it is an inherited recessive of beta hemoglobin synthesis due to beta globin genes mutations on chromosome 11 , leading to ineffective erythropoiesis and anaemia requiring regular blood transfusions . chronic transfusion therapy results to iron overload that cause a wide spectrum of complications due to heart , liver and endocrine glands damage . although improvement of management of patients with tm have increased life span , other comorbidities of the disease including bone disease have emerged . there are numerous studies presenting the beneficial effect of bisphosphonates ( bps ) on bone disease and their use is widespread in tm patients with low bone mass ( bmd ) and high fracture risk[4 - 6 ] . although bisphosphonates have been widely used , they present several adverse events including osteonecrosis of the jaw ( onj ) and atypical femoral fractures ( aff ) . only recently 3 cases of onj have been reported in these patients following bp therapy . to our knowledge , this is the first reported case of a male adult patient suffering from tm that sustained an aff after previous zoledronic acid use . a 36-year - old male patient with beta - thalassemia major sustained a left tibial medial condyle and shaft fracture after a motor vehicle accident ( figure 1 ) . the tibial fractures were treated with two free cannulated screws and a reamed static locked intramedullary nail . rehabilitation started on forth postoperative day with partial weight bearing on the left leg using crutches . on the eleventh postoperative day , the patient felt a sudden acute pain , with no reported prodromal pain , when walking on his right thigh and became unable to walk on his right leg . radiographs revealed a short oblique femoral shaft fracture without comminution , and absence of cortical thickness and cortical beaking ( figure 2 ) . anteroposterior radiograph of the left tibia after a motor vehicle accident presents a tibial medial condyle and shaft fracture . anteroposterior radiograph of the right femur , eleven days after operation of the tibial fracture , reveals a short oblique femoral shaft fracture without comminution . the patient suffers from beta - thalassemia major requiring transfusion twice a month since childhood and iron chelating - therapy with desferoxamine until 2007 and deferiprone since that time . other comorbidities include type 2 diabetes mellitus , hypertension , osteoporosis with a compressive fracture of the lumbar spine ( l4 ) sustained 6 years earlier , esophageal varices treated with banding and cholochystectomy . his medications consisted of metformin , glyclazide , magnesium , sotalol and ramipril / hydrochlorothiazide . as for the osteoporosis treatment , after the occurrence of the vertebral fracture , the patient had been treated with intranasal calcitonin 200 iu daily for one year followed by intravenous zoledronic acid 5 mg once yearly for 3 years along with calcium and vitamin d supplementation . thus , the patient at the time of the tibial and femoral fractures had remained without osteoporosis treatment for one year . bone densitometry measured by lunar prodigy dual - energy x - ray absorptiometry ( dxa ) was consistent with bmd lower than that expected for age in the left hip 5 and one year before tibial and femoral fracture ( z - score , -3.4 and 3.5 , respectively ) . biochemical evaluation revealed normal testosterone levels , acceptable levels of 25(oh ) vitamin d ( 27 ng / ml ) , while bone markers were within normal range ( p1np and sctx ) three months after tibial and femoral fracture , similarly with values reported in most of the patients with aff treated with bps ( table 1 ) . alp , alkaline phosphatase ; tsh , thyroid - stimulating hormone ; 25(oh)d , 25-hydroxy vitamin d ; pth , parathyroid hormone ; pinp , procollagen type i n - terminal propeptide ; sctx , serum c - telopeptide cross - link of type - i collagen . after the second operation , patient s rehabilitation included lower - extremity isometric and range of motion exercises for 4 weeks and initiation of a weight - bearing as tolerated ambulation with bilateral axillary crutches on the first postoperative week . patient returned to work and was able to perform activities of daily living on forth postoperative month . thalassemia - related bone disease had been first described by cooley et al as  peculiar bone changes  consisted by cranial , facial and limb marked deformities mainly due to bone marrow expansion . the introduction of transfusion therapy in 1960 have been resulted to amelioration of such bone deformities . nowadays , bone disease is characterised by low bmd , increased risk of fractures and bone pain . possible risk factors for fracture are age older than 20 years , male gender , hypothyroidism , hypogonadism , lack of spontaneous puberty in females , active hepatitis , heart disease and diabetes . most of the fractures are presented in the upper extremity and spine mainly caused by a fall . pathogenesis of bone disease in tm is complex and some of the underlying mechanisms are still unclear . already known genetic factors include polymorphisms at the sp1 site of the collagen type ia1 ( colia 1 ) gene , at foki and bsmi of vitamin d receptor ( vdr ) gene and at 713 - 8delc of transforming growth factor - beta ( tgf - b ) gene . acquired factors include ineffective erythropoiesis and subsequent bone marrow expansion due to increased erythropoietin levels , iron overload and iron chelation therapy ( particularly deferoxamine ) , endocrine complications such as hypogonadism , hypothyroidism , dysfunction of gh / igf-1 axis , diabetes , calcium and vitamin c and d deficiencies , as well as decreased physical activity . these factors lead to an imbalance in bone remodelling by inhibiting bone formation and increasing bone resorption . general principles of management of tm patients are regular blood transfusions and iron chelation therapy with deferasirox , hormone replacement therapy , adequate calcium and vitamin d supplementation and increase of physical activity . annual bmd measurement , starting in adolescence , is recommended for the early diagnosis of bmd below the expected values for age and initiation of antiosteoporotic treatment . bps are the most widely used drugs for the prevention and treatment of bone loss . a systematic review of randomised controlled trials have concluded that reliable clinical studies in tm patients showed improved bmd , reduced bone and back pain and decreased bone turnover markers without causing any severe or unexpected adverse event after various dose regimens of an amino - bp ( alendronate , neridronate , or zoledronic acid ) compared to baseline and to placebo . however , long - term studies are required to answer about the reduction of fracture risk . there is lack of evidence on the treatment of patients suffering from tm with other antiosteoporotic agents such as trp . to our knowledge , there is only one case presenting encouraging results of trp use in tm associated bone disease in the english literature . according to the updated task force of the asbmr , an aff should present all the major features that include its location in the subtrochanteric region and femoral diaphysis , association with no or minimal trauma , transverse or short oblique configuration and lack of comminution . these fractures may present also some of the minor features that include periosteal reaction of the lateral cortex , prodromal symptoms , fractures or symptoms bilaterally , delayed healing , comorbid conditions and use of certain pharmaceutical agents such as bps . recently , affs have been considered as stress/ fatigue or insufficiency fractures that develop over the time and present specific features . they have been described mostly as a potent complication of bp use , while the risk remains albeit decreased by about 70% per year after bp discontinuation . although the causal association between bp use and aff remains uncertain , the most likely mechanisms relate to the suppression of bone turnover include increase of degree and homogenicity of mineralization , collagen maturity , microcrack accumulation , propagation and impairment of crack repair . empirical management for aff includes application of intramedullary full - length nails , discontinuation of bp treatment , adequate supplementation with calcium and vitamin d and anabolic therapy with trp or strontium ranelate[18,21 - 23 ] . there are many aspects needing to be addressed regarding treatment of bone disease of tm patients . although there is evidence that bps demonstrate beneficial effects in bone disease of tm , the dose regimen , duration of therapy and drug - free holidays have not yet been clarified . given the young age of patients , there is concern about their safety in use in reproductive age and their effect on reducing morbidity and mortality of such patients . there is also lack of evidence in prediction of fracture risk by using dxa in tm patients . furthermore , existing data support that haemoglobin levels are positively correlated with bmd , however it is still unclear if regular blood transfusions and preservation of haemoglobin at a higher level could lead to higher bmd by reduction of hypoxia and erythropoietin levels that participate in the pathogenesis of bone disease . in the present case , a male adult patient suffering from tm sustained an aff fulfilling all major and two minor criteria ( comorbid conditions and use of bps ) . biochemical evaluation revealed normal levels of bone markers three months after tibial and femoral fracture that could be a cause of concern . before aff , the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy . to our knowledge , this is the first reported case of aff in a patient suffering from tm , probably due to the small sample size of patients with thalassemia in the general population . the purpose of the present case is to increase the awareness amongst haematologists , who mainly deal with tm patients , of the adverse events of bp use .
there are numerous studies presenting the beneficial effect of bisphosphonates ( bps ) on bone disease of patients suffering from beta - thalassemia major ( tm ) . 
 although bps have been widely used , adverse events have been described including atypical femoral fractures ( aff ) . in the present case , a male adult patient suffering from tm sustained an aff fulfilling all major and two minor criteria . before aff , 
 the patient had been treated with zoledronic acid for three years and remained another one year without osteoporosis therapy . to our knowledge , this is the first reported case of aff in a patient suffering from tm , probably due to the small sample size of patients with thalassemia . the purpose of the present case is to increase the awareness amongst haematologists , who mainly deal with tm patients , of the adverse events of bp use .