Bisphosphonate-related Atypical Femoral Fracture with Bone Metastasis of Breast Cancer: Case Report and Review

Transcription

1 Bisphosphonate-related Atypical Femoral Fracture with Bone Metastasis of Breast Cancer: Case Report and Review KAZUNORI HAYASHI, MASANARI AONO, KOUSUKE SHINTANI and KENICHI KAZUKI Department of Orthopedic Surgery, Osaka City General Hospital, Osaka, Japan Abstract. Background: Intravenous bisphosphonates (BPs) have been used to reduce the frequency of skeletal-related events due to bone metastases of several kinds of cancers. Although many studies on BP-related atypical fractures (BRAFs) due to the use of BP for osteoporosis treatment have been reported, few reports on BRAFs arising as a complication of long-term BP use for bone metastasis of cancer are available. Case Report: A 62-year-old woman with a history of breast cancer presented with right thigh pain after she had a fall. Radiographs indicated a transverse fracture in the shaft of the right femur. She had been on zoledronate treatment for six years. Based on radiographic and histopathological findings, we concluded that the fracture was not a pathological fracture associated with metastasis but was a complication of long-term BP treatment. Conclusion: Clinical oncologists should consider the possibility of BRAFs in patients on long-term zoledronate treatment for bone metastases. Breast cancer is the most common malignant neoplasm in women (1). Recently, treatment methods for primary breast tumors have improved. Although the consequent improvement in prognosis leads to an increase in the occurrence of skeletal-related events (SREs), intravenous bisphosphonates (BPs) particularly zoledronate have helped reduce the frequency of such occurrences and improved patients quality of life, which are considered to be merits of BP use. In addition, recent studies have demonstrated that osteolytic metastases changed to osteosclerotic lesions as an effect of of zoledronate (2). However, osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) caused by long-term BP treatment have been recently reported, which are considered to be demerits of BP use (3-10). Although most investigations have Correspondence to: Kazunori Hayashi, MD, Miyakojimahondori Miyakojima-ku, Osaka, Japan. Tel: , Fax: , kh_ocg@yahoo.co.jp Key Words: Zoledronate, atypical femoral fracture, breast cancer, bone metastasis. indicated that the use of peroral alendronate in women with osteoporosis is associated with the risk of AFF, few reports about AFF are available on intravenous BP administration in patients with bone metastasis from solid tumors (3, 4). In the present report, we describe a case of BP-related atypical fracture (BRAF) with long-term zoledronate use for bone metastases of breast cancer. Such prolonged administration prevented pathological fractures, but consequently caused AFF. In addition, we also describe findings of histological examination of a sample from the fracture site. Case Report A 62-year-old woman with a 15-year history of breast cancer presented to our clinic with right thigh pain and a deformity after falling while walking. She had experienced discomfort in the right thigh one month prior to the present event, and had been using a walker. Radiography indicated that the patient had a transverse displaced fracture in the shaft of the right femur. An old fracture line with surrounding sclerosis in the same area of the left femur was also noted. Thickening of the lateral side of the cortical bone was observed in the shaft of the right and left femurs (Figure 1). The patient underwent right lumpectomy at the age of 47 years, following diagnosis for breast cancer (pt2 N1 M0, stage II). Anastrozole was administered as adjuvant therapy. In addition, intravenous BPs had been administered for osteolytic metastases to the right pubis, right sacral ala, and thoracic spine for 10 years prior to the present admission (Figure 2). Pamidronate or incadronate was initially used; thereafter, zoledronate was administered at 4 mg/month for five years and 10 months until the development of osteonecrosis of the jaw one year prior to the current admission. Radiation therapy targeted at the sacral spine was performed, and several courses of chemotherapy (leuprolide, followed by toremifene and tegafur/uracil) were administered. However, multiple metastatic lesions in the bone, liver, and lymph nodes were detected. Because metastatic lesions in both femoral shafts had changed to osteosclerotic lesions after BP use, radiation therapy was not required for these femoral lesions (Figure 3) /2014 $

2 Figure 1. Radiographs upon patient s admission. Antero-posterior (a) and lateral (b) views of the right femur. Displaced transverse fracture and sclerosis of the medullary cavity of the shaft were observed. c: Antero-posterior view of the left femur. Note the old fracture line with surrounding sclerosis in the same area of the other femur (arrow). Surgical treatment of intramedullary nailing was performed for the right femoral fracture on day two after admission (Figure 4). However, during surgery, we were unable to insert the implant nail through the medullary cavity as usual due to sclerosis of the proximal femoral shaft. Therefore, we attempted to expose the fracture site, but we were still unable to easily place the nail due to the severity of bone marrow sclerosis; thus, we fixed the fracture only by performing osteotomy of the fracture site. The patient experienced pain relief after surgery, and could be easily transferred to a wheelchair. However, she died due to liver failure as a result of metastasis four months after the surgery. We performed a histopathological examination of the fracture site and the surrounding sclerotic lesions in the femur, that were detected during osteotomy. We found that the medullary cavity mostly comprised of lamellar bone (Figure 5a). A few osteoblasts were present, but no osteoclasts were observed. In addition, some cement lines were observed (Figure 5b). Moreover, we noted the aggregation of cancer cells encircled by conspicuous lamellar bone formation in a major portion of the examined specimen (Figure 5c and d). Based on the radiographic and histological findings in addition to the clinical history, we concluded that the cause of the fractures was not pathologically related to the metastasis but a complication of long-term BP treatment. Therefore, our final diagnosis of the case was BRAF of both femoral shafts. Discussion Zoledronate, a third-generation amino-bp, is one of the most frequently-used drugs for bone metastases of solid tumors. The efficacy of the administration of 4 mg of zoledronate is superior to that of 90 mg of pamidronate (11). The effect of zoledronate is exerted via inhibition of the mevalonate pathway (12). Subsequently, differentiation and migration of osteoclasts are inhibited, and apoptosis is triggered. Inhibition of osteoclasts consequently leads to prevention of SRE, which is a merit of using BPs for the treatment of bone metastasis (13). However, reports of BRAF and osteonecrosis of the jaw caused by long-term BP administration have raised concerns about such usage (3-10). BRAF is usually reported to occur in the sub-trochanteric region and the femoral shaft. BRAFs often present with transverse or short oblique fracture lines and medial beak-like spikes in complete fractures. In addition, they are characterized by dense thickening and periosteal reaction of the lateral cortex, and prodromal pain, which usually occurs bilaterally (14). Odvina et al. reported 4 cases of BRAF following long-term alendronate use for osteoporosis and defined them histologically as cases of severely suppressed bone turnover due to reduced osteoblastic and osteoclastic activity (5). The odds ratio of BP use in AFF was reported to be 17.0 (6). However, very few reports are available on BRAF in patients with bone metastasis from solid tumors who receive 1246

3 Hayashi et al: Bisphosphonate-related Fracture with Bone Metastasis of Breast Cancer Figure 2. Computed tomography of the thoracic spine when bisphosphonate treatment was started. Osteolytic metastasis can be seen (arrow). intravenous BPs, particularly zoledronate (3, 4). Puhaindran et al. reported that 4 out of 327 patients with BRAF received intravenous BP for a minimum of 24 doses (3). Chang et al. indicated that greater doses of intravenous BPs, a longer treatment duration, and zoledronate use are responsible for a higher rate of BRAFs (4). The present case had a history of long-term zoledronate treatment for metastatic bone lesions from breast cancer. Based on the clinical history and radiographic findings, the case was suspected to be BRAF instead of a pathological fracture associated with metastasis. Recently, improvement of breast cancer prognosis due to the development of effective molecular-targeted agents has led to improved overall survival of patients with breast cancer (15). Consequently, the occurrence of metastatic bone lesions and associated SREs is relatively high, and use of zoledronate is expected to increase (16). Although occurrence of osteonecrosis of the jaw was previously reported as only 6-7%, it has been increasing (7). Therefore, we expect that the frequency of cases of BRAF, similar to the present case, will increase in the future. Prevention of BRAF is challenging. Although a guideline for the treatment of multiple myeloma recommends that discontinuation of zoledronate should be seriously considered after two years administration, the development of new metastatic bone lesions often makes the decision to discontinue this treatment difficult (17). Moreover, the skeletal half-life period of zoledronate activity is believed to be a few years (18). Although patients receiving BPs for osteoporosis are believed to experience a reduced risk of BRAF when they have drug holidays, it is unclear whether Figure 3. Antero-posterior view of the right femur two years before the fracture. The sclerotic lesion was already apparent at that time (arrow). the discontinuation of zoledronate for metastases would reduce the risk of BRAF (19, 20). Teriparatide may advance healing or prevent BRAF in patients with osteoporosis (21). However, it has been reported to increase the incidence of bone neoplasms such as osteosarcoma during long-term administration in rats, and its prescription for patients with cancer is contraindicated (22). The treatment of BRAF is also challenging. Under conditions where both osteoclasts and osteoblasts are inhibited, delay in bone union is expected; therefore, BRAF is difficult to control. Thus, we should carefully follow-up patients with long-term BP usage, particularly those presenting with femoral pain. Molecular markers of bone metabolism such as type 1 collagen cross-linked N-telopeptide should be measured, and characteristic cortical thickening of the femur should be radiographically-examined (23). If clinically indicated, further examination with magnetic resonance imaging or bone scintigraphy should be performed, and conservative management or preventive surgery should be considered. Recent studies have demonstrated the change of osteolytic metastases to osteosclerotic lesions as an effect of zoledronate (2). The histopathological examination in the 1247

4 Figure 4. Photomacrographs of the fracture site at surgery. The bone marrow has been almost completely replaced by cortical bone. present case indicated conspicuous lamellar bone formation in the osteosclerotic lesions surrounding the fracture site and clumps of cancer cells encircled by lamellar bone. These findings are consistent with the change from osteolytic metastases to osteosclerotic lesions due to zoledronate use, and also demonstrated the efficacy of zoledronate against SREs caused by bone metastasis from solid tumors. In conclusion, we described a case of BRAF diagnosed based on the clinical history, and the radiographic and histopathological findings, in a patient with metastatic bone disease from breast cancer who received long-term intravenous zoledronate therapy. BPs, particularly zoledronate, are proven to be effective in preventing SREs, including pathological fractures due to bone metastasis of solid tumors. However, clinicians should carefully consider the risk of BRAFs in cases where the duration of zoledronate administration is prolonged. Moreover, orthopaedic surgeons should acquaint themselves with the challenges of achieving fixation and bone union in cases of BRAF. Figure 5. Histopathology of the fracture site in the right femur (hematoxylin and eosin staining). a: The medullary cavity is occupied by lamellar bone ( 40). b: Few osteoblasts and no osteoclasts, and cement lines can be seen (arrow) ( 200). c: An aggregation of cancer cells is apparent ( 40). d: The aggregation is surrounded by conspicuous lamellar bone formation ( 200). 1248

5 Hayashi et al: Bisphosphonate-related Fracture with Bone Metastasis of Breast Cancer References 1 Siegel R, Naishadham D and Jemal A: Cancer statistics, CA Cancer J Clin 62: 10-29, Quattrocchi CC, Piciucchi S, Sammarra M, Santini D, Vincenzi B, Tonini G, Grasso RF and Zobel BB: Bone metastases in breast cancer: higher prevalence of osteosclerotic lesions. Radiol Med 112: , Puhaindran ME, Farooki A, Steensma MR, Hameed M, Healey JH and Boland PJ: Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am 93: , Chang ST, Tenforde AS, Grimsrud CD, O Ryan FS, Gonzalez JR, Baer DM, Chandra M and Lo JC: Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy. Bone 51: , Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA and Pak CY: Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90: , Giusti A, Hamdy NA, Dekkers OM, Ramautar SR, Dijkstra S and Papapoulos SE: Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone 48: , Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E and Dimopoulos MA: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23: , Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci- Rechtweg C, Cauley J, Leung PC, Boonen S, Santora A, de Papp A and Bauer DC: Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362: , Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler PJ and Laupacis A: Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 305: , Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61: , Dhillon S and Lyseng-Williamson KA: Zoledronic acid: a review of its use in the management of bone metastases of malignancy. Drugs 68: , Alakangas A, Selander K, Mulari M, Halleen J, Lehenkari P, Monkkonen J, Salo J and Vaananen K: Alendronate disturbs vesicular trafficking in osteoclasts. Calcif Tissue Int 70: 40-47, Mundy GR and Yoneda T: Bisphosphonates as anticancer drugs. N Engl J Med 339: , Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, Ebeling PR, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O Keefe R, Papapoulos S, Howe TS, van der Meulen M, Weinstein RS and Whyte MP: Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the american society for bone and mineral research. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 29: 1-23, Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V and D Amico R: Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev 4: CD006243, Jensen AO, Jacobsen JB, Norgaard M, Yong M, Fryzek JP and Sorensen HT: Incidence of bone metastases and skeletal-related events in breast cancer patients: a population-based cohort study in Denmark. BMC Cancer 11: 29, Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, Orlowski RZ, Roodman DG, Twilde P and Anderson K: American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 25: , Perry CM and Figgitt DP: Zoledronic acid: a review of its use in patients with advanced cancer. Drugs 64: , Schilcher J, Michaelsson K and Aspenberg P: Bisphosphonate use and atypical fractures of the femoral shaft. The New England journal of medicine 364: , McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, Hanley DA, Kendler DL, Yuen CK and Lewiecki EM: Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday. Am J Med 126: 13-20, Chiang CY, Zebaze RM, Ghasem-Zadeh A, Iuliano-Burns S, Hardidge A and Seeman E: Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy. Bone 52: , Watanabe A, Yoneyama S, Nakajima M, Sato N, Takao-Kawabata R, Isogai Y, Sakurai-Tanikawa A, Higuchi K, Shimoi A, Yamatoya H, Yoshida K and Kohira T: Osteosarcoma in Sprague- Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34)). J Toxicol Sci 37: , Clemons M, Cole DE and Gainford MC: Can bone markers guide more effective treatment of bone metastases from breast cancer? Breast Cancer Res Treat 97: 81-90, Received December 10, 2013 Revised January 7, 2014 Accepted January 9,