human
***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: Proton pump inhibitors ( PPIs ) increase  osteoporotic fracture  risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption ( FCA ) . Existing studies provide conflicting information regarding the direct effects of PPIs on FCA . We evaluated the effect of PPI therapy on FCA . We recruited women at least 5 years past menopause who were not taking acid suppressants . Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method . Two FCA studies were performed 1 month apart to establish baseline calcium absorption . The third study occurred after taking omeprazole ( 40 mg/day ) for 30 days . Each participant consumed the same foods during all FCA studies ; study meals replicated subjects ' dietary habits based on 7-day diet diaries . Twenty-one postmenopausal women ages 58 ± 7 years ( mean ± SD ) completed all study visits . Seventeen women were white , and 2 each were black and Hispanic . FCA ( mean ± SD ) was 20 % ± 10 % at visit 1 , 18 % ± 10 % at visit 2 , and 23 % ± 10 % following 30 ± 3 days of daily omeprazole ( p = .07 , ANOVA ) . Multiple linear regression revealed that age , gastric pH , serum omeprazole levels , adherence to omeprazole , and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3 . The 1,25-dihydroxyvitamin D3 level at visit 2 was the only variable ( p = .049 ) associated with the change in FCA between visits 2 and 3 . PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use . Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture . © 2010 American Society for Bone and Mineral Research This study was performed to investigate the effects of the co-administration of proton pump inhibitor ( PPI ) on the efficacy of bisphosphonate ( BP ) treatment for osteoporosis . A total of 180 women with low bone mineral density were r and omly divided into four groups , one in which sodium risedronate was administered with sodium rabeprazole and one in which only risedronate was administered ( BP + PPI and BP groups , respectively ) . The biomarkers were measured at the baseline and every 3 months , inlcuding : N-terminal telopeptide of type I collagen corrected for creatinine , bone-specific alkaline phosphatase ( BAP ) , parathyroid hormone , bone mineral density ( BMD ) of the lumbar spine and physical parameters evaluated according to the SF-36v2 ™ Health Survey . Statistical comparisons of these parameters were performed after 9 months . Data were available for a total of 137 patients ( 62 in the BP group and 75 in the BP + PPI group ) . The Δ % value of increase in BMD and improvement of physical functioning in the BP + PPI group were significantly larger , and its decrease in BAP in the BP + PPI group was significantly smaller than that in the BP group . It is expected that risedronate administration in combination with a PPI may be more effective not only for treating osteoporosis but also improving physical fitness than treatment with risedronate alone We studied the effect of proton pump inhibitors , histamine H2 receptor antagonists , and other types of antacid drugs on  fracture risk . All cases were subjects with any fracture sustained during the year 2000 ( n = 124,655 ) . For each case , three controls ( n = 373,962 ) matched on age and gender were r and omly drawn from the background population . The primary exposure variables were use of proton pump inhibitors , histamine H2 antagonists , and other antacid drugs . Adjustments were made for several confounders , including diagnosis of an ulcer , nonsteroidal anti-inflammatory drug use , use of histamine H1 antagonists , stomach resection , previous fracture , and use of corticosteroids . The effect of dose was examined by stratifying for cumulated dose ( defined daily dose ) . Use of proton pump inhibitors was associated with an increase in fracture risk for use within the last year [ odds ratio ( OR ) = 1.18 , 95 % confidence interval ( CI ) 1.12–1.43 for overall fracture risk ; OR = 1.45 , 95 % CI 1.28–1.65 for hip fractures ; and OR = 1.60 , 95 % CI 1.25–2.04 for spine fractures ) . Histamine H2 antagonists were associated with a decreased fracture risk if they had been used within the last year ( OR = 0.88 , 95 % CI 0.82–0.95 for any fracture , OR = 0.69 , 95 % CI 0.57–0.84 for hip fractures ) . Other antacids were not associated with overall fracture risk but were associated with hip and spine fractures . Proton pump inhibitors appeared to be associated with a limited increase in fracture risk , in contrast to histamine H2 antagonists , which seemed to be associated with a small decrease in fracture risk . In all cases , the changes in risk estimates were small and the clinical significance was limited There has been recent media attention to the possibility that long-term proton pump inhibitor ( PPI ) prescribing may be linked to an increased risk of hip fracture  according to data from the United Kingdom ( UK ) ( 1 ) and Canada ( 2 ) . The Canadian Association of Gastroenterology has prepared the following position statement on the association between PPI therapy and hip fracture in light of this evidence . The present position statement is outlined in greater detail elsewhere ( 3 ) . Yang et al ( 1 ) reported a nested case-control study using the UK General Practice Research Data base that selected patients older than 50 years of age with an incident hip fracture , and age and sex-matched controls . There were 13,556 hip fracture cases and 135,386 controls ;  PPI therapy for more than one year was associated with an increased risk of hip fracture ( adjusted OR 1.44 ; 95 % CI 1.30 to 1.59 ) . Targownik et al ( 2 ) reported a further nested case-control study using the Manitoba Population Health Research Data Repository , in which 15,792 patients with osteoporosis-related fractures were compared with 47,289 controls . There was no overall association between  PPI use and fracture until after five or more years of exposure , when the risk of osteoporotic fracture became significant ( adjusted OR 1.62 ; 95 % CI 1.02 to 2.58 ) . Similarly , the risk of hip fracture became significant after seven years of PPI exposure ( adjusted OR 4.55 ; 95 % CI 1.68 to 12.29 ) . The clinical significance of this is uncertain because extrapolation of these figures ( assuming 1.8 per 1000 patients develop a hip fracture [ 1 ] ) suggests that 1263 patients need to be treated with a PPI for more than one year to develop one excess hip fracture , although the number needed to harm may be much lower after seven years according to the Canadian study . These studies use reputable data bases and are rigorously conducted and analyzed appropriately . The discussion s in both of these articles suggest quite strongly that the association they have found is likely to be causal . Large data bases provide a wonderful opportunity to evaluate benefits and harms of medical interventions , but caution must be exercised before assuming the latest finding represents a risk to patients . The ready availability of data bases means that literally millions of associations can be tested ; even within a particular hypothesis there are a variety of approaches to splitting the data ( eg , duration of therapy , therapy dose , length of follow-up , patient age , male versus female ) . Research ers and journals are prone to emphasize positive findings and tend to underplay the role of chance or confounding factors . These issues are less likely to be important if a consistent association is found . An accompanying editorial ( 4 ) to the Canadian study also cites a third Danish data base study ( 5 ) that supports an association between PPI therapy and fracture . It is interesting to note that the Danish study had a much greater number of cases ( 124,655 ) than the other two studies , and yet had much more muted conclusions and was published in a lower impact factor journal . The Danish study was circumspect in their conclusions because there were inconsistencies in the data and there was no dose response information . For example , there seemed to be an increased risk with taking less than 25 doses of a PPI in one year with a lower ( but still statistically significant ) risk in those taking one dose per day for a year . There seemed to be no biologically plausible hypothesis why such infrequent use of PPI therapy would be associated with an increased risk of fracture . There were also inconsistencies with the UK and Canadian studies . The UK study reported an increased risk of hip fracture after one year of PPI therapy ; there seemed to be little increase in risk over the next four years , whereas the Canadian study only found a significant association after seven years . Targownik et al ( 2 ) suggest that perhaps the UK data base included patients that had in fact been taking PPIs for much longer ; however , this is speculation . Furthermore , a Canadian cohort study ( 6 ) followed-up on elderly patients in Ontario on  warfarin ( n=52,701 ) , thyroid replacement  ( n=40,555 ) , oral corticosteroid ( n=43,915 ) and PPI therapy  ( n=60,383 ) for five years . There was no increased risk of hip fracture in those taking warfarin compared with those on PPI therapy ( adjusted OR 0.94 ; 95 % CI 0.81 to 1.09 ) , but there was an increased risk with  corticosteroid therapy compared with PPI therapy ( adjusted OR 1.44 ; 95 % CI 1.21 to 1.70 ) . It could be that warfarin is also associated with an increased risk of hip fracture ; however , it is interesting that Targownik et al ( 2 ) found little increase in fracture risk in those taking anticoagulants ( 14.5 % of fracture cases taking anticoagulants compared with 13.4 % of controls ) . The CAG is proud to acknowledge its Benefactor Corporate Sponsors : Abbott Canada AstraZeneca Canada Inc Axcan Pharma Inc Olympus Canada Inc Pentax Canada Inc. Procter & Gamble Pharmaceuticals Schering-Plough Canada Inc. UCB Pharma Inc. Finally , there is the issue of biological plausibility . It has been proposed that acid suppression may reduce calcium absorption and increase the risk of fracture ( 1 ) . The role of pH in calcium absorption is , however , controversial . The dissolution of calcium carbonate is pH-dependent in vitro , although the clinical significance of this is uncertain given that calcium is absorbed in the small intestine where the pH is nonacidic regardless of stomach pH. A review of the literature ( 7 ) identified seven r and omized trials that evaluated calcium absorption with acid suppression in healthy subjects or those with ulcer disease . There were major method ological issues with many of the studies and they were all small . Four studies found no impact on calcium absorption while three reported decreased absorption . Further work is needed in this area , but there are no conclusive data that would make the association between fracture and PPI biologically plausible . Furthermore , some research suggests that PPI therapy may inhibit bone resorption ( 8) , which may protect against fracture risk . PPIs are one of the most well-tolerated classes of drugs on the market . They have also improved the quality of life of countless patients with acid-related disease . There are risks in prescribing any drug and this should be borne in mind by all prescribing clinicians . PPI therapy should only be prescribed for indications where there is a proven or likely benefit and the need for these drugs should be review ed on a regular basis . This applies particularly to frail and elderly patients with multiple comorbidities and those taking a number of different medications where the possibility for drug interactions increases . This message applies to all the drugs clinicians prescribe including PPI therapy . Current data would not support particular care in prescribing PPI therapy due to concerns about the risk of hip fracture . There is no persuasive evidence that the association is causal , although this can never be excluded as a possibility . The Canadian Association of Gastroenterology encourages health professionals to keep continually up date d on the medical literature and will endeavour to disseminate further guidance if more information on the possible harms of PPI therapy becomes available Patients with gastroesophageal reflux disease ( GERD ) receive long-term therapy with proton pump inhibitor ( PPI ) agents . Several studies have recently been published suggesting that treatment with PPI may cause bone fractures , although the number of prospect i ve studies in this regard is limited . The aim of this study is to prospect ively investigate the effect of PPIs on bone density . Between March 2009 and January 2011 , 114 GERD patients ( 18–56 years ) and 110 healthy controls were included in the present study .  Bone mineral densitometry ( BMD ) by using dual-energy X-ray absorptiometry was assessed at lumbar spine and femur neck . BMD measurements were performed on all subjects at the beginning of the study . The patients were divided according to three drugs by their treatment with esomeprazole , lansoprazole , or pantoprazole . The study group was followed for at least 6 months on PPI therapy , and then BMD measurements 
    Output:
    
agent
The magnitude of the association is modest and is most likely due to confounding factors as patients prescribed PPI therapy  tend to be more frail with more risk factors for fractures than those not given these drugs .
There is no clear dose – response relationship and there is no association between PPI therapy and risk of fracture in those at highest risk .
Finally , there is no clear mechanism through which PPI therapy increases the risk of fracture , as recent r and omized trials show no impact of PPI therapy on calcium absorption and there is no association between PPI therapy and risk of osteoporosis .
We therefore feel there is insufficient evidence to change PPI prescribing habits based on risk of fracture .
There is no evidence to support prescription of calcium and /or vitamin D in patients simply because they are taking PPI therapy .
***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: Proton pump inhibitors ( PPIs ) increase  osteoporotic fracture  risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption ( FCA ) . Existing studies provide conflicting information regarding the direct effects of PPIs on FCA . We evaluated the effect of PPI therapy on FCA . We recruited women at least 5 years past menopause who were not taking acid suppressants . Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method . Two FCA studies were performed 1 month apart to establish baseline calcium absorption . The third study occurred after taking omeprazole ( 40 mg/day ) for 30 days . Each participant consumed the same foods during all FCA studies ; study meals replicated subjects ' dietary habits based on 7-day diet diaries . Twenty-one postmenopausal women ages 58 ± 7 years ( mean ± SD ) completed all study visits . Seventeen women were white , and 2 each were black and Hispanic . FCA ( mean ± SD ) was 20 % ± 10 % at visit 1 , 18 % ± 10 % at visit 2 , and 23 % ± 10 % following 30 ± 3 days of daily omeprazole ( p = .07 , ANOVA ) . Multiple linear regression revealed that age , gastric pH , serum omeprazole levels , adherence to omeprazole , and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3 . The 1,25-dihydroxyvitamin D3 level at visit 2 was the only variable ( p = .049 ) associated with the change in FCA between visits 2 and 3 . PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use . Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture . © 2010 American Society for Bone and Mineral Research This study was performed to investigate the effects of the co-administration of proton pump inhibitor ( PPI ) on the efficacy of bisphosphonate ( BP ) treatment for osteoporosis . A total of 180 women with low bone mineral density were r and omly divided into four groups , one in which sodium risedronate was administered with sodium rabeprazole and one in which only risedronate was administered ( BP + PPI and BP groups , respectively ) . The biomarkers were measured at the baseline and every 3 months , inlcuding : N-terminal telopeptide of type I collagen corrected for creatinine , bone-specific alkaline phosphatase ( BAP ) , parathyroid hormone , bone mineral density ( BMD ) of the lumbar spine and physical parameters evaluated according to the SF-36v2 ™ Health Survey . Statistical comparisons of these parameters were performed after 9 months . Data were available for a total of 137 patients ( 62 in the BP group and 75 in the BP + PPI group ) . The Δ % value of increase in BMD and improvement of physical functioning in the BP + PPI group were significantly larger , and its decrease in BAP in the BP + PPI group was significantly smaller than that in the BP group . It is expected that risedronate administration in combination with a PPI may be more effective not only for treating osteoporosis but also improving physical fitness than treatment with risedronate alone We studied the effect of proton pump inhibitors , histamine H2 receptor antagonists , and other types of antacid drugs on  fracture risk . All cases were subjects with any fracture sustained during the year 2000 ( n = 124,655 ) . For each case , three controls ( n = 373,962 ) matched on age and gender were r and omly drawn from the background population . The primary exposure variables were use of proton pump inhibitors , histamine H2 antagonists , and other antacid drugs . Adjustments were made for several confounders , including diagnosis of an ulcer , nonsteroidal anti-inflammatory drug use , use of histamine H1 antagonists , stomach resection , previous fracture , and use of corticosteroids . The effect of dose was examined by stratifying for cumulated dose ( defined daily dose ) . Use of proton pump inhibitors was associated with an increase in fracture risk for use within the last year [ odds ratio ( OR ) = 1.18 , 95 % confidence interval ( CI ) 1.12–1.43 for overall fracture risk ; OR = 1.45 , 95 % CI 1.28–1.65 for hip fractures ; and OR = 1.60 , 95 % CI 1.25–2.04 for spine fractures ) . Histamine H2 antagonists were associated with a decreased fracture risk if they had been used within the last year ( OR = 0.88 , 95 % CI 0.82–0.95 for any fracture , OR = 0.69 , 95 % CI 0.57–0.84 for hip fractures ) . Other antacids were not associated with overall fracture risk but were associated with hip and spine fractures . Proton pump inhibitors appeared to be associated with a limited increase in fracture risk , in contrast to histamine H2 antagonists , which seemed to be associated with a small decrease in fracture risk . In all cases , the changes in risk estimates were small and the clinical significance was limited There has been recent media attention to the possibility that long-term proton pump inhibitor ( PPI ) prescribing may be linked to an increased risk of hip fracture  according to data from the United Kingdom ( UK ) ( 1 ) and Canada ( 2 ) . The Canadian Association of Gastroenterology has prepared the following position statement on the association between PPI therapy and hip fracture in light of this evidence . The present position statement is outlined in greater detail elsewhere ( 3 ) . Yang et al ( 1 ) reported a nested case-control study using the UK General Practice Research Data base that selected patients older than 50 years of age with an incident hip fracture , and age and sex-matched controls . There were 13,556 hip fracture cases and 135,386 controls ;  PPI therapy for more than one year was associated with an increased risk of hip fracture ( adjusted OR 1.44 ; 95 % CI 1.30 to 1.59 ) . Targownik et al ( 2 ) reported a further nested case-control study using the Manitoba Population Health Research Data Repository , in which 15,792 patients with osteoporosis-related fractures were compared with 47,289 controls . There was no overall association between  PPI use and fracture until after five or more years of exposure , when the risk of osteoporotic fracture became significant ( adjusted OR 1.62 ; 95 % CI 1.02 to 2.58 ) . Similarly , the risk of hip fracture became significant after seven years of PPI exposure ( adjusted OR 4.55 ; 95 % CI 1.68 to 12.29 ) . The clinical significance of this is uncertain because extrapolation of these figures ( assuming 1.8 per 1000 patients develop a hip fracture [ 1 ] ) suggests that 1263 patients need to be treated with a PPI for more than one year to develop one excess hip fracture , although the number needed to harm may be much lower after seven years according to the Canadian study . These studies use reputable data bases and are rigorously conducted and analyzed appropriately . The discussion s in both of these articles suggest quite strongly that the association they have found is likely to be causal . Large data bases provide a wonderful opportunity to evaluate benefits and harms of medical interventions , but caution must be exercised before assuming the latest finding represents a risk to patients . The ready availability of data bases means that literally millions of associations can be tested ; even within a particular hypothesis there are a variety of approaches to splitting the data ( eg , duration of therapy , therapy dose , length of follow-up , patient age , male versus female ) . Research ers and journals are prone to emphasize positive findings and tend to underplay the role of chance or confounding factors . These issues are less likely to be important if a consistent association is found . An accompanying editorial ( 4 ) to the Canadian study also cites a third Danish data base study ( 5 ) that supports an association between PPI therapy and fracture . It is interesting to note that the Danish study had a much greater number of cases ( 124,655 ) than the other two studies , and yet had much more muted conclusions and was published in a lower impact factor journal . The Danish study was circumspect in their conclusions because there were inconsistencies in the data and there was no dose response information . For example , there seemed to be an increased risk with taking less than 25 doses of a PPI in one year with a lower ( but still statistically significant ) risk in those taking one dose per day for a year . There seemed to be no biologically plausible hypothesis why such infrequent use of PPI therapy would be associated with an increased risk of fracture . There were also inconsistencies with the UK and Canadian studies . The UK study reported an increased risk of hip fracture after one year of PPI therapy ; there seemed to be little increase in risk over the next four years , whereas the Canadian study only found a significant association after seven years . Targownik et al ( 2 ) suggest that perhaps the UK data base included patients that had in fact been taking PPIs for much longer ; however , this is speculation . Furthermore , a Canadian cohort study ( 6 ) followed-up on elderly patients in Ontario on  warfarin ( n=52,701 ) , thyroid replacement  ( n=40,555 ) , oral corticosteroid ( n=43,915 ) and PPI therapy  ( n=60,383 ) for five years . There was no increased risk of hip fracture in those taking warfarin compared with those on PPI therapy ( adjusted OR 0.94 ; 95 % CI 0.81 to 1.09 ) , but there was an increased risk with  corticosteroid therapy compared with PPI therapy ( adjusted OR 1.44 ; 95 % CI 1.21 to 1.70 ) . It could be that warfarin is also associated with an increased risk of hip fracture ; however , it is interesting that Targownik et al ( 2 ) found little increase in fracture risk in those taking anticoagulants ( 14.5 % of fracture cases taking anticoagulants compared with 13.4 % of controls ) . The CAG is proud to acknowledge its Benefactor Corporate Sponsors : Abbott Canada AstraZeneca Canada Inc Axcan Pharma Inc Olympus Canada Inc Pentax Canada Inc. Procter & Gamble Pharmaceuticals Schering-Plough Canada Inc. UCB Pharma Inc. Finally , there is the issue of biological plausibility . It has been proposed that acid suppression may reduce calcium absorption and increase the risk of fracture ( 1 ) . The role of pH in calcium absorption is , however , controversial . The dissolution of calcium carbonate is pH-dependent in vitro , although the clinical significance of this is uncertain given that calcium is absorbed in the small intestine where the pH is nonacidic regardless of stomach pH. A review of the literature ( 7 ) identified seven r and omized trials that evaluated calcium absorption with acid suppression in healthy subjects or those with ulcer disease . There were major method ological issues with many of the studies and they were all small . Four studies found no impact on calcium absorption while three reported decreased absorption . Further work is needed in this area , but there are no conclusive data that would make the association between fracture and PPI biologically plausible . Furthermore , some research suggests that PPI therapy may inhibit bone resorption ( 8) , which may protect against fracture risk . PPIs are one of the most well-tolerated classes of drugs on the market . They have also improved the quality of life of countless patients with acid-related disease . There are risks in prescribing any drug and this should be borne in mind by all prescribing clinicians . PPI therapy should only be prescribed for indications where there is a proven or likely benefit and the need for these drugs should be review ed on a regular basis . This applies particularly to frail and elderly patients with multiple comorbidities and those taking a number of different medications where the possibility for drug interactions increases . This message applies to all the drugs clinicians prescribe including PPI therapy . Current data would not support particular care in prescribing PPI therapy due to concerns about the risk of hip fracture . There is no persuasive evidence that the association is causal , although this can never be excluded as a possibility . The Canadian Association of Gastroenterology encourages health professionals to keep continually up date d on the medical literature and will endeavour to disseminate further guidance if more information on the possible harms of PPI therapy becomes available Patients with gastroesophageal reflux disease ( GERD ) receive long-term therapy with proton pump inhibitor ( PPI ) agents . Several studies have recently been published suggesting that treatment with PPI may cause bone fractures , although the number of prospect i ve studies in this regard is limited . The aim of this study is to prospect ively investigate the effect of PPIs on bone density . Between March 2009 and January 2011 , 114 GERD patients ( 18–56 years ) and 110 healthy controls were included in the present study .  Bone mineral densitometry ( BMD ) by using dual-energy X-ray absorptiometry was assessed at lumbar spine and femur neck . BMD measurements were performed on all subjects at the beginning of the study . The patients were divided according to three drugs by their treatment with esomeprazole , lansoprazole , or pantoprazole . The study group was followed for at least 6 months on PPI therapy , and then BMD measurements 
    Output:
    