bisphosphonates are have been used for many years for a variety of conditions including paget 's disease , osteoporosis , multiple myeloma , and hypercalcemia of malignancy . a number of randomized clinical trials have shown that they increase bone density and reduce the incidence of fractures in osteoporosis . although bisphosphonates are generally safe and effective , concerns have been raised about the potential risk of over - suppression of bone turnover during long - term use . have reported on nine patients who sustained spontaneous non - spinal fractures while on alendronate therapy . schneider   also described a 59-year - old previously healthy woman who experienced two non - traumatic stress fractures of the femur , 4 years apart , while on alendronate therapy . reported a 35-year - old man who , after 6 years of treatment with 10 mg / day alendronate , had a sub - trochanteric fracture of the right femur after mild trauma . a bone biopsy showed a lack of osteoid on trabecular surfaces and an absence of tetracycline labeling , suggesting marked suppression of bone turnover . here , we describe a 63-year - old korean woman who presented with non - traumatic spontaneous diaphyseal fractures of both femurs and delayed fracture healing after 5 years bisphosphonate therapy . a 63-year - old woman was admitted to hospital because of severe pain in both anterior thighs for 5 months . when she presented with osteoporosis and degenerative arthritis 5 years ago , she started to take alendronate 70 mg / wk , alfacalcidol 0.5 g / day and calcium citrate 1,900 mg / day . three years later , she switched to risedronate 35 mg / wk and calcitriol 0.25 g / day because of dyspepsia . she had total abdominal hysterectomy with bilateral salpingo - oophorectomy 35 years ago due to endometriosis . at the time of admission , her height was 147 cm , and her weight was 54 kg ; these had been 158 cm and 55 kg in her fourth decade . there was no history of any trauma , falling , or medication that predisposed to osteoporosis and fracture . her lifestyle had not been sedentary because she had to work in the fields for her living . physical examination revealed blood pressure of 100/80 mmhg , pulse rate of 80 beats / min , respiratory rate of 20 breaths / min , and body temperature was 36.5. cardiac and abdominal examinations were normal . here walking pattern laboratory tests showed hemoglobin 12.2 g / dl , white blood cell count 4,910/mm , platelet count 334,000/l , serum calcium 9.3 mg / dl , serum phosphorus 3.2 mg / dl , total protein 7.5 g / dl , serum albumin 4.7 g / dl , uric acid 5.1 mg / dl , and alkaline phosphatase 72 iu / l . daily urinary calcium excretion was 369.2 mg ( normal , 70 to 180 ) , and daily urinary phosphorous excretion was 959.92 mg ( normal , 400 to 1,300 ) . serum parathyroid hormone ( pth ) was 18.92 pg / ml ( normal , 10 to 65 ) , and 25-(oh)-vitamin d , determined by commercially available radioimmunoassay kit ( diasorin , stillwater , mn , usa ) , was 15.33 ng / ml ( normal , 9.0 to 37.6 ) . osteocalcin was 18.93 ng / ml ( normal postmenopausal , 19.6 to 41.2 ) , serum c - telopeptide , 0.301 ng / ml ( normal postmenopausal , 1.008 ) , and urine n - telopeptide was 55.7 nbce / mm cr ( normal postmenopausal , 6.0 to 125.72 ) . simple x - rays of the thoracic and lumbar spine showed diffusely decreased vertebral height with osteoporosis and multiple compression fractures of t4 , t5 , t11 , l1 , l2 , l4 , and l5 vertebrae . there was no additional compression spinal fracture compared with x - rays taken 2 years earlier ( fig . 1 ) . the most recent bone mineral density ( bmd ) , measured by dual - energy x - ray absorptiometry ( qdr-4500a , hologic , waltham , ma , usa ) , showed a t - score at the third lumbar vertebra of -3.8 and a total hip t - score of -3.3 ( table 1 ) . all of the results showed severe osteoporosis , and no improvement in bmd was seen , despite bisphosphonate treatment . whole spine magnetic resonance imaging revealed multiple compression fractures in the t4 , t5 , t11 , l1 , l2 , l4 , and l5 vertebral bodies and diffuse disk bulging at l2 - 3 , l3 - 4 , and l4 - 5 , with degenerative changes of facet joints and thickening of ligamentum flavum . a whole - body bone scan , which was obtained 2 hours after injecting technetium-99 m hydroxymethylene diphosphonate ( hdp ) intravenously , showed intense uptake at both distal femurs . simple x - rays also showed fracture lines in both distal femur shafts , compatible with sites of pain ( fig . 2 ) . after spinal nerve block with walking rehabilitation therapy was done for pain control , pain was not improved . therefore , we speculated that the delayed fracture healing of both distal femurs due to the long - term bisphosphonates therapy was the main cause of the pain . bisphosphonate therapy was discontinued . however , the pain continued , and the fracture lines seemed to become aggravated and showed delayed fracture healing . however , the patient had surgical internal fixation at both femoral diaphyses because of non - union of the femoral fractures even after 6 months of observation without bisphosphonates ( fig . the elapsed time from the first visit to surgical internal fixation was 7 months . during the operation , severe osteoporotic fracture was noted , but structural displacement was mild . bone biopsy performed with surgical fixation showed decreased trabecular bone with massive fibrosis in the marrow space . alendronate , risedronate , ibandronate , and zoledronate , which are classified as amino - bisphosphonates , have much higher potency because they contain nitrogen in their side chain . however , concerns have been raised about potential risk of over - suppression of bone remodeling during long - term use . prolonged use of bisphosphonates may suppress bone turnover to the point that micro - damage persists and accumulates . in experimental animals , alendronate has been shown to inhibit normal repair of micro - damage arising from marked suppression of bone turnover , which results in macro - cracks . chronic over - suppression of bone turnover by bisphosphonates may allow secondary mineralization to continue , resulting in hard , brittle bone with an increased risk for fracture . other supportive evidence on over - suppression includes several reports of jaw osteonecrosis in patients treated with high doses of bisphosphonates . recently , odvina et al .   reported nine patients ( eight postmenopausal women and one man ) who sustained unusual spontaneous non - spinal fractures while on alendronate therapy ( 10 mg / day or 70 mg / wk ) for 3 - 8 years . six of the nine patients had delayed or absent fracture healing for 4 months to 2 years during alendronate therapy , and four showed delayed fracture healing for 8 - 12 months even after discontinuation of alendronate . although co - administration of estrogen or glucocorticoids appears to be a predisposing factor , this apparent complication also occurred with bisphosphonate monotherapy . our case report described a woman who experienced non - traumatic spontaneous stress fractures while on bisphosphonate therapy and non - union of the femoral shaft fracture despite discontinuation of bisphosphonates . we were able to ensure good adherence to medication by her self - report and serial measurements of urinary n - telopeptide , one of the bone turnover markers , which showed a decrease of 62.5% , from 40.8 to 15.3 nbce / mm cr , during the first 3 months after initiation of bisphosphonate therapy and similar levels afterwards . therefore , this case had the possibility of delayed fracture healing due to suppression of bone turnover by long - term use of bisphosphonates . other possible causes of insufficiency or pathological fracture include osteoporosis - include osteomalacia , osteogenesis imperfecta , bone tumors ( primary or metastatic ) , and paget 's disease of bone . however , she had no definite clinical and laboratory evidence of such diseases . the residual effect on bone density is known to remain for 3 years after drug withdrawal , and it is possible that the suppressive effect of bisphosphonates on bone resorption might also be cumulative over time . therefore , close monitoring and assessment of fracture healing after internal fixation in this patient was mandatory , considering the risk of re - fracture . the fixed pins were maintained , and she showed full union status 6 months after internal fixation . in this patient , the biochemical markers such as n- and c - telopetides and serum osteocalcin showed normal levels and did not reveal magnitude of the suppression of bone turnover . the discordance between the histomorphometric and biochemical markers of bone turnover could be related to the variable degree of suppression at different skeletal sites , as the changes in biochemical markers are more reflective of changes in the whole skeleton . additionally , this patient showed somewhat elevated daily urinary calcium excretion , with normal serum calcium , phosphorus , and pth level . the active vitamin d , calcitriol , was thought to be the cause of this hypercalciuria . although previous studies have shown the efficacy of bisphosphonates in the first 5 years of therapy in terms of improving bone density and reduced risk of fractures , additional studies are needed to determine how long bisphosphonates can safely be given . recently , black et al .   have compared the effects of discontinuing alendronate treatment after 5 years versus continuing for 10 years . the results confirmed the safety of alendronate for up to 10 years , including no increased fracture risk with long - term use . however , even those who discontinued alendronate after 5 years showed no higher fracture risk , other than for clinical vertebral fractures , compared with those who continued alendronate . these results suggest that discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk , except for the patients at very high risk of vertebral fractures . furthermore , considering some definitive case reports , we must emphasize the need for awareness of recent controversies about the effect of long - term reduction of bone turnover on bone strength , especially the occurrence of awkward fractures at an unexpected site , as in this patient . the benefits of prolonged use of bisphosphonates must be carefully weighed against the potential adverse effects of over - suppression of bone metabolism .
bisphosphonates are potent inhibitors of bone resorption and widely used to treat osteoporosis . 
 extensive studies have shown that therapy with bisphosphonates improves bone density and decreases fracture risk . 
 however , concerns have been raised about potential over - suppression of bone turnover during long - term use of bisphosphonates , resulting in increased susceptibility to and delayed healing of non - spinal fractures . 
 we report a patient who sustained non - traumatic stress fractures in bilateral femoral shafts with delayed healing after long - term bisphosphonate therapy . 
 she underwent open reduction and surgical internal fixation . 
 although bisphosphonates effectively prevent vertebral fractures , and their safety has been tested in randomized trials , we must emphasize the need for awareness of the possibility that long - term suppression of bone turnover with bisphosphonates may eventually lead to an accumulation of fatigue - induced damage and adverse skeletal effects such as delayed fracture healing .