***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Proper r and omisation means little if investigators can not include all r and omised participants in the primary analysis . Participants might ignore follow-up , leave town , or take aspartame when instructed to take aspirin . Exclusions before r and omisation do not bias the treatment comparison , but they can hurt generalisability . Eligibility criteria for a trial should be clear , specific , and applied before r and omisation . Readers should assess whether any of the criteria make the trial sample atypical or unrepresentative of the people in which they are interested . In principle , assessment of exclusions after r and omisation is simple : none are allowed . For the primary analysis , all participants enrolled should be included and analysed as part of the original group assigned ( an intent-to-treat analysis ) . In reality , however , losses frequently occur . Investigators should , therefore , commit adequate re sources to develop and implement procedures to maximise retention of participants . Moreover , research ers should provide clear , explicit information on the progress of all r and omised participants through the trial by use of , for instance , a trial profile . Investigators can also do secondary analyses on , for instance , per- protocol or as-treated participants . Such analyses should be described as secondary and non-r and omised comparisons . Mish and ling of exclusions causes serious method ological difficulties . Unfortunately , some explanations for mish and ling exclusions intuitively appeal to readers , disguising the seriousness of the issues . Creative mismanagement of exclusions can undermine trial validity 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 SUMMARY Objective : To compare the effects of alendronate ( ALN ) 70 mg once weekly ( OW ) and risedronate ( RIS ) 5 mg daily between-meal dosing on biochemical markers of bone turnover and bone mineral density ( BMD ) in postmenopausal women with osteoporosis . Research design and methods : This was a 3-month , r and omised , double-blind , placebo-controlled study with a double-blind extension to 12 months . The study enrolled 549 postmenopausal women ( ALN 219 , RIS 222 and placebo ( PBO ) 108 ) who were > 60 years of age at outpatient centres . Main outcome measures : The primary endpoint was reduction in urine N-telopeptides of type 1 collagen ( NTx ) corrected for creatinine level at 3 months . Secondary parameters included change in BMD at the spine and hip at 6 and 12 months , NTx at 1,6 and 12 months , and serum bone-specific alkaline phosphatase ( BSAP ) at 1 , 3 , 6 and 12 months . Adverse experiences ( AEs ) were recorded throughout the study for an assessment of treatment safety profiles and tolerability . Results : Over 3 months , ALN produced a significantly greater mean reduction in urine NTx than did RIS ( −52 % vs −32 % , p < 0.001 ) , which was maintained at 12 months . ALN produced a significantly greater mean BMD increase than did RIS at 6 months , and it was maintained at 12 months at the lumbar spine ( 4.8 % vs 2.8 % , p < 0.001 ) and total hip ( 2.7 % vs 0.9 % , p < 0.001 ) , as well as at the trochanter and femoral neck . Significant reductions in BSAP  with ALN compared to RIS were maintained over the 12 months of treatment . Study size did not allow for meaningful assessment of differences in fracture rates . Tolerability was generally similar between ALN , RIS and PBO , and the incidence of upper GIAEs causing discontinuation and oesophageal AEs was similar in the ALN and RIS groups . Conclusion : In this study , ALN 70 mg OW produced a 50 % greater reduction in bone resorption as measured by urine NTx and significantly greater increases in lumbar spine and hip BMD than did RIS 5 mg daily . The treatments had similar safety profiles and were generally well-tolerated . Additional studies are needed comparing OW ALN with OW RIS , which became available after the commencement of the present study Blinding embodies a rich history spanning over two centuries . Most research ers worldwide underst and blinding terminology , but confusion lurks beyond a general comprehension . Terms such as single blind , double blind , and triple blind mean different things to different people . Moreover , many medical research ers confuse blinding with allocation concealment . Such confusion indicates misunderst and ings of both . The term blinding refers to keeping trial participants , investigators ( usually health-care providers ) , or assessors ( those collecting outcome data ) unaware of the assigned intervention , so that they will not be influenced by that knowledge . Blinding usually reduces differential assessment of outcomes ( information bias ) , but can also improve compliance and retention of trial participants while reducing biased supplemental care or treatment ( sometimes called co-intervention ) . Many investigators and readers naïvely consider a r and omised trial as high quality simply because it is double blind , as if double-blinding is the sine qua non of a r and omised controlled trial . Although double blinding ( blinding investigators , participants , and outcome assessors ) indicates a strong design , trials that are not double blinded should not automatically be deemed inferior . Rather than solely relying on terminology like double blinding , research ers should explicitly state who was blinded , and how . We recommend placing greater credence in results when investigators at least blind outcome assessment s , except with objective outcomes , such as death , which leave little room for bias . If investigators properly report their blinding efforts , readers can judge them . Unfortunately , many articles do not contain proper reporting . If an article cl aims blinding without any accompanying clarification , readers should remain sceptical about its effect on bias reduction Both raloxifene ( RLX ) and alendronate ( ALN ) can treat and prevent new vertebral fractures , increase bone mineral density ( BMD ) , and decrease biochemical markers of bone turnover in postmenopausal women with osteoporosis . This phase 3 , r and omized , double-blind 1-yr study assessed the effects of combined RLX and ALN in 331 postmenopausal women with osteoporosis ( femoral neck BMD T-score , less than -2 ) . Women ( aged < or = 75 yr ; > or = 2 yr since their last menstrual period ) received placebo , RLX 60 mg/d , ALN 10 mg/d , or RLX 60 mg/d and ALN 10 mg/d combined . At baseline , 6 and 12 months , BMD was measured by dual x-ray absorptiometry . The bone turnover markers serum osteocalcin , bone-specific alkaline phosphatase , and urinary N- and C-telopeptide corrected for creatinine were measured . The effects of RLX and ALN were considered to be independent and additive if the interaction effect was not statistically significant ( P > 0.10 ) in a two-way ANOVA model . All changes in BMD and bone markers at 12 months were different between placebo and each of the active treatment groups , and between the RLX and RLX+ALN groups ( P < 0.05 ) . On average , lumbar spine BMD increased by 2.1 , 4.3 , and 5.3 % from baseline with RLX , ALN , and RLX+ALN , respectively . The increase in femoral neck BMD in the RLX+ALN group ( 3.7 % ) was greater than the 2.7 and 1.7 % increases in the ALN ( P = 0.02 ) and RLX ( P < 0.001 ) groups , respectively . The changes from baseline to 12 months in bone markers ranged from 7.1 to -16.0 % with placebo , -23.8 to -46.5 % with RLX , -42.3 to -74.2 % with ALN , and -54.1 to -81.0 % in the RLX+ALN group . RLX and ALN increased lumbar spine and femoral neck BMD , and decreased osteocalcin and C-telopeptide corrected for creatinine in an additive and independent manner , because the interaction effects were not significant . Although the ALN group had changes in BMD and bone markers that were approximately twice the magnitude as in the RLX group , it is not known how well these changes correlate to the clinical outcome of fracture .  RLX+ALN reduced bone turnover more than either drug alone , result ing in greater BMD increment , but whether this difference reflects better fracture risk reduction was not assessed in this study BACKGROUND Up to 3 years of treatment with alendronate , 5 mg/d , prevents  postmenopausal bone loss .  OBJECTIVE To determine whether the effect of alendronate is sustained at 4 years of treatment and persists after treatment is discontinued . DESIGN R and omized , controlled trial . SETTING United States and Europe . PARTICIPANTS 1609 postmenopausal women 45 to 59 years of age . INTERVENTION Participants were r and omly assigned to receive oral alendronate , 5 mg/d or 2.5 mg/d ; placebo ; or open-label estrogen-progestin . Women in the alendronate groups received alendronate for the first 2 years of the study . Treatment was then continued without change or replaced with placebo for the last 2 years of the study . MEASUREMENTS Annual measurement of bone mineral density . RESULTS By year 4 , the bone mineral density of participants in the placebo group had decreased by 1 % to 6 % ( P < 0.001 ) . Four years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine ( mean change [ + /-SE ] , 3.8%+/-0.3 % ) , hip ( mean , 2.9%+/-0.2 % ) , and total body ( mean , 0.9%+/-0.2 % ) ( P < 0.001 overall ) . By year 4 , bone mineral density at most skeletal sites was greater in participants who switched from alendronate to placebo than in those who continuously received placebo . In years 3 and 4 , bone loss in participants who switched from alendronate to placebo was similar to that seen during years 1 and 2 in those who continuously received placebo . Compared with 5 mg of alendronate per day , estrogen-medroxyprogesterone acetate produced similar increases in bone mineral density and estradiol-norethisterone acetate produced increases that were substantially greater . CONCLUSIONS Four years of treatment with alendronate or estrogen-progestin prevented postmenopausal bone loss . A residual effect was seen 2 years after alendronate therapy was stopped ; however , continuous alendronate treatment was more effective in preventing postmenopausal bone loss than 2 years of alendronate followed by 2 years of placebo OBJECTIVE To investigate whether the incidence of vertebral fractures is related to the magnitude of change in bone mineral density ( BMD ) during alendronate treatment . METHODS Women in this study were age 55 - 81 years ( n = 2,984 ) . While participating in the Fracture Intervention Trial , they received 5 mg/day of alendronate for 2 years followed by 10 mg/day for the remaining 12 - 30 months of the study . Their BMD was measured at baseline and at 12 and 24 months , and spine radiographs were obtained at baseline and again at 36 or 48 months to identify new vertebral fractures . RESULTS After 12 months of alendronate treatment , 35 % of participants had increases of > or =3 % in total hip BMD , and 21 % had either decreased total hip BMD or no change . Women who had larger increases in total hip BMD during the first 12 months had a lower incidence of new vertebral fractures during the entire followup period . Only 3.2 % of women with increases of > or =3 % in total hip BMD experienced new vertebral fractures , whereas twice as many women ( 6.3 % ) whose BMD declined or stayed the same experienced new fractures ( adjusted odds ratio 0.45 , 95 % confidence interval 0.27 - 0.72 ) . Similar patterns were observed for spine BMD at 12 months , and for both sites using change in BMD at 24 months . CONCLUSION Women with increases of > or =3 % in B 
    Output:
    
The clinical implication of these results is that there are important differences in anti-fracture efficacy among currently available agents .