***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: Summary A longitudinal study was performed to document the effect of surgical menopause and postmenopausal etidronate disodium therapy on several nonhistomorphometric indices of bone turnover . Twenty healthy , premenopausal women undergoing oophorectomy for nonmalignant conditions were studied preoperatively and at 3 monthly intervals postoperatively . Sequential measurements of serum calcium ( Ca ) , alkaline phosphatase ( AP ) , bone Gla protein ( BGP ) , and urinary calcium and hydroxyproline excretion , expressed as a ratio of urinary creatinine ( UCa/Cr and UOHp/Cr , respectively ) were obtained . Twenty-four-hour whole body retention of diphosphonate ( WBR ) and radial bone density were also measured . When a postoperative increase in bone turnover was observed , patients were r and omized to receive either 400 mg etidronate disodium daily or placebo for 3 months . Oophorectomy was associated with a significant increase in WBR , Ca , AP , and BGP and an insignificant rise in UCa/Cr . A variable pattern of UOHp/Cr was seen . Patients on placebo maintained these elevated levels of Ca , BGP , and UCa/Cr . WBR and AP continued to rise . Etidronate disodium therapy result ed in a fall towards premenopausal levels in WBR , Ca , and UCa/Cr . AP and BGP were unchanged . Three months after stopping etidronate , BGP fell significantly and the decrease in Ca was maintained ; however , WBR and UCa/Cr had returned towards pretreatment values . Bone density measurements did not change significantly . An increase in several of the indices of bone turnover was seen following oophorectomy . Etidronate disodium suppressed this increase , affecting indices of both resorption and formation . This effect on formation may be an unavoidable consequence of normal resorption-formation coupling . The ability of etidronate alone to maintain postmenopausal bone mass has yet to be established . However , the suppressive effect of this diphosphonate on the accelerated bone turnover found after oophorectomy suggests that etidronate may have a potentially useful role as an inhibitor of resorption in a pulsed regimen The bisphosphonate alendronate and conjugated equine estrogens are both widely used for the treatment of postmenopausal osteoporosis . Acting by different mechanisms , these two agents decrease bone resorption and thereby increase or preserve bone mineral density ( BMD ) . The comparative and combined effects of these medications have not been rigorously studied . This prospect i ve , double blind , placebo-controlled , r and omized clinical trial examined the effects of oral alendronate and conjugated estrogen , in combination and separately , on BMD , biochemical markers of bone turnover , safety , and tolerability in 425 hysterectomized postmenopausal women with low bone mass . In addition , bone biopsy with histomorphometry was performed in a subset of subjects . Treatment included placebo , alendronate ( 10 mg daily ) , conjugated equine estrogen ( CEE ; 0.625 mg daily ) , or alendronate ( 10 mg daily ) plus CEE ( 0.625 mg daily ) for 2 yr . All of the women received a supplement of 500 mg calcium daily . At 2 yr , placebo-treated patients showed a mean 0.6 % loss in lumbar spine BMD , compared with mean increases in women receiving alendronate , CEE , and alendronate plus CEE of 6.0 % ( P < 0.001 vs. placebo ) , 6.0 % ( P < 0.001 vs. placebo ) , and 8.3 % ( P < 0.001 vs. placebo and CEE ; P = 0.022 vs. alendronate ) , respectively . The corresponding changes in total proximal femur bone mineral density were + 4.0 % , + 3.4 % , + 4.7 % , and + 0.3 % for the alendronate , estrogen , alendronate plus estrogen , and placebo groups , respectively . Both alendronate and CEE significantly decreased biochemical markers of bone turnover , specifically urinary N-telopeptide of type I collagen and serum bone-specific alkaline phosphatase . The alendronate plus CEE combination produced slightly greater decreases in these markers than either treatment alone , but the mean absolute values remained within the normal premenopausal range . Alendronate , alone or in combination with CEE , was well tolerated . In the subset of patients who underwent bone biopsies , histomorphometry showed normal bone histology with the expected decrease in bone turnover , which was somewhat more pronounced in the combination group . Thus , alendronate and estrogen produced favorable effects on BMD . Combined use of alendronate and estrogen produced somewhat larger increases in BMD than either agent alone and was well tolerated Abstract : The purpose of this r and omized , double-masked , placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis . The study was conducted at 80 study centers in Europe and Australia . Postmenopausal women ( n= 1226 ) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo ; all subjects also received elemental calcium 1000 mg/day , and up to 500 IU/day vitamin D if baseline levels were low . The study duration was 3 years ; however , the 2.5 mg group was discontinued by protocol amendment after 2 years . Lateral spinal radiographs were taken annually for assessment of vertebral fractures , and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals . Risedronate 5 mg reduced the risk of new vertebral fractures by 49 % over 3 years compared with control ( p<0.001 ) . A significant reduction of 61 % was seen within the first year ( p= 0.001 ) . The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years . The risk of nonvertebral fractures was reduced by 33 % compared with control over 3 years ( p= 0.06 ) . Risedronate significantly increased bone mineral density at the spine and hip within 6 months . The adverse-event profile of risedronate , including gastrointestinal adverse events , was similar to that of control . Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis , reducing the incidence of vertebral fractures and improving bone density in women with established disease Summary To develop an improved treatment schedule for osteoporosis , a study was undertaken in 100 postmenopausal women using a modified ADFR 90-day cyclical regimen with etidronate .  After one year of treatment , the etidronate-treated group showed a significant increase in bone density of the spine , which continued over the following 2 years of treatment and remained stable during the fourth year . In contrast , in the non-etidronate group , bone density decreased significantly after four years . In addition , the fracture rate was significantly lower in the etidronate group than in the non-etidronate group . Side effects were minimal in both groups and no serious adverse reactions were reported . In conclusion , it appears that a cyclical regimen using 1,25-dihydroxyvitamin D3 , etidronate and calcium increases bone mass and reduces fractures with no significant side effects , thus making a useful contribution in the treatment of postmenopausal osteoporosis The purpose of this study was to determine factors that could predict the one-year response of the lumbar bone mineral density ( BMD ) to alendronate treatment in elderly Japanese women with osteoporosis . Eighty-five postmenopausal women with osteoporosis , all of whom were between 55 - 88 years of age , were treated with alendronate ( 5 mg daily ) for 12 months . Serum calcium , phosphorus , and alkaline phosphatase ( ALP ) and urinary NTX levels were measured at the baseline and 6 months , and lumbar ( L1-L4 ) BMD was measured by dual energy X-ray absorptiometry at the baseline and 12 months . Multiple regression analysis was used to determine factors that were correlated with the percent change in lumbar BMD at 12 months . Lumbar BMD increased by 8.1 % at 12 months with a reduction in the urinary NTX level by 51.0 % at 6 months . Baseline lumbar BMD ( R2=0.226 , p < 0.0001 ) and percent changes in serum ALP and urinary NTX levels ( R2=0.044 , p < 0.05 and R2=0.103 , p < 0.001 , respectively ) had a negative correlation with the percent change in lumbar BMD at month 12 , while the baseline number of prevalent vertebral fractures ( R2=0.163 , p < 0.001 ) , serum ALP level , and urinary NTX level ( R2=0.074 , p < 0.05 and R2=0.160 , p < 0.001 , respectively ) had a positive correlation with it . However , baseline age , height , body weight , body mass index , years since menopause , serum calcium and phosphorus levels , and percent changes in serum calcium and phosphorus levels at 6 months did not have any significant correlation with the percent change in lumbar BMD at 12 months . These results suggest that lumbar BMD was more responsive to one-year of alendronate treatment in elderly osteoporotic Japanese women with lower lumbar BMD , more prevalent vertebral fractures , and higher bone turnover , who showed a greater decrease in bone turnover at 6 months , regardless of age , years since menopause , and physique . Alendronate may be efficacious in elderly Japanese women with evident osteoporosis that is associated with high bone turnover , and the percent changes in serum ALP and urinary NTX levels at 6 months could predict the one-year response of lumbar BMD to alendronate treatment BACKGROUND Administration of estrogen or etidronate has been shown to increase bone mineral density in postmenopausal women . This 4-year , prospect i ve , r and omized study was carried out to monitor any added beneficial effect on bone mineral density when hormone-replacement therapy ( HRT ) was combined with etidronate . PATIENTS AND METHODS Fifty-eight early postmenopausal women attending metabolic bone disease outpatient clinics were r and omly allocated into four treatment groups and monitored for up to 4 years . All patients received 1.0 g/d of elemental calcium . In addition , group 1 received percutaneously administered HRT ( n = 15 ) ; group 2 , intermittent cyclical etidronate ( ICE ) ( n = 14 ) ; group 3 , HRT and ICE ( n = 15 ) ; and group 4 , calcium alone ( n = 14 ) . The bone mineral density ( measured by dual-energy x-ray absorptiometry ) , biochemical variables of bone turnover , including bone-specific alkaline phosphatase , and urinary hydroxyproline : creatinine ratios were measured before treatment and at 2 and 4 years after treatment . RESULTS In patients who received the combined therapy , bone mineral density was increased in the vertebrae by 10.9 % ( P < 0.001 ) and in the femora by 7.25 % ( P < 0.001 ) at 4 years . For patients treated with ICE , the increase was 6.79 % ( P < 0.001 ) and 1.20 % ( P < 0.05 ) , and with HRT , 6.78 % ( P < 0.001 ) and 4.01 % ( P < 0.01 ) in the vertebrae and femora , respectively . The group treated with calcium alone lost 3.81 % ( P < 0.01 ) and 4.96 % ( P < 0.01 ) of bone mineral density in vertebrae and femora . Patients who received no specific therapy lost 8.58 % ( P < 0.01 ) from vertebrae , and 7.83 % ( P < 0.01 ) from the femora over 4 years . Patients who received combined therapy had significantly higher bone mineral density in both vertebrae ( P < 0.05 ) and femora ( P < 0.01 ) , in comparison to patients who were treated with HRT , or ICE , alone . Three of 9 patients ( 33 % ) in the ICE group developed osteomalacia , as shown by bone histomorphometry , whereas in women who received combined HRT and ICE therapies , none of the 11 patients tested had evidence of bone mineralization defects . CONCLUSION This 4-year , prospect i ve , r and omized study in early postmenopausal women showed an additive effect of ICE and HRT on the bone mineral density in both vertebrae and the hip . Furthermore , the combined therapy prevented the occurrence of osteomalacia associated with etidronate . This is the first study to demonstrate the effects of etidronate in early postmenopausal women , and the additive beneficial effects of HRT and ICE on bone mineral density To demonstrate the clinical benefit of risedronate at 2.5 mg daily in the treatment of involutional osteoporosis , the effect of risedronate on incidence of vertebral fracture was compared with that of etidronate . A total of 547 patients with one to four 
    Output:
    
However , observational data has led to concerns regarding potential risk for upper gastrointestinal injury .
AUTHORS ' CONCLUSIONS Etidronate , at 400 mg per day , demonstrated a statistically significant and clinical ly important benefit in the secondary prevention of vertebral fractures .
No statistically significant reductions in vertebral fractures were observed when it was used for primary prevention .
In addition , no statistically significant reductions in non-vertebral , hip , or wrist fractures were found , regardless of whether etidronate was used for primary or secondary prevention .