***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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    Input: It seems logical to use fluoride in osteoporosis , because fluoride can stimulate osteoblastic proliferation and new bone formation [ 1 , 2 ] . However , clinical trials with fluoride have yielded mixed results because excessive exposure to fluoride may cause abnormal bone formation , microfractures , and gastric bleeding [ 3 , 4 ] . Thus , treatment with a high dosage of plain sodium fluoride did not decrease the spinal fracture rate despite markedly increasing vertebral bone density , and it increased the rate of appendicular fractures and microfractures [ 4 ] . To overcome the complications associated with sodium fluoride , we have advocated the cyclical , intermittent use of a lower dose of less bioavailable , slow-release sodium fluoride and continuous supplementation with calcium citrate [ 5 , 6 ] . This treatment has been shown to maintain serum fluoride concentrations within the narrow therapeutic window [ 7 , 8 ] , thus avoiding toxic peaks in serum [ 9 ] , and to stimulate the formation of normally mineralized bone [ 5 , 10 ] with an improved intrinsic quality of cancellous bone [ 11 - 13 ] . We previously reported the results of an interim analysis [ 6 ] of a placebo-controlled r and omized trial ( median duration of treatment for fracture analysis , 2 years ) . Here , we present the final report of that trial ( median duration of treatment for fracture analysis , 3 years ) . Methods Clinical Data Demographic and baseline presentations were described in the interim report [ 6 ] . We recruited 110 women with postmenopausal osteoporosis into the trial . All had radiologic evidence of osteopenia and osteoporosis ; one or more vertebral fractures believed to be nontraumatic ; and no secondary cause of bone loss . They were r and omly assigned to one of two groups and stratified according to estrogen treatment . All study personnel were unaware of group assignment while data were being gathered . Ninety-nine patients completed at least 1 study cycle ( 1 year of actual treatment ) . The demographic or baseline presentations of these 99 patients did not differ according to treatment group [ 6 ] ( Table 1 ) . The two groups were similar in age , time since menopause , dietary calcium intake , height , weight , and number of spinal fractures . Both groups had moderate to severe osteoporosis : The average L2-L4 bone density was approximately 30 % less than of a normal 30-year-old woman , and each group had a median of two spinal fractures at baseline . Table 1 . Baseline Characteristics * Treatment Patients in the fluoride group received slow-release sodium fluoride ( Slow Fluoride , Mission Pharmacal Co. , San Antonio , Texas ) , 25 mg twice daily , orally before breakfast and at bedtime in repeated 14-month cycles ( 12 months receiving treatment followed by 2 months not receiving treatment ) . They also received calcium citrate ( Citracal , Mission Pharmacal ) , 400 mg calcium twice daily , before breakfast and at bedtime continuously throughout the study . Those in the placebo group received placebo ( identical in appearance to Slow Fluoride but containing excipient only [ provided by Mission Pharmacal ] ) on the same time schedule . The Mission Pharmacal Company had no role in the design of the study or in data retrieval , analysis , or interpretation . Thirteen of 48 patients in the fluoride group and 16 of 51 patients in the placebo group received concurrent treatment with estrogen .  Nine of the 29 patients treated with estrogen were recruited at the primary site at Dallas ; the other 20 were enrolled and evaluated at the Scott and White Clinic , Temple , Texas .  Fracture Quantitation Before treatment and at 12 months of each cycle , a lateral spine roentgenogram was obtained for the assessment of spinal fractures . In the interim analysis [ 6 ] , prevalent fractures ( fractures present at baseline ) were identified with the aid of radiology reports . For this final report , prevalent fractures were also analyzed using a computer program that calculated the vertebral dimensions of clearly unaffected vertebrae from l and marks ( anterior and posterior corners and midpoints ) . By comparing these dimensions with published normal values [ 14 ] , we obtained a correction factor . Using this correction factor , we estimated idealized vertebral dimensions before a fracture had occurred for the remaining vertebrae in the given baseline radiograph . A reduction in any height of more than 20 % ( from idealized to actual ) accompanied by a decrease of at least 10 % in vertebral area represented a prevalent fracture . Incident spinal fractures ( fractures occurring during the trial ) were identified as described previously [ 6 ] , using a computer-derived method . A reduction in any vertebral height of more than 20 % accompanied by a decrease in vertebral area of more than 10 % from one year to the next constituted a fracture [ 15 ] . A new incident fracture was a fracture that occurred during treatment in a previously unaffected vertebrae . A recurrent fracture was one that developed on a previously fractured vertebra . Bone Mass Measurements The use of different densitometers prompted us to calculate and use percentage changes per year rather than absolute values . The method for calculating changes in L2-L4 bone mineral content and bone density of the femoral neck and the radial shaft was described previously [ 6 ] . Safety Variables Serum fluoride concentrations were measured before the morning dose of the test drug at 0 , 3 , 6 , 9 , and 12 months of each cycle , and they were analyzed using an ion-specific electrode . At the same visits , a history was taken for gastrointestinal and musculoskeletal side effects . A microfracture was defined clinical ly as moderate to severe lower-extremity pain that persisted for more than 6 weeks despite a reduction in treatment dose and objective ly as changes on bone scan or radiograph . The relation of each side effect to treatment was assessed . A symptom was considered to be related to treatment if it was moderate to severe in intensity , had no other cause , had newly appeared and persisted during the treatment phase , or had disappeared during the withdrawal period or with dose reduction . It was considered to be unrelated if it was present at baseline or during the late withdrawal phase , or if it had newly appeared but was not persistent . The severity and frequency of side effects were also quantitated as adverse symptom scores . We identified 10 gastrointestinal items ( symptoms such as nausea , vomiting , and diarrhea ) , 4 rheumatic items ( pain in the foot , knee , hip , and other joints ) , and 3 skeletal items ( pain in the lower , mid- , or upper back ) . Each item was given a numerical value of 1 to 3 for frequency ( infrequent , frequent , or very frequent ) and a numerical value of 1 to 3 for severity ( mild , moderate , or severe ) . Side-effect score was the product of the value for frequency and the value for severity for each item . Thus , a constant , severe back pain yielded a score of 9 ( 3 3 ) . A gastrointestinal score was derived for each patient by adding the scores of the 10 gastrointestinal items for all relevant visits and dividing the sum by the number of visits . A similar computation was done to derive rheumatic and skeletal scores for each patient . Statistical Analysis The data for incident spinal fractures were compared between the two groups-using three methods . Individual Vertebral Fracture Rate For each patient , the individual vertebral fracture rate was obtained by dividing the total number of new fractures by the duration of treatment . Because the data were skewed , this rate was compared between the two groups using the Wilcoxon rank-sum test . Fracture-Free Rate This rate was the percentage of patients without new fractures , unadjusted for covariates . The two groups were compared using the log-rank test to account for differential follow-up . Survival The Cox proportional-hazards regression model [ 16 ] was constructed to estimate the relative risk for a new spinal fracture while adjusting for covariates ( treatment group , age , prevalent spinal fractures , years since menopause , height , weight , estrogen treatment , and stratum of baseline L2-L4 bone density ) . Time ( in years ) to the first fracture was considered to be the survival time . Analyses of fracture rates and logistic regression were also done [ 6 ] ; the data are not presented because findings were similar to those obtained using the above methods . The arithmetic difference in height from baseline to the end of treatment for each patient was compared between groups using a two- sample t-test and a two-way analysis of variance with the following factors : 1 ) treatment [ fluoride vs placebo ] and 2 ) fracture status ( fracture-free vs one or more new or recurrent fractures ) . For each patient , we calculated the percentage change per year for L2-L4 bone mineral content and bone density of femoral neck and radial shaft . The individual mean change for each patient was calculated as the average of yearly changes . The group mean was obtained by averaging the individual means . One- sample t-tests were then used to compare the percentage change to zero for each year or for the mean . Comparisons between groups were made using two- sample t-tests . Missing data precluded implementing a repeated- measures analysis of variance . For related adverse events , the frequency of each event was compared between the two groups by using the Fisher exact test . Adverse symptom scores were compared between the groups by using the Wilcoxon rank-sum test and within the groups by using the Wilcoxon signed-rank test . For nonvertebral fractures , the exact tests based on the binomial distribution using person-year data were used to compare the two groups . Most analyses were done using BMDP Statistical Software ( BMDP , Los Angeles , California ) . Programs for analyzing person-time data were developed by the authors . Data are presented as mean SD unless otherwise indicated . All reported P values are two-sided . Results Duration of Treatment The total duration of follow-up , including withdrawal periods , was 193 patient-years in Although fluoride can cause osteoblastic proliferation [ 1 , 2 ] and stimulate new bone formation [ 3 ] , its use in managing osteoporosis has been associated with frequent and sometimes serious complications , including gastric bleeding and microfractures [ 3 ] . Excessive exposure may lead to fluorosis [ 4 ] , characterized by a formation of abnormal bone that may be poorly mineralized and mechanically defective . Further , in a placebo-controlled r and omized trial [ 3 ] , continuous treatment with plain ( nonsustained release ) sodium fluoride and calcium carbonate supplementation did not produce a statistically significant decrease in the spinal fracture rate despite a substantial increase in the lumbar vertebral bone mass . We previously reported [ 5 , 6 ] a nonr and omized trial in which intermittent slow-release sodium fluoride with continuous calcium citrate supplementation stimulated the formation of normally mineralized bone and decreased the spinal fracture rate without serious complications . In 1986 , we initiated a r and omized trial using slow-release sodium fluoride plus calcium citrate compared with placebo plus calcium citrate in 99 patients with postmenopausal osteoporosis . The trial is ongoing , with an average duration of treatment in the two study groups of 2.44 and 2.14 cycles ( 14 mo/cycle ) and with 15 patients completing the intended 4 cycles of treatment . Although the study is not expected to be completed until August 1996 , this interim analysis was done in response to a request for an up date at the Fourth International Symposium on Osteoporosis [ 7 ] . The trial will be completed in order to determine if the treatment effect is sustained . We believe that the interim analysis will not affect the conduct of the remainder of the trial . Methods Clinical Data Recruited into the trial were 110 fully ambulatory white women with postmenopausal osteoporosis , all of whom were referred for symptomatic osteoporosis by practicing physicians because of an inadequate response to conventional therapy or the unwillingness of physicians to care for them . No other ethnic groups were enrolled , probably because of the rarity of postmenopausal osteoporosis and the nature of the referred patients in the study areas . The entry criteria were as follows : postmenopausal state , radiographic evidence of osteoporosis , and one or more vertebral fractures believed to be nontraumatic . Exclusion criteria were as follows : the presence of conditions causing bone loss such as hyperparathyroidism , adrenocorticosteroid excess , thyrotoxicosis , chronic diarrheal state or malabsorption , renal tubular acidosis , renal impairment ( endogenous creatinine clearance less than 0.7 mL/min per kg ) ; previous treatment with diphosphonate , calcitonin , or fluoride ; active peptic ulcer disease ; and skeletal fractures that could not be quantified for anatomic or technical reasons . Those taking pharmacologic doses of vitamin D preparations were accepted if they had discontinued the drug for at least 6 months . At recruitment , 31 patients were taking estrogen ( treatment initiated after osteoporosis was diagnosed ) . Thirteen patients had documented recurrent spinal fractures while receiving estrogen .  The total duration of estrogen therapy represented about a third of their postmenopausal state ( mean , 8 years ) . This treatment , usually consisting of conjugated estrogen , 0.625 mg/d given continuously or intermittently ( 25 d/mo ) , and intermittent progesterone ( 5 mg/d for 10 d/mo ) , was continued during the trial . Patients receiving estrogen  had similar baseline demographic characteristics as patients not receiving estrogen and were considered at increased risk for further fractures . R and omization and Treatment Scheme Participants were r and omly assigned to the two treatment groups , stratified according to estrogen treatment ( untreated or estrogen-treated ) . Patients in 
    Output:
    
REVIEW ER 'S CONCLUSIONS Although fluoride has an ability to increase BMD at lumbar spine , it does not result in a reduction of vertebral fractures .
In increasing the dose of fluoride , one increases the risk of non-vertebral fracture and gastrointestinal side effects without any effect on the vertebral fracture rate