***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: 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 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 vertebral fractures were r and omized to receive either treatment with 2.5 mg/day of risedronate or intermittent treatment ( treatment of 2 weeks and off period of 10 weeks ) with 200 mg/day of etidronate for 96 weeks in a double-masked fashion . All patients received 200 mg calcium supplement daily . Lateral and anteroposterior thoracic and lumbar spine radiographs were obtained at baseline and at 24 , 48 , 72 , and 96 weeks . Cumulative incidence rates of patients who had at least one new or worsening vertebral fracture during the 96-week period were 12.3 % for risedronate and 14.2 % for etidronate , and it was verified that the fracture prevention effect of risedronate was not inferior to that of etidronate . The incidence rates of fracture during the initial 24-week period were 8.8 % for risedronate and 6.0 % for etidronate , but the cumulative incidence rate of fracture from 24 to 96 weeks was lower in the risedronate group ( 3.9 % ) as compared to the etidronate group ( 8.7 % ) . Height loss was significantly less in the risedronate group ( −0.28 cm ) than in the etidronate group ( −0.70 cm ) after 96 weeks . Decreases in bone resorption markers including urinary total deoxypyridinoline and NTX were significantly greater in the risedronate group than in the etidronate group throughout the treatment period . An improvement of patient QOL was observed in both groups . No significant difference in the incidence of adverse events was observed between the two treatments . Daily oral risedronate ( 2.5 mg ) was shown to provide an effective therapy for involutional osteoporosis in Japanese patients with good tolerability BACKGROUND Risedronate increases bone mineral density in elderly women , but whether it prevents hip fracture is not known . METHODS We studied 5445 women 70 to 79 years old who had osteoporosis ( indicated by a T score for bone mineral density at the femoral neck that was more than 4 SD below the mean peak value in young adults [ -4 ] or lower than -3 plus a nonskeletal risk factor for hip fracture , such as poor gait or a propensity to fall ) and 3886 women at least 80 years old who had at least one nonskeletal risk factor for hip fracture or low bone mineral density at the femoral neck ( T score , lower than -4 or lower than -3 plus a hip-axis length of 11.1 cm or greater ) . The women were r and omly assigned to receive treatment with oral risedronate ( 2.5 or 5.0 mg daily ) or placebo for three years . The primary end point was the occurrence of hip fracture . RESULTS Overall , the incidence of hip fracture among all the women assigned to risedronate was 2.8 percent , as compared with 3.9 percent among those assigned to placebo ( relative risk , 0.7 ; 95 percent confidence interval , 0.6 to 0.9 ; P=0.02 ) . In the group of women with osteoporosis ( those 70 to 79 years old ) , the incidence of hip fracture among those assigned to risedronate was 1.9 percent , as compared with 3.2 percent among those assigned to placebo ( relative risk , 0.6 ; 95 percent confidence interval , 0.4 to 0.9 ; P=0.009 ) . In the group of women selected primarily on the basis of nonskeletal risk factors ( those at least 80 years of age ) , the incidence of hip fracture was 4.2 percent among those assigned to risedronate and 5.1 percent among those assigned to placebo ( P=0.35 ) . CONCLUSIONS Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density BACKGROUND Many women using hormone replacement therapy ( HRT ) will discontinue HRT and lose its bone-protective effect . Methods to preserve bone density in these women need to be explored . This multicenter , international , r and omized , blinded , 12-month study was conducted to assess the effect of alendronate sodium on bone density in women who had recently discontinued HRT . METHODS The 144 postmenopausal women included in the study were diagnosed as having low bone mineral density ( BMD ) and had recently discontinued HRT . They were r and omized to receive either a daily dose of 10 mg of alendronate sodium or matching placebo . The main outcome measures were spine , hip , and total body BMD ; biochemical markers of bone turnover ; and tolerability . RESULTS Alendronate treatment was associated with a 2.3 % mean increase ( 95 % confidence interval [ CI ] , 1.7%-3.0 % ) in spine BMD compared with a mean loss of 3.2 % ( 95 % CI , - 4.6 % to - 1.7 % ) in patients receiving placebo , for a difference of 5.5 % ( 95 % CI , 4.2%-6.8 % ) between alendronate and placebo . Greater hip and total body BMD preservation was also observed with alendronate use . Bone turnover decreased significantly with alendronate ( bone-specific alkaline phosphatase levels decreased by 20 % and urinary N-telopeptide/creatinine ratio by 47 % ) , but increased in the placebo group ( by 18 % and 36 % , respectively ) . Alendronate was well tolerated , with no increase in adverse events compared with placebo . CONCLUSIONS A high rate of bone loss was observed in the first 12 to 15 months after discontinuation of HRT in postmenopausal women with low BMD . Treatment with alendronate increased or maintained both spine and hip BMD and prevented the increase in bone resorption seen with withdrawal of HRT in this population GH increases bone turnover and stimulates osteoblast activity . We hypothesized that administration of MK-677 , an orally active GH secretagogue , together with alendronate , a potent inhibitor of bone resorption , would maintain a higher bone formation rate relative to that seen with alendronate alone , thereby generating greater enhancement of bone mineral density ( BMD ) in women with postmenopausal osteoporosis . We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation ( osteocalcin and bone-specific alkaline phosphatase ) and resorption [ urinary N-telopeptide cross-links ( NTx ) ] for 12 months and BMD for 18 months . In a multicenter , r and omized , double blind , placebo-controlled , 18-month study , 292 women ( 64 - 85 yr old ) with low femoral neck BMD were r and omly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months : MK-677 ( 25 mg ) plus alendronate ( 10 mg ) ; alendronate ( 10 mg ) ; MK-677 ( 25 mg ) ; or a double dummy placebo .  Patients who received MK-677 alone or placebo through month 12 received MK-677 ( 25 mg ) plus alendronate ( 10 mg ) from months 12 - 18 . All other patients remained on their assigned therapy . All patients received 500 mg/day calcium . The primary results , except for BMD , are provided for month 12 . MK-677 , with or without alendronate  , increased insulin-like growth factor I levels from baseline ( 39 % and 45 % ; P < 0.05 vs. placebo ) . MK-677 increased osteocalcin and urinary NTx by 22 % and 41 % , on the average , respectively ( P < 0.05 vs. placebo ) . MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin ( -40 % vs. -54 % ; P < 0.05 , combination vs. alendronate ) and reduced the effect of alendronate on resorption ( NTx ) as well ( -52 % vs. -61 % ; P < 0.05 , combination vs. alendronate ) . MK-677 plus alendronate increased BMD at the femoral neck ( 4.2 % vs. 2.5 % for alendronate ; P < 0.05 ) . However , similar enhancement 
    Output:
    
We found that zoledronic acid had the highest chance of causing gastrointestinal adverse events .
Etidronate had the highest chance of discontinuation due to an adverse event .
No difference was found for serious adverse events .
Etidronate had the highest probability ( 56 % ) of having the greatest number of upper GI symptoms among oral bisphosphonates .
Conclusion Zoledronic acid had the highest probability of causing the greatest number of GI AE , possibly related to nausea .
These results question the assumption that annual zoledronic acid will translate into better adherence .
Little difference was found between alendronate and risedronate for serious AE .