following earlier reports of spontaneous femur fracture in patients using alendronate , we present three cases with a similar course . all three of these patients presented with typical prodromal symptoms resulting in a specific fracture type discussed afterwards . patient a , a 65-year - old woman , was seen at the emergency room with sudden pain in her right leg after getting up from a chair and an inability to bear weight . her medical history showed rheumatoid arthritis since 2001 and hypertension . the medication list consisted of alendronate sodium 70  mg o.w . for four years , omeprazole 20  mg o.d . , prednisone 10  mg o.d . for seven years , and metoprolol 100  mg o.d . , plaquenil 200  mg t.d . , etanercept 50  mg o.w . four months prior to the patient 's visit to the emergency room , the rheumatologist had consulted the neurologist and the orthopaedic surgeon because of persisting pain in the right leg and groin , but no neurological or orthopaedic explanation could be found . the only abnormality found was a thickening of the medial and lateral cortex of the right femur with a discrete local periostal reaction on the lateral cortex ( figure 1 ) . radiological examination on admission showed a transverse subtrochanteric fracture of the right femur with a medial spike . the fracture was located at the same spot as the cortical thickening ( figure 2 ) . patient b , a 79-year - old woman , was seen at the emergency room because of a sudden inability to bear weight on her left leg . the patient related that she had heard a crack in her leg and had then fallen down . her medical history showed osteoporosis and rheumatoid arthritis since 1987 . the medication list consisted of prednisone 5  mg o.d . for 8 years , alendronic acid 70  mg o.w . methotrexate 20  mg o.w . for 7 years , furosemide 40  mg o.d . , acenocoumarol , gliclazide 30  mg o.d . , folic acid 10  mg o.w . , and tramadole 100  mg o.d . prior to the patient 's visit to the emergency room , the rheumatologist had referred her to the orthopaedic surgeon because of pain in the left thigh . radiological examination at that time showed a thickening of the medial and lateral cortex of the left femur with a discrete local periostal reaction on the lateral cortex ( figure 3 ) . a bone scintigraphy showed a small focal lesion in the left femoral midshaft , and an additional computer tomography ( ct ) scan revealed a small thickening of the cortex at the level of the hotspot . on physical examination in the emergency room , a diffuse swollen left thigh was noted with evident pain when stress was applied through the femur . the pathological examination showed small fragments of cancellous bone tissue and bone marrow without signs of malignancy , the aspect of normal bone . patient c , a 76-year - old woman , was admitted to hospital by the rheumatologist because of persisting pain in her left leg without a clear diagnosis . the medication list consisted of prednisone 5  mg o.d . for 9 years , omeprazole 20  mg o.d . , alendronate sodium 70  mg o.w . for 12 years , methotrexate 15  mg o.w . for 8 years , folic acid 5  mg o.w . and infliximab infusion 200  mg once per 8 weeks for 3 years . the patient 's complaints of leg pain had started approximately three months earlier without any preceding trauma . since the start of the leg complaints , she had not been able to walk more than a few steps at a time . the neurologist was consulted but no neurological explanation was found . as blood samples , including hydroxyvitamin d , showed no abnormalities , the orthopaedic surgeon was consulted .   radiological examination of the pelvis and left upper - leg showed a thickening of the medial and lateral cortex with a discrete thickening of the cortex on the lateral side of the proximal femur ( figure 5 ) . single - photon emission computer tomography ( spect ) of this region also demonstrated a discrete thickening of the cortex without changes of the periost . the cortex was intact both internally and externally and showed increased thickness ( figure 6 ) . an additional dual - energy x - ray absorptiometry ( dexa ) scan of the lumbar vertebrae showed no signs of osteoporosis or osteopenia ( t - score 0.1 ) . before any more tests could be performed , this turned out to be a transverse subtrochanteric fracture through the cortical thickening with a medial spike ( figure 7 ) . closed reduction and internal fixation took place . a biopsy taken intraoperatively showed blood and fat with a normal haematopoiesis microscopically . after the operation , the patient very quickly regained mobility and was free of pain . the patient had been suffering from pain in her right thigh for two weeks and had sustained a spontaneous subtrochanteric fracture of the right femur while walking ( figure 8) . upon examination it turned out that the patient had again suffered a transverse fracture at the exact location of a cortical thickening . a closed reduction and internal fixation took place . postoperatively , the patient very quickly regained mobility and was discharged from the hospital after ten days . since their introduction in the netherlands in 1996 , bisphosphonates are often prescribed for the prevention and treatment of osteoporosis . general practitioner 's guidelines mention it along with calcium and vitamin d as the preferred preventive medical treatment . one of the guidelines ' core messages is that patients with long - term use of corticosteroids as well as patients with osteoporosis could be treated with bisphosphonates ( alendronate and risendronate ) . bisphosphonates act as bone resorption inhibitors in healthy individuals as well as in individuals with increased resorption , in whom they can restore the balance . the guidelines advise against prescribing bisphosphonates for longer than five years as data on the long - term effects of bisphosphonates are lacking . however , they do recommend continuing the use of bisphosphonates in patients with long - term use of corticosteroids . in these patients , the bisphosphonates recently , several reports have warned for the possible negative effects of long - term alendronate use . it has been known for a long time that the subtrochanteric region is subjected to maximal bending stress and is , as such , the strongest part of the femur . only 1034% of all proximal femur fractures occur in the subtrochanteric region . in a retrospective study , describe a group of 13 asian female patients who presented with low - energy subtrochanteric fractures . there was a clear difference in age and fracture type between patients who used alendronate and patients who did not . those using alendronate mainly presented with a simple transverse fracture at a mean age of 66.9 years . the other patients presented with more comminutive fractures and had an average age of 80.3 years . the average use of alendronate was 4.2 years ( range 2.55 years ) . remarkably , five of the women who used alendronate reported experiencing pain in the fractured limb two to six months prior to the injury . neviaser et al . collected data retrospectively on 70 low - energy femoral shaft fractures . in this group , 25 female patients ( 23 caucasian and 2 asian ) used alendronate . the average period that alendronate was used was 6.2 years ( range 110 years ) . data analysis showed that 76% of the patients using alendronate had a specific fracture pattern , which was seen in only 2% of the patients without alendronate use . this fracture pattern consists of a simple transverse fracture of the femur with a unicortical spike in an area of hypertrophy . furthermore , it was calculated that such a fracture pattern is 98% specific for alendronate - using patients . it is worth noting that in the alendronate group the patients that did display the fracture pattern had been using alendronate significantly longer ( 6.9 years versus 2.5 years for short - term users ) . the same specific fracture pattern is also described by kwek et al . . they carried out a retrospective study on 17 asian female patients with low - energy trauma subtrochanteric fractures . all patients had received alendronate therapy for a mean of 4.4 years ( range of 28 years ) . the average age of the patients was 66 years ( range of 5382 years ) . six patients had a stress zone in the subtrochanteric region of the contra - lateral femur . the affected region might just be due to the maximal bending stress of the subtrochanteric region , especially the lateral cortex . in the three cases related above , the patients are all female and are respectively 65 , 76 , and 79 years of age . an average use of 10 years ( range of 413 years ) is present . following the dutch general practitioner 's guidelines , they should use alendronate for an extended period as long as they are using corticosteroids too . all three patients showed the typical prodromal symptoms and a thickening of the lateral cortex that resulted in subtrochanteric fractures . the fractures were not caused by any trauma and might be described as spontaneous fractures . but in our opinion the thickening of the cortex prior to the fracturing of the femur makes it a stress or fatigue fracture . this evolving of a cortical thickening into a ( fatigue ) fracture is particularly clear in our third case . the fracture patterns itself accorded with the typical pattern described by kwek et al . .     additionally , the prodromal complaints and cortical thickening fitted the cases described by goh et al .   and kwek et al . . we find it very peculiar that radiologically there seemed to be no sign of osteoporosis . the radiological examination of the femurs showed a thick cortex and small lumen of the femur , while osteoporotic bone typically shows cortical thinning and increased radiolucency . the dexa scan in our third case did not show any sign of osteoporosis or osteopenia . additionally , there was no sign of fracture at the time of the periosteal reaction . this reaction is most likely due to microfractures at these high stressed points in the skeleton that produce a callus osteoid ( so - called looser 's transformation ) . the patients in the cases were receiving more types of medication than only the bisphosphonates . also can corticosteroids induce apoptosis in osteoblasts and clasts thus resulting in osteoporosis and related fractures . but it concerns vertebral fractures and hip fractures and no cases of subtrochanteric fractures have been described , hence the possibility of corticosteroids causing these fractures is highly improbable . but still , no cases are known with normal bmd and subtrochanteric fractures in chronic ppi use . the influence of methotrexate on bone metabolism is not known , but in our cases 1 patient did not use methotrexate at all . in the pathology reports of the taken biopsies in patients it was remarkable that there was a normal concentration of osteoclasts while bisphosphonates are assumed to inhibit osteoclasts . also there was an imbalance between bone formation and bone resorption , resulting in increased resorption . this is in contrast with the presumption that these fractures are caused by suppressed bone turnover . we have a strong suspicion but no definite evidence , backed by recent reports [ 1215 ] , that there might be a causal relation between long - term alendronate use and low - energy subtrochanteric fractures with prodromal pain . the course of the aforementioned cases seems reason enough to discontinue alendronate and to strictly follow - up the patient in order to prevent a fracture on the contra - lateral side , even , or perhaps especially , in patients using prednisone as well . discontinuation does not significantly change the risk of non - vertebral fracture in the first 5 years . in a group of women with discontinued therapy after 5 years , the bmd remained at or above baseline values 10 years earlier and bone turnover was still somewhat reduced . furthermore , it should be noted that a negative dexa scan and a thick cortex on radiological examination do not exclude the possibility of spontaneous fracture in a specific population . additional research is necessary to determine the exact correlation between the use of alendronate and spontaneous or low - energy trauma fractures . at the annual meeting of the american academy of orthopaedic surgeons on the 11th of march 2008 , goh and neviaser warned for the risks of fractures in alendronate use . they stated that further research on the negative effects of long - term alendronate use is necessary . in addition , they argued that the above mentioned fracture pattern in an area of cortical thickening could be specific to alendronate - using patients . in our opinion , the fractures seen are most appropriately named stress or fatigue fractures . in this view , patients with these prodromal symptoms should at least refrain from weight bearing of the affected limb . the alendronate should be discontinued . in case of bilateral symptoms , resulting in inability to mobilise without weight bearing , or inability to refrain from weight bearing for any other reason it remains unknown whether changed calcification results in loss of elasticity or whether the cellular response to micro - fractures in the area of the femur subjected to maximal bending stress is disturbed .
a previously unknown side effect of biphosphonate use is emerging . in a specific patient group on long term biphosphonate therapy stress femur fractures seem to occur . 
 the typical presentation consists of prodromal pain in the affected leg and/or a discrete cortical thickening on the lateral side of the femur in conventional radiological examination or the presentation with a spontaneous transverse subtrochanteric femur with typical features . 
 we present three cases of this stress fracture in patients on bisphosphonate therapy . 
 one of these patients suffered a bilateral femur fracture of the same type . in our opinion , in patients on bisphosphonate therapy who present with a spontaneous femur fracture , seizing therapy is advisable . in bilateral cases 
 preventive nailing should be considered .