***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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    ***EXAMPLES*** 
    Input: BACKGROUND The advent of bisphosphonates advanced therapy for Paget 's disease , but more effective and convenient agents are needed to increase adherence . Zoledronic acid , a bisphosphonate administered as a single intravenous infusion , might meet these needs . METHODS In two identical , r and omized , double-blind , actively controlled trials of 6 months ' duration , we compared one 15-minute infusion of 5 mg of zoledronic acid with 60 days of oral risedronate ( 30 mg per day ) . The primary efficacy end point was the rate of therapeutic response at six months , defined as a normalization of alkaline phosphatase levels or a reduction of at least 75 percent in the total alkaline phosphatase excess . The results of the studies were pooled . RESULTS At six months , 96.0 percent of patients receiving zoledronic acid had a therapeutic response ( 169 of 176 ) , as compared with 74.3 percent of patients receiving risedronate ( 127 of 171 , P<0.001 ) . Alkaline phosphatase levels normalized in 88.6 percent of patients in the zoledronic acid group and 57.9 percent of patients in the risedronate group ( P<0.001 ) . Zoledronic acid was associated with a shorter median time to a first therapeutic response ( 64 vs. 89 days , P<0.001 ) . Higher response rates in the zoledronic acid group were consistent across all demographic , disease-severity , and treatment-history subgroups and with changes in other bone-turnover markers . The physical-component summary score of the Medical Outcomes Study 36-item Short-Form General Health Survey , a measure of the quality of life , increased significantly from baseline at both three and six months in the zoledronic acid group and differed significantly from those in the risedronate group at three months . Pain scores improved in both groups . During post-trial follow-up ( median , 190 days ) , 21 of 82 patients in the risedronate group had a loss of therapeutic response , as compared with 1 of 113 patients in the zoledronic acid group ( P<0.001 ) . CONCLUSIONS A single infusion of zoledronic acid produces more rapid , more complete , and more sustained responses in Paget 's disease than does daily treatment with risedronate Several Biophosphonates have been used as therapeutic agents for Paget 's bone disease .  ( Chloro-4 phenyl)thiomethylene-bisphosphonate ( CIPsMBP ) has recently been shown to have significant antiosteoclastic activity while an affect of CIPsMBP on mineralization was only observed at high doses . We tested this drug for 6 months in 23 pagetic patients distributed in three groups . Gr 1 ( n = 5 ) receiving 200 mg/day showed a decrease of serum alkaline phosphatase ( SAP ) to 42 + /- 4 % ( p less than 0.01 ) of initial value ( 100 % ) while hydroxyprolinuria/creatinuria ratio ( OH/Cr ) dropped to 69 + /- 8 % of baseline . In 4 patients receiving 400 mg/day , SAP improved to 48 + /- 9 % of initial value ( p less than 0.01 ) and OH/Cr to 40 + /- 3 % ( p less than 0.01 ) . In the last group ( n = 14 ) receiving 200 mg/day for 3 months , and 400 mg/day thereafter up to the 6th month SAP decreased to 53 + /- 4 % and OH/Cr to 62 + /- 6 % of initial value ( p less than 0.01 ) . Clinical improvement was significant from the first month of treatment . No resistance ( mean decrease of SAP lower than 30 % ) was recorded and no radiological or clinical evidence of mineralization defect appeared . The clinical and biological tolerance was excellent throughout the study Summary Daily oral tablet bisphosphonate therapy for Paget ’s disease of bone may cause serious upper gastrointestinal adverse events . A once-weekly alendronate 280 mg oral buffered solution was compared with an alendronate 40 mg/day tablet . While both were similarly effective , the tablet appeared to be better tolerated in this study . Introduction Although daily doses of oral bisphosphonates are a generally safe and effective treatment for Paget ’s disease of bone ( PDB ) , some patients may experience upper gastrointestinal adverse events ( UGI AEs ) or find the dosing requirements inconvenient and become noncompliant . A once-weekly ( OW ) oral dose of bisphosphonate in buffered solution ( OBS ) may be as effective , better tolerated , and more convenient . Methods Sixty-three patients were r and omized to either alendronate ( ALN ) 280 mg OW OBS ( n = 42 ) or an ALN 40 mg/day tablet ( n = 21 ) during a 6-month , r and omized , double-blind , active-controlled trial . The primary endpoint was the mean percent decrease in total serum alkaline phosphatase ( total ALP ) from baseline at 6 months . Results There were no significant differences in total ALP between groups during the 6-month period . There was a higher incidence of clinical AEs in the ALN 280 mg OW OBS ( 79 % ) vs. the ALN 40 mg/day tablet group ( 67 % ) , including drug related AEs ( 48 % and 10 % , respectively ) , which led to study discontinuation ( 19.0 % and 10 % , respectively ) . Conclusions Although ALN 280 mg OW OBS was similarly effective as ALN 40 mg/day in reducing total ALP in patients with PDB , the ALN 40 mg/day tablet appears to be better tolerated than ALN 280 mg OW OBS Abstract The diphosphonate , sodium etidronate ( disodium ethane-1-hydroxy-1,1-diphosphonate ) ( E.H.D.P. ) , which inhibits the growth and dissolution of calcium phosphate crystals in vitro , was given at doses of 0 , 1 , 5 , 10 , or 20 mg . per kg . per day for up to 6 months to forty-seven patients with Paget 's disease of bone . There was a dose-related suppression of the raised alkaline phosphatase in plasma and total hydroxyproline in urine , and at 20 mg . per kg . per day nearly half of the patients had normal values at the end of treatment . A single course of E.H.D.P. could maintain biochemical remission for at least 2 years after stopping treatment . Bone biopsy specimens confirmed the suppression of the Paget 's disease . Increases in unmineralised osteoid were only seen in biopsy specimens taken after the higher doses of E.H.D.P. and were usually small . There was also a reversible rise in plasma-phosphate at 20 mg . per kg . per day . It is suggested that E.H.D.P. given for short periods could provide a simple and reliable oral therapy in those cases of Paget 's disease in which treatment is regarded as desirable Bisphosphonates are widely regarded as the treatment of choice for Paget 's disease of bone ( PDB ) because of their potent inhibitory effects on bone turnover , but the effects of bisphosphonate therapy on symptoms and complications of PDB have been little studied . Here we report the results of a r and omized trial that compared the effects of symptomatic treatment with intensive bisphosphonate therapy in a cohort of 1324 patients with PDB who were followed up for a median of 3 years ( range 2 to 5 years ) . The symptomatic treatment group was treated only if they had pagetic bone pain , for which they were first given analgesics or anti-inflammatory drugs , followed by bisphosphonates if they did not respond . The intensive group received repeat courses of bisphosphonates irrespective of symptoms with the aim of reducing and maintaining serum alkaline phosphatase ( ALP ) levels within the normal range . The endpoints were fracture , orthopedic surgery , quality of life , bone pain , and hearing thresholds . Serum ALP levels were significantly lower in the intensive treatment group than in with the symptomatic treatment group within 4 months of commencing treatment and remained lower throughout the study ( p < .001 ) . There was no difference between the groups in quality of life ( as assessed by the SF36 question naire ) , in overall bodily pain , or in pagetic bone pain . Hearing thresholds , as assessed by audiometry did not change significantly and did not differ between the treatment groups . Clinical fractures occurred in 46 of 661 patients ( 7.0 % ) in the intensive treatment group compared with 49 of 663 patients ( 7.4 % ) in the symptomatic treatment group , and orthopedic surgery was required in 50 of 661 patients ( 7.3 % ) in the intensive treatment group and in 55 of 663 patients ( 8.3 % ) in the symptomatic treatment group . These differences were not significant . Subgroup analyses of patients with elevated ALP levels at baseline and those who did or did not receive bisphosphonates during the study yielded similar results to those in the study group as a whole . We conclude that striving to maintain normal ALP levels with intensive bisphosphonate therapy confers no clinical advantage over symptom-driven management in patients with established PDB . Neither management strategy had a significant beneficial impact on pain or quality of life ( Clinical trial registration number IS RCT N12989577 ) Subjects ( 109 ) with symptomatic Paget 's disease of bone were treated with 5 , 10 , or 20 mg of sodium etidronate (EHDP)/kg body weight - day for 6 to 24 months . Significant decreases in serum alkaline phosphatase and urinary hydroxyproline were noted after 6 months of therapy ; no significant further improvement result ed after prolonged therapy . Some patients maintained biochemical remission after withdrawal of EHDP but others showed a relapse , related primarily to the pretreatment severity . Clinical improvement was noted in 61 % of the patients . Similar findings were seen after a second course of EHDP .  No side-effects were noted in patients treated with 5 mg of EHDP/kg body weight - day . In patients treated with 10 or 20 mg of EHDP/kg body weight - day , severe diarrhea , bone pain , and nontraumatic fractures were noted in 3 , 13 , and 12 patients respectively . Quantitative histomorphometry showed mineralization delay in patients receiving 10 or 20 mg of EHDP/kg body weight - day but not in those receiving 5 mg/kg body weight - day . Five milligrams of EHDP/kg body weight - day was effective and appears to be safer than the higher doses The use of disodium ethane-1 hydroxy-1 , 1-diphosphonate ( EHDP ) therapy for Paget 's disease of bone was examined in 75 affected patients . Forty-eight patients received r and omly assigned oral doses of either 0 , 2.5 , 5 , 10 , or 20 mg/kg/day in a controlled , double-blind protocol , and the remainder received either 10 or 20 mg/kg/day in a non-r and om protocol . The clinical status of the patients and appropriate laboratory tests were evaluated before treatment and at frequent intervals during a six-month period of initial therapy . There were no significant changes in either urinary hydroxyproline or serum alkaline phosphatase in those patients receiving placebos , while both these parameters decreased significantly at all dose levels of EHDP , with the greatest decline noted in the highest dose group . However , statistical analysis of the data related to changes in symptoms in the double-blind study revealed that patients receiving the higher dose of EHDP ( 10 or 20 mg/kg/day ) had less favorable outcomes than those receiving the lower doses ( 2.5 or 5 mg/kg/day ) . The high does group had a relatively lower rate of symptom improvement and a relatively greater rate of deterioration than did the low dose group . Twenty-one of forty-nine patients followed for at least 18 months have shown a sustained suppression of their serum alkaline phosphatase and urinary hydroxyproline values for 12 months following cessation of EHDP , while therapy has been reinstituted for the other 28 patients because of increases in these measurements , with or without accompanying symptomatic deterioration . Eight patients sustained fractures through Pagetic bone during the period of study and all of these were treated with higher doses of EHDP . On the basis of the biochemical and clinical data in this study it appears that initial therapy of Paget 's disease of bone with 5 mg EHDP/kg/day maximizes benefits while minimizing possible adverse effects Paget ’s disease of bone is a relatively common condition of unknown aetiology characterized by an increase in bone turnover . Many forms of treatment have been advocated but at the present time only the calcitonins ( 2 , 4 , 7 ) and the diphosphonates ( 1 , 3 , 5 , 11 ) offer practical forms of specific therapy Alendronate , an aminobisphosphonate , is much more potent than etidronate , an older bisphosphonate , in inhibiting osteoclast-mediated bone resorption , and unlike etidronate , therapeutic doses of alendronate are not associated with abnormal mineralization . In the present study , we compared the effectiveness , safety , 
    Output:
    
There was insufficient evidence to confirm or exclude differences in adverse effects of bisphosphonates ( RR 1.05 , 95 % CI 0.95 to 1.76 ; 2 studies , 437 participants ; low- quality evidence ) and treatment discontinuation ( 2 studies , 437 participants ) ( RR 2.04 , 95 % CI 0.43 to 9.59 ; 2 studies , 437 participants ; very low- quality evidence ) .Intensive versus symptomatic treatmentThere was no consistent evidence of difference to response in bone pain , bodily pain or quality of life in participants who received intensive versus symptomatic treatment .
We found moderate- quality evidence that bisphosphonates improved pain in people with Paget 's disease of bone when compared with placebo .
We found insufficient evidence of benefit in terms of pain or quality of life from intensive treatment .