Insufficiency fracture after radiation therapy

Abstract

Insufficiency fracture occurs when normal or physiological stress applied to weakened bone with demineralization and decreased elastic resistance. Recently, many studies reported the development of IF after radiation therapy (RT) in gynecological cancer, prostate cancer, anal cancer and rectal cancer. The RT-induced insufficiency fracture is a common complication during the follow-up using modern imaging studies. The clinical suspicion and knowledge the characteristic imaging patterns of insufficiency fracture is essential to differentiate it from metastatic bone lesions, because it sometimes cause severe pain, and it may be confused with bone metastasis.

Introduction

Insufficiency fracture (IF) is a type of stress fracture, which occurs when normal or physiological stress applied to weakened bone with demineralization and decreased elastic resistance. It is sometimes confused with fatigue fracture, another type of stress fracture, which occurs with abnormal stress on normal bone [1]. The various conditions can weaken bone strength. The osteoporosis is the most frequently associated with IF [2], and the long-term use of steroid or bisphosphonate and rheumatoid arthritis are known to be risk factors for IF [3,4]. Recently, many studies reported the development of IF after radiation therapy (RT) in gynecological cancer [5,6,7,8,9,10,11,12], prostate cancer [13], anal cancer [11], and rectal cancer [11,14,15]. The Surveillance, Epidemiology, and End Results (SEER) data also showed that the RT can substantially increase the risk of fracture [11]. Clinically, the development of IF after RT is sometimes the cause of severe pain, and it may be confused with the bone metastasis during the follow-up in cancer patients.

The purpose of the review is to describe the clinical characteristics of IF and illustrate various imaging features. The pathophysiology and management will be also discussed.

Incidence

The actual incidence of IF after RT is unknown, although it has been regarded as rare complication in the era of megavoltage equipment. The various factors in patients (e.g., the gender, menopausal state, age, body weight, and comorbidity) and treatment parameters (e.g., RT volume, dose per fraction, total dose, RT technique, and the use of chemotherapy) also affect the development of IF, thus RT effect to bone damage cannot be solely evaluated. Nevertheless, recent study showed that RT substantially increases the fracture risk by hazard ratio of 1.65 to 3.16 [11]. In addition, several studies reported the cumulative incidence of IF after RT as 8.2% to 45.2% in cervical cancer [5,6,8,10], 9.0% to 11.2% in rectal cancer [11,14], and 6.8% in prostate cancer [13] (Table 1). The wide use of imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy, during the follow-up may increase detection of the asymptomatic IF. Imaging studies to detect the IF also affect the incidence of IF after RT. One study reported 89% of patients had findings compatible with IF after RT using MRI [16], while another study reported 34% using bone scintigraphy [17].

Table 1.

Recently reported studies for radiation-induced insufficiency fracture

RT, radiation therapy; IF, insufficiency fracture; BS, bone scintigraphy; CT; computed tomography; MRI, magnetic resonance imaging; SEER, The Surveillance, Epidemiology, and End Results; AVN, avascular necrosis.

Clinical Features

The clinical presentation is diverse, from asymptomatic to severe pain which needs hospitalization. Most patients have no or minor trauma history [4,18,19]. On the physical examination, tenderness over the sacral area [19] may be present, but there are generally no specific findings that allow a specific diagnosis to be made [4,18]. The time to development of IF after RT is usually several months but variable ranging from 5 to 44 months [8]. About 50% of patients who were detected by various imaging studies are symptomatic [8,12]. Extent of lesions may correlate with severity of symptoms. A few patients have severe pain and they may be associated with multiple site fractures [8]. Blomlie et al. [16] showed that smaller lesions (<1 cm²) on MRI might be not painful.

IF associated with RT can be developed anywhere within RT field. The sacral fracture by pelvic RT is most frequently reported in the literatures, because the development of IF is associated with weight-bearing. The sacrum, sacroiliac joints, and medial parts of the iliac bones are the major weight-bearing structures of the body. The pubic bone or acetabulum fractures can be accompanied with sacral fracture (Fig. 1), but they rarely present with solitary lesion [8], because initial mechanical fracture of the sacrum usually causes other subsequent other pelvic bone fractures [16,20]. Femur neck or sub-trochanteric fracture is infrequently reported [10,21]. Actually, the vertebral body fracture is the most common clinical presentation of IF associated with osteoporosis, but in association with RT, it is mostly presented with pathologic fracture rather than IF. After pelvic RT, low lumbar spines are often involved (Fig. 2) and non-traumatic vertebral fracture after RT in patients with esophageal cancer was reported [22].

Fig. 1.

Insufficiency fractures in multiple sites in 79-year-old woman who had undergone radiation therapy for cervical carcinoma with stage IIIB 17 months ago. Bone scintigraphy shows increased uptake in both sacral alae and pubic bone (small arrow) and there is fracture in pubic bone on plain X-ray (long arrow) and computed tomography.

Fig. 2.

Insufficiency fracture in low lumbar spine in 49-year-old woman who received pelvic irradiation with extended filed of para-aortic lymph nodes 19 months ago for cervical cancer. Bone scintigraphy shows increased uptake in lower lumbar spines (long arrow) and right sacral alae (short arrow) after radiation therapy.

Pathophysiology

The direct effect of radiation on mature bone is damage to osteoblast cells which result in osteopenia by decrease of collagen production and alkaline phosphatase activity [23,24]. The threshold for these changes is known to be 30 Gy, with cell death occurring at 50 Gy with conventional fractionation [25]. The indirect effect of radiation, generally late effect, is the RT-induced vascular injury [23,24]. These combined radiation effects ultimately result in the structural weakness of the mature bone which is susceptible to stress fracture following a normal or physiological stress (Fig. 3). A tolerance dose (TD5/5-TD50/5) of mature bone is reported as 60-77 Gy for radioosteonecrosis of mandible [26], however, there have been no data for IF.

Fig. 3.

The development of insufficiency fracture.

Risk Factors

The various risk factors of osteoporosis are closely associated with the development of IF, which include low body weight, female gender, current smoking, old age, rheumatoid arthritis, diabetes mellitus, hyperthyroidism, and corticosteroid therapy [3,4,5,6,15,27]. The treatment-related risk factors, such as the higher dose of RT [8,28], pelvic RT technique (the 4-field box vs. the AP/PA parallel opposing technique) [8,12], and the use of chemotherapy [29], were also reported despite these associations have not always been statistically significant.

Imaging Study

1. Plain radiography

Plain radiographs of pelvis, sacrum and lumbar spines showed sclerotic bands, cortical disruptions and fracture lines (Fig. 4), however the subtle changes are not usually seen [4,30] or sometimes an aggressive appearance of bone healing mimicking malignancy may be seen [18].

Fig. 4.

Plain X-ray of pelvic insufficiency fracture: sclerotic changes of sacral alae in 54-year-old woman who had received radiation therapy for cervical carcinoma with stage IVA 6 months ago (A) and in 61-year-old woman who had received radiation therapy for cervical carcinoma with stage IIIA 42 months ago (B).

2. Bone scintigraphy

Bone scintigraphy is sensitive to detect IF. The fractures usually show increased uptake on bone scintigraphy. The typical appearance of pelvic IF is called the butterfly or Honda sign (H-sign), which means the fractures of both sacral alae and sacral body (Fig. 5). The H-sign is often absent. Finiels et al. [4] reported that it was documented in just 40%. Oh et al. [8] also reported that 46.8% of patients who developed IF have unilateral lesions of the sacroiliac joints.

Fig. 5.

Butterfly or H-sign in 57-year-old woman who had received radiation therapy for cervical carcinoma with stage IIA 13 months ago. There are increased uptakes in both sacral alae (long arrow) and sacral body (short arrow) on bone scintigraphy.

3. MRI

MRI is highly sensitive to detect IF with these abnormal marrow changes during the follow-up after RT [16,31]. The irradiated bone has bone marrow changes from the cellular bone components to fat, which shows high signal intensity on T1-weighted images, except an initial reactive marrow changes during the first 2 weeks of RT [32]. When fracture occurs, the diffuse reactive bone marrow changes with fracture line is noted on MRI, which shows reversed signal intensity with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Linear areas with this abnormal signal intensity indicate the fracture line. The contrast-enhanced T1-weighted image is sometimes helpful to detect the fracture line (Fig. 6). IF can be diagnosed when these abnormal bone marrow signal with linear fracture line in the typical locations associated with IF. MRI is helpful to distinguish IF from the metastatic bone lesion. MRI is very useful tool to detect the soft-tissue component, thus the absence of focal or discrete mass lesion on MRI around fracture sites is important finding to distinguish it from metastatic bone lesion.

Fig. 6.

Sacral insufficiency fracture on magnetic resonance imaging (MRI) in 57-year-old woman who had received radiation therapy for cervical carcinoma with stage IIB 9 months ago. MRI shows low signal intensity on T1-weighted image (A), high signal intensity on T2-weighted image (B), and fracture line on contrast-enhanced T1-weighted image (C).

4. ¹⁸F FDG-PET or PET/CT

¹⁸F-fluorodeoxyglucose-positron emission tomography (FDG-PET) has been used as an important imaging tool for the evaluation of patients with cancer, but there have been only a few reports describing the findings of FDG-PET scanning in patients with IF [33,34,35,36]. The FDG-PET shows a variable degree of uptake depending on the stages of fracture (Fig. 7), sometimes it shows prolonged uptake. The standardized uptake value has a trend toward lower in the benign than in malignant lesions [37], but it is not a good indicator of a malignant lesion [36]. Many factors, such as the interval between the PET and the development of a fracture, the age of the patients, the stability of the fracture, and the site of the fracture, are associated with the intensity of FDG uptake [37].

Fig. 7.

FDG-PET findings of insufficiency fracture. (A) In 64-year-old woman who had received concurrent chemoradiotherapy for cervical carcinoma with stage IVA 21 months ago, FDG-PET shows diffuse vertical FDG-uptake (SUV_max = 3.8) in left sacral ala. (B) The FDG-uptake is decreased (SUV_max = 2.0) 6 months later. (C) In 49-year-old woman who had received postoperative radiotherapy for cervical carcinoma with stage IIB 12 months ago, FDG-PET/CT images show increased FDG-uptake in both sacral alae (SUV_max = 2.7). FDG-PET, fluorodeoxyglucose-positron emission tomography; SUV_max, the maximum of standardized uptake values.

Differential Diagnosis and Management

IF can be diagnosed if the radiologic fracture line is present in typical locations and there is no definite soft-tissue lesion indicating the metastatic disease. The clinical suspicion to rule out metastatic disease is important for preventing inappropriate treatment. Biopsy should be avoided for differential diagnosis from metastatic bone lesion, because of the high risk of osteonecrosis and low diagnostic yield [20,38,39]. Furthermore, sometime the histologic findings of the healing bone can mimic malignancy [18].

Most symptomatic patients were fully resolved after conservative treatment using analgesics and rest [5,6,7,8,9,10,13,15,18,19,30], but some patients needs narcotics or hospitalization because of severe pain and disability those who generally have multiple sites of fracture [8] or larger lesions [16]. Pentoxifylline may be effective in recovering symptoms [40]. CT-guided sacroplasty for sacral IF was reported to be helpful in patients with pain resistant to conservative treatment [41].

Conclusion

The RT-induced IF is a common complication during the follow-up using modern imaging study. The clinical suspicion and knowledge the characteristic imaging patterns of IF is essential to differentiate it from metastatic bone lesions, thus avoid inappropriate further management.