Clinical presentation and pathological features of atypical subtrochanteric fracture after bisphosphonate treatment
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- Lin, H., Huang, T., Hung, S. et al. Eur J Orthop Surg Traumatol (2012) 22: 417. doi:10.1007/s00590-011-0835-5
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In recent years, there have been increasing reports of fractures associated with long-term bisphosphonate treatment. Clinical presentation should be examined carefully because fractures after long-term bisphosphonate treatment present typical symptoms and radiological and pathological findings. The unique clinical features of such fractures include prodromal thigh pain and complete absence of trauma. The radiological features include stress reaction of the thickened cortex and transverse or short oblique fractures on plain-film radiography and bone marrow edema on magnetic resonance imaging. Careful surveillance and early preventive internal surgical fixation must be considered by both orthopedic and non-orthopedic physicians. In this study, we reviewed recent articles on atypical subtrochanteric fractures after long-term bisphosphonate treatment. We also present the case of a 72-year-old woman with this type of a fracture who had been using a bisphosphonate for 2 years. The findings at presentation and pathological features of the fracture are discussed, including those of imaging studies, and the treatment administered is described.
KeywordsStress fractureLow-energy fractureOsteoporosisBisphosphonate
Fractures associated with osteoporosis are common among elderly people and postmenopausal women. In Taiwan, the proportion of osteoporosis among women aged between 70 and 79 years is 17.30%, and that among women older than 80 years old is 24% . Chinese women have a 30% lifetime risk of developing at least one osteoporotic fracture.
Bisphosphonates are widely used to treat osteoclast-mediated metabolic bone diseases such as osteoporosis. However, the effects of long-term use of the bisphosphonate alendronate on bone metabolism remain unclear. The incidence of fractures after prolonged alendronate use in older patients has recently increased. Most of these fractures reportedly resulted from low-energy trauma, and some were preceded by prodromal pain in the affected limb. A series of studies has tried to identify the specific pattern of these low-energy femoral shaft fractures on plain-film radiographs. Some studies revealed the histological characteristics and possible pathophysiological features of these fractures on stress reaction.
Here, we review recent articles related to fractures occurring after prolonged bisphosphonate use and present a case of atypical subtrochanteric fracture associated with 2-year bisphosphonate use. The patient was treated with the preventive femoral interlocking nail intervention. The clinical course and preoperative and postoperative images, including plain-film radiographs and magnetic resonance (MR) images, are presented and compared with those in the reviewed studies.
Atypical subtrochanteric fractures
Unlike common hip fractures, which involve the femoral neck or intertrochanteric region, atypical subtrochanteric fractures involve the subtrochanteric femur, which of all body parts, is the part subjected to the highest stress. The “typical” radiological pattern associated with bisphosphonate use is cortical thickening with a horizontal fracture line originating precisely at the lateral femoral subtrochanteric cortex. Some individual cases have shown that the femoral shaft is also fractured . Patients may report that the origin of pain as deep within the thigh, and this discomfort is often noted without any trauma. The bilateral occurrence of these fractures has also been reported [3–5]. In a retrospective chart review of 70 low-energy hip fracture patients in a single hospital, the typical radiographic pattern was evident in 76% patients (19/25) who were on alendronate and in only 2% (1/45) of those who were not .
The computed tomographic (CT) and MR characteristics of these atypical fractures have been identified. CT demonstrates radiolucent resorption cavities within the lateral thickened cortex. These resorption cavities have been described as early lesions that precede the formation of cortical fractures. MR images show marrow insinuating into the lesions with thickening of the overlying cortex . Most atypical subtrochanteric fractures are related to >2 years of bisphosphonate treatment. More research is needed to identify the distinct characteristics and the pathophysiological features of these fractures.
The markers for bone turnover of a possible atypical fracture are not known. No markers of bone formation or bone resorption have been found to exhibit consistently suppressed levels in patients with atypical fractures. A recent systematic review showed that more than 85% of patients with atypical subtrochanteric fractures had normal or elevated bone turnover marker levels . These findings may help identify individuals at risk of atypical subtrochanteric fractures.
Histological features of atypical subtrochanteric fractures
The histological features of undisplaced and fractured cortices in association with bisphosphonate treatment have been analyzed. Dynamic bone formation assessment demonstrated a decreased amount of or no osteoid. Adynamic bone condition with a decreased amount of calcified trabecular bone and reduced number of both osteoblasts and osteoclasts have been shown in patients with chronic kidney disease receiving oral bisphosphonate . Total absence of fracture healing over the chronic process with no cellular reaction has also been noted. In one study, cracks were seen only in the osteocyte-less matrix and not in the younger osteocyte-rich bone. They appeared as bands of osteonecrosis, consisting of diffusely damaged and disintegrated bone. A wide vascular canal with some bone formation and newly formed bone with rounded osteocytes were seen near the sharp border of the fracture . By conducting cortical biopsy, markedly increased resorption in such fractures is found. It appeared that the fracture had occurred in bone that was almost completely devoid of osteocytes, and some osteoclasts showed pathological and histological features such as detachment and a large size. Their findings suggest that the bone was weakened because of resorption. Almost all osteocyte lacunae were empty; only 25% (488/1967) contained visible cellular material. However, in the newly formed bone in the endosteal callus, 86% of the lacunae contained cellular material . These findings challenge the assumption that osteoclast inhibition allows aggressive bone formation leading to stronger bones, though the exact mechanism remains unclear.
In July 2010, a 72-year-old woman experienced sudden right thigh pain while walking. In 2007, she had been diagnosed with osteoporotic vertebral compression fracture, with a femoral neck T-score of −2.0. There had been a compression fracture over the L3 and T12 vertebra, and she had undergone successful vertebroplasty. The symptoms of lower back pain and sciatica had improved after surgery. The patient had been taking bisphosphonate (Fosamax®; Merck) at a standard dose of 70 mg once a week. Otherwise, there was no specific medical or surgical history.
The patient denied the occurrence of any traumatic accident prior to the onset of right thigh pain. A radiograph of the lumbar spine showed stationary degenerative joint disease with no spondylolisthesis. MR imaging was conducted to rule out disc problems. She was initially treated conservatively for the pain, with the assumption that it had a spinal origin.
Because of the unconfirmed nature and prevention of a pathological fracture, the patient was admitted for preventive intramedullary nailing over the right femur in October 2010. A curettage biopsy sample taken from over the lesion was sent for pathological examination.
Over the past 5 years, concerns have been raised about prolonged bisphosphonate therapy suppressing bone remodeling and resulting in an increased fracture risk. Bisphosphonates, such as alendronate, risedronate, and ibandronate, inhibit bone resorption. Alendronate is used by a large number of postmenopausal women worldwide. Suppression of remodeling alters the material properties of bone and allows microdamage accumulation. A study showed changes in the architectural and structural characteristics of the skeleton with trabecular microdamage after 1 year of alendronate treatment . The suppression of remodeling significantly reduces bone loss. The rapid reduction in newly initiated remodeling sites combined with the refilling of preexisting remodeling sites is responsible for the early increase in bone mass.
The net result will depend on whether the rate of microdamage is similarly reduced, that is, if the mineral content is high and remodeling-induced stress risers are less . The acceptable level of suppression at which fracture risk is lowered is difficult to determine. However, it is important, given the growing number of side effects, such as osteonecrosis of the jaw and atypical femoral fractures.
“Drug holidays,” that is, temporary termination of treatment with a particular drug, are receiving increasing interest from the research community. Although some data exist on the recovery of remodeling following treatment withdrawal, the kinetics of this recovery and the dose and duration of treatment remain unclear . Drug holidays can be considered for patients who have been treated with bisphosphonate therapy for 5 years who have a stable bone density and no fractures . The benefits of long-term bisphosphonate therapy outweigh the risks in patients at high risk of fracture . One study assessing the risk and time course of oral bisphosphonate-induced osteonecrosis of the jaws revealed that bone remodeling increased if the oral bisphosphonate was discontinued . The “drug holiday” group showed a linear correlation corresponding to a monthly improvement. In Taiwan, the prescription of bisphosphonate treatment continuously for 9 months followed by a 3-month break is becoming increasingly popular. However, large trials are needed to guide treatment decisions.
Typically, osteoporotic fractures are low energy and involve the wrist, the proximal humerus or tibia, the pelvis, and the hip. At our institution, a recent increase in the incidence of these fractures among older patients who had been receiving alendronate over fractures at atypical sites was noted. Neviaser et al.  reported on 70 low-energy femoral fractures among 25 patients (36%) who were being treated with alendronate. Of these, 76% patients had a simple, transverse fracture with a unicortical break in a cortical hypertrophic area. In a large randomized trial comparing atypical fractures with and without bisphosphonate use, no significant increase in risk associated with bisphosphonate use was noted . A study suggested that the increased risk of atypical femoral shaft fracture associated with the use of bisphosphonates may be confined to a small subgroup of patients . Another study showed that hypoparathyroidism, chronic glucocorticoid treatment, and parathyroid insufficiency are known to reduce bone turnover and can exaggerate the effect of alendronate . In this study, non-spinal fractures appeared to develop sooner in patients who met the above criteria than in those who only met the alendronate use criterion. Other proposed risk factors included concurrent use of proton-pump inhibitors.
Case reports and case series suggest that atypical femur fractures typically occurred after an average of 5–6 years of bisphosphonate therapy, although some fractures occurred much earlier, within 1–2 years of the initiation of therapy . The groin and thigh that pain develops in patients on long-term bisphosphonate therapy should alert both orthopedic surgeons and non-orthopedic physicians to the possible risk of atypical subtrochanteric fractures. The initial clinical assessment must include the mechanism of injury, duration of bisphosphonate usage, and other risk factors for metabolic disease. Prophylactic fixation is recommended for symptomatic patient with radiological evidence of stress reaction in case they subsequently develop insufficiency fractures. There is no definite consensus about the correlation between terminating bisphosphonate therapy for patients with osteoporosis and bisphosphonate-related stress fractures.
Long-term alendronate treatment may lead to suppressed bone turnover and unusual fractures in high-risk patients. The prodromal symptoms are mainly groin or thigh pain and weakness, and their duration ranges from weeks to years. Most patients are treated in the early stage for myofascial pain and weakness believed to be of spinal origin. More research is needed to accurately determine the epidemiology, incidence, and etiology of atypical subtrochanteric fractures after prolonged bisphosphonate use. The characteristic image findings of these fractures, including those of bone scans and MRI, alert doctors about the risks for such patients at an early stage. Early detection of atypical fracture patterns helps prevent further fracture progression by enabling early intervention. In patients who have atypical fractures and have been on bisphosphonate treatment, discontinuation of the medication must be considered. For asymptomatic patients with radiological findings of stress fractures, close observation is needed. Prophylactic surgery may not be justified in the absence of functional disability. Bisphosphonate treatment is widely used by non-orthopedic and orthopedic surgeons, and the clinical evidence presented here will help both identify susceptible individuals.
Conflicts of interest
No funds were received in support of this study.