***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: Introduction : Chronic mild endogenous glucocorticoid excess has been shown to cause bone loss and to increase fracture risk in both post-menopausal and premenopausal women . Currently , it is unclear if patients with sub clinical Cushing ’s syndrome ( SCS ) with osteoporosis or osteopenia may benefit from antiresorptive treatment and the type of therapy to be given . Objective : This pilot r and omized study was aim ed at evaluating the effects of 12-month i m administration of clodronate ( 100 mg every week ) on vertebral and femoral bone mineral density ( BMD ) , bone turnover markers and on subjective pain in premenopausal women with SCS due to adrenal incidentalomas . Methods : Forty-six women ( age , 43.1 ±7.7 yr ) with SCS due to adrenal incidentaloma and osteoporosis/osteopenia were r and omized to receive clodronate plus supplement of Calcium ( 500 mg daily ) and Vitamin D3 ( 800 mg daily ) ( group 1 , no.=23 ) or supplements only ( group 2 , no.=23 ) . Both groups were similar in terms of age , body mass index , cortisol levels , BMD values , and bone turnover markers . All of the women were re-evaluated after 12 months . Results : After 12 months of treatment , in group 1 , a significant increase in lumbar BMD occurred ( p=0.04 ) , while bone turnover markers decreased by about one third ( p<0.05 ) . In group 2 , bone turnover markers did not change and BMD values slightly decreased ( p = ns ) . The differences in bone turnover markers and in lumbar BMD between the two groups were significant ( p<0.05 , all ) . No new vertebral fracture occurred in group 1 , while in group 2 the spine radiographies revealed 2 new fractures and a worsening of two pre-existent fractures . An improvement in subjective back pain , assessed by visual analogue scale pain score was observed in group 1 ( from 4.3±2.7 to 2.9±2.0 ; p<0.05 ) but not in group 2 ( from 4.4±3.1 to 4.2±3.4 ; p = ns ) . No significant changes occurred in cortisol secretion or clinical picture of the SCS during the study . Conclusions : Intramuscular administration of clodronate effectively increased lumbar BMD values , preserved bone mass at the femoral neck , stabilized vertebral fracture index , and decreased subjective back pain in pre-menopausal women with SCS . Since the untreated group continued to lose bone , antiresorptive treatment should be considered in patients with SCS , according to the prevision of surgical treatment , prevalent fractures , BMD values , age , concomitant morbidities , and desire for pregnancy We report the long-term effects of dichloromethylene diphosphonate ( CI2MDP ) , an inhibitor of bone resorption , on the skeletal lesions in multiple myeloma . Thirteen patients received either CI2MDP 1600 mg/d ( seven patients ) or a placebo ( six patients ) in addition to other chemotherapy  , and the effects of treatment were followed over a period of up to 18 months in a double-blind study . CI2MDP treatment result ed in a marked reduction in bone pain , with no progression of radiologic skeletal lesions during the first year . This contrasted with a clinical deterioration and the occurrence of new fractures in half of the patients receiving the placebo . Two patients with  hypercalciuria  and increased excretion of hydroxyproline before treatment had normalized values following CI2MDP . Finally , iliac crest bone biopsies showed a reduction in osteoclast number after CI2MDP administration . We conclude from these results that CI2MDP could be of use in preventing the bone loss that occurs in multiple myeloma UNLABELLED The efficacy of oral clodronate 800 mg daily to reduce vertebral fractures was studied in 593 women with postmenopausal or secondary osteoporosis . The incidence of vertebral fractures was significantly reduced by 46 % . The effect was not modified by the underlying cause of osteoporosis or other baseline factors including bone mineral density , QUS , weight , and smoking . INTRODUCTION This study aim ed to determine if the bisphosphonate , clodronate ( Bonefos ) , reduced the incidence of vertebral fractures in osteoporotic women . MATERIAL S AND METHODS Women fulfilling the WHO criteria for osteoporosis at the lumbar spine ( T-score < /= -2.5 ) and /or with at least one prevalent vertebral fracture were recruited to a 3-year double-blind , placebo-controlled study . A total of 593 patients were r and omized to two strata comprised of women with postmenopausal osteoporosis ( I , n = 483 ) and secondary osteoporosis ( II , n = 110 ) . They received either clodronate 800 mg daily orally ( n = 292 ) or an identical placebo ( n = 301 ) . All patients received a calcium supplement of 500 mg daily . BMD was measured at 6 , 12 , 24 , and 36 months , and lateral spine radiographs were obtained at baseline and annually thereafter for vertebral morphometry . RESULTS Treatment with clodronate was associated with a significant increase in mean spine BMD over 3 years ( percent change from baseline , 4.35 + /- 6.34 % versus 0.64 + /- 6.02 % in the placebo group , p < 0.0001 ) . At the hip , clodronate maintained total BMD , whereas a significant decrease was observed in the placebo group ( percent change from baseline 0.70 + /- 5.67 % versus -3.03 + /- 6.32 % in the placebo group , p < 0.0001 ) . The changes at the spine and hip were similar in both strata . Incident vertebral fractures at 3 years were observed in 63 women in the placebo group and 33 patients receiving clodronate ( relative risk , 0.54 ; 95 % CI , 0.37 - 0.80 ; p = 0.001 ) . Clodronate significantly reduced vertebral fracture risk in both strata and in women with or without prior vertebral fracture at baseline . Nonvertebral osteoporosis-associated fractures occurred in 21 women in the placebo group and in 14 women treated with clodronate . Treatment was well tolerated , with no significant difference in adverse event rates , including esophagitis , during clodronate treatment . CONCLUSION We conclude that clodronate 800 mg daily is a safe and effective treatment to reduce fracture risk in women with osteoporosis , regardless of causation PURPOSE To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma . PATIENTS AND METHODS Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles . At study entry , the patients were stratified according to whether they were to receive first-line ( stratum 1 ) or second-line ( stratum 2 ) antimyeloma chemotherapy .  Skeletal events ( pathologic fracture , radiation or surgery to bone , and spinal cord compression ) and hypercalcemia were assessed monthly . RESULTS The results of the first nine previously reported cycles are extended to 21 cycles . Of the 392 r and omized patients , efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo .  After 21 cycles , the proportion of patients who developed any skeletal event was lower in the pamidronate-group ( P = .015 ) . The mean number of skeletal events per year was less in the pamidronate-group ( 1.3 ) than in placebo-treated patients ( 2.2 ; P = .008 ) . Although survival was not different between the pamidronate-treated group and placebo patients overall , stratum 2 patients who received pamidronate  lived longer than those who received placebo ( 14 v 21 months , P = .041 ) . Pamidronate was safe and well tolerated during the 21 cycles of therapy . CONCLUSION Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients , and may improve the survival of patients on salvage therapy Abstract : To examine the risk of mortality following all clinical fractures , we followed 6459 women age 55–81 years participating in the Fracture Intervention Trial for an average of 3.8 years . All fractures and deaths were confirmed by medical record or death certificate . Clinical fractures were fractures that came to medical attention . Fracture status was used as a time-dependent covariate in proportional hazards models . The 907 women who experienced a fracture were older , had lower bone mineral density and were more likely to report a positive fracture history . A total of 122 women died  over the course of the study with 23 of these deaths occurring after a clinical fracture . The age-adjusted relative risk ( 95 % confidence intervals ) of dying following a clinical fracture was 2.15 ( 1.36 , 3.42 ) . This primarily reflected the higher mortality following a hip fracture , 6.68 ( 3.08 , 14.52 ) ; and clinical vertebral fracture , 8.64 ( 4.45 , 16.74 ) . Results were similar after adjusting for treatment assignment , health status and specific common comorbidities . There was no increase in mortality following a forearm or other fracture ( non-hip , non-wrist , non-vertebral fracture ) . In conclusion , clinical vertebral fractures and hip fractures are associated with a substantial increase in mortality among a group of relatively healthy older women Introduction Experimental and clinical data show that the oral bisphosphonate clodronate ( Bonefos ® ) can inhibit tumor-induced osteoclastic bone resorption . This r and omized , double-blind , placebo-controlled , multicenter trial was design ed to determine if the addition of oral clodronate to st and ard treatment for primary operable breast cancer could reduce the subsequent occurrence of bone metastases and thereby improve overall survival . Methods 1,069 patients with primary operable stage I-III breast cancer were r and omized to receive oral clodronate ( 1,600 mg/day ) or placebo for 2 years , in conjunction with st and ard treatment for primary breast cancer including surgery , radiotherapy , adjuvant chemotherapy , and /or tamoxifen . All patients were assessed for bone metastases at two and five years and additionally when clinical ly indicated . Survival status was determined as of the close of the study on 30 June 2000 with a median follow up of 5.6 years . The treatment arms were compared using the unstratified log-rank test . Hazard ratios ( HRs ) with 95 % confidence intervals were calculated . Results Oral clodronate significantly reduced the risk of bone metastases in all patients over the 5 year study period ( 51 patients versus 73 patients with placebo ; HR = 0.692 , P = 0.043 ) ; the difference was also statistically significant over the 2 year medication period ( 19 patients versus 35 patients with placebo ; HR = 0.546 , P = 0.031 ) . These differences were most pronounced in patients with stage II/III disease ( 39 patients versus 64 patients with placebo , HR = 0.592 , P = 0.009 over 5 years ; 16 patients versus 32 patients with placebo , HR= 0.496 , P = 0.020 over 2 years ) . Survival data also favoured the clodronate arm ( HR for all patients = 0.768 , P = 0.048 ; HR for stage II/III disease = 0.743 , P = 0.041 ) , although this was not significant due to multiple analyses . Oral clodronate was well tolerated , with mild-to-moderate diarrhoea being the most frequently reported adverse event . Conclusion These results confirm that oral clodronate will significantly improve the 5 year bone relapse free survival when used as a supplementary adjuvant treatment for patients receiving st and ard treatment for primary operable breast cancer Data on the long-term treatment of myeloma bone disease with bisphosphonates are scanty . In a prospect i ve pilot trial we evaluated the effect of long-term parenteral administration of dichloromethylene bisphosphonate ( Clodronate ) , in addition to st and ard chemotherapy , in 30 patients with active myeloma bone disease . Patients were treated with a mean of 4 courses ( range 2 - 8 ) of Clodronate : 300 mg/day i.v . for seven days followed by 100 mg/day i.m . for 10 days , administered at a mean interval of 4 months ( range 3 - 6 ) . The median follow-up was 24 months ( range 8 - 36 ) . Clodronate reduced bone pain rapidly and significantly , and reduced the mean values of the biochemical indices of bone resorption to within normal limits ; these effects 
    Output:
    
The results of the meta- analysis have demonstrated that clodronate is effective in reducing the risk of vertebral , non-vertebral , and overall fractures in patients with skeletal fragility