al.: Treatment of bisphosphonate-related osteonecrosis of the jaws: presentation of a protocol and an observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg 2012; 50: 425.
35. Montebugnoli L, Felicetti L, Gissi DB et al.: Biphosphonate-associated osteonecrosis can be controlled by nonsurgical management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 104: 473.
36. Marx RE, Cillo JE Jr, Ulloa JJ: Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007; 65: 2397.
37. Tsao C, Darby I, Ebeling PR et al.: Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 2013; 71: 1360.
38. Cetiner S, Sucak GT, Kahraman SA et al.: Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid. J Bone Miner Metab 2009; 27: 435.
39. Sarasquete ME, García-Sanz R, Marín L et al.: Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 2008; 112: 2709.
40. Dimopoulos MA, Kastritis E, Bamia C et al.: Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2009; 20: 117.
41. European Medicines Agency: CHMP Assessment Report on Bisphosphonates and Osteonecrosis of the Jaw. EMA/CHMP, London 2011; http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500051383.pdf.
42. Saita Y, Ishijima M, Kaneko K: Atypical femoral fractures and bisphosphonate use: current evidence and clinical implications. Therapeutic Advances in Chronic Disease 2015; 6(4): 185-193.
43. Ettinger B, Burr DB, Ritchie RO: Proposed pathogenesis for atypical femoral fractures: lessons from materials research. Bone 2013 Aug; 55(2): 495-500.
44. Schilcher J, Sandberg O, Isaksson H et al.: Histology of 8 atypical femoral fractures: remodeling but no healing. Acta Orthop 2014; 85(3): 280-286.
45. Girgis CM, Sher D, Seibel MJ: Atypical femoral fractures and bisphosphonate use. N Engl J Med 2010; 362(19): 1848-1849.
46. Feldstein AC, Black D, Perrin N et al.: Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res 2012; 27(5): 977-986.
47. Schilcher J, Aspenberg P: Atypical fracture of the femur in a patient using denosumab – a case report. Acta Orthop 2014 Feb; 85(1): 6-7.
48. Bone HG, Chapurlat R, Brandi ML et al.: The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 2013; 98(11): 4483-4492.
49. Roux C, Hofbauer LC, Ho PR et al.: Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: efficacy and safety results from a randomized open-label study. Bone 2014; 58: 48-54.
50. Khow KS, Yong TY: Atypical femoral fracture in a patient treated with denosumab. J Bone Miner Metab 2015; 33(3): 355-358.
51. Odvina CV, Zerwekh JE, Rao DS et al.: Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90(3): 1294-1301.
52. Nieves JW, Bilezikian JP, Lane JM et al.: Fragility fractures of the hip and femur: incidence and patient characteristics. Osteoporos Int 2010; 21(3): 399-408.
53. Paparodis R, Buehring B, Pelley EM et al.: A case of an unusual subtrochanteric fracture in a patient receiving denosumab. Endocr Pract 2013 May-Jun; 19(3): 64-68.