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: The effects of calcium supplementation ( as calcium citrate malate , 1000 mg elemental Ca/d ) with and without the addition of zinc ( 15.0 mg/d ) , manganese ( 5.0 mg/d ) and copper ( 2.5 mg/d ) on spinal bone loss ( L2-L4 vertebrae ) was evaluated in healthy older postmenopausal women ( n = 59 , mean age 66 y ) in a 2-y , double-blind , placebo-controlled trial . Changes ( mean + /- SEM ) in bone density were -3.53 + /- 1.24 % ( placebo ) , -1.89 + /- 1.40 % ( trace minerals only ) , -1.25 + /- 1.46 % ( calcium only ) and 1.48 + /- 1.40 % ( calcium plus trace minerals ) . Bone loss relative to base-line value was significant ( P = 0.0061 ) in the placebo group but not in the groups receiving trace minerals alone , calcium alone , or calcium plus trace minerals . The only significant group difference occurred between the placebo group and the group receiving calcium plus trace minerals ( P = 0.0099 ) . These data suggest that bone loss in calcium-supplemented , older postmenopausal women can be further arrested by concomitant increases in trace mineral intake Three hundred ten normal postmenopausal volunteers were invited to enter a controlled trial of the effects of calcium supplementation on forearm mineral content ( FMC ) ; 269 entered the study and 210 completed it . Of those who completed the study , 158 were allocated to one of three calcium-supplemented treatment regimes and 52 were allocated to a control group . Twenty-two of the subjects allocated to the treatment group were unable to take supplementary calcium but agreed to remain in the study as additional controls . There were therefore 136 treated subjects , 52 strict controls and 74 controls altogether . During the initial observation period of 9 mo , there was a highly significant loss of bone in all groups ( P less than 0.001 ) . During the 9-mo period of treatment , there was a highly significant reduction in the rate of bone loss in the treated subjects ( P less than 0.001 ) , a just significant reduction in the strict controls ( P less than 0.05 ) and a nonsignificant reduction in the rate of loss in all controls . The difference between the treated and strict controls in the second period was not significant but the difference between the treated and all controls in the second period was significant ( P less than 0.025 ) . When the analysis was applied only to women within 10 yr of menopause , the difference between the treated and strict control groups in period 2 was significant ( P less than 0.025 ) and the difference between the treated and all controls was highly significant ( P less than 0.001 ) During a two-year study , we examined the effect of calcium supplementation on postmenopausal bone loss in 43 women in the early postmenopausal period who were assigned to one of three treatment groups : percutaneous 17 beta-estradiol ( combined with progesterone during the second year ) , oral calcium ( 2000 mg daily ) , and placebo . All participants were examined every three months . Bone mineral content in the forearm ( measured by single-photon absorptiometry ) and in the entire body and spine ( measured by dual-photon absorptiometry ) remained constant in the estrogen-treated group but decreased significantly in the groups receiving calcium and placebo . In the calcium-treated group , we observed a tendency toward a slowed loss of compact bone ( in the proximal forearm and total skeleton ) as compared with the placebo group , while the rate of loss of trabecular bone ( the distal forearm and spine ) was the same as in the placebo group . Our preliminary data suggest that calcium supplementation in the dosage we used is not as effective as estrogen therapy for the prevention of early postmenopausal bone loss .  Calcium supplementation may have had a minor effect on the loss of cortical bone , but it had no effect on the trabecular bone Postmenopausal bone loss is a major factor in the increasing prevalence of osteoporotic fractures . Evidence is abundant that hormonal replacement therapy prevents the bone loss that follows natural or surgical menopause and reduces the prevalence of osteoporotic fractures in later life [ 1 - 4 ] . However , only about 10 % of American women elect to receive replacement therapy because of attitudes of physicians and patients , the undesirability of menstrual bleeding , and unresolved questions about the relation of the use of estrogen to breast cancer [ 5 ] . Moreover , the duration of hormonal therapy may need to be prolonged because bone loss recurs when therapy is discontinued , yet the incidence of some adverse effects increases with the duration of estrogen use . Safer alternatives to estrogen use have been sought . Epidemiologic and cross-sectional studies have suggested that increasing calcium intake might prevent postmenopausal bone loss , and prospect i ve studies have yielded conflicting results [ 6 - 17 ] . Moreover , some investigators have suggested that effects differ on the various skeletal sites used to determine the rate of bone loss [ 18 ] . We compared the efficacy of calcium augmentation in early postmenopause with calcium augmentation plus hormonal replacement therapy and with placebo . The study had a three-arm , r and omized , parallel design . The patients receiving hormonal replacement therapy were obviously not blinded nor were their physicians , whereas the placebo and calcium groups were double blinded . Methods Healthy , white women between 6 months and 6 years after a natural menopause were recruited to participate in the study . The protocol was approved by the Human Investigation Review Committees of Winthrop-University Hospital and Brookhaven National Laboratory ; written informed consent was obtained from each participant . Participants were recruited by announcements in the local press and in hospital and university publications and through a direct mail campaign . All participants had a history and physical examination . Exclusion characteristics included any disorder known to affect bone metabolism such as glucocorticoid use , gastrointestinal disease , or any chronic illness . Previous or current malignancy was an exclusion characteristic as were absolute contraindications to estrogen replacement or calcium supplements . Absolute contraindications to estrogen replacement therapy included estrogen-dependent neoplasm ( breast or uterus ) , undiagnosed vaginal bleeding , thrombophlebitis or thromboembolism , and acute liver disease .  Women with the following problems considered by some investigators to be relative contraindications to estrogen therapy were also excluded : gallbladder disease , history of liver disease , first-degree relatives with breast cancer , and hypertension . Calcium urolithiasis was also an exclusion factor . Women with known osteoporosis or with a vertebral compression fracture were not eligible for the study . One hundred eighteen women entered the study . The women were r and omly assigned to three groups : 1 ) hormonal replacement [ estrogen-progesterone-calcium carbonate ] , 2 ) calcium carbonate , or 3 ) placebo . Assignment to the groups was based on computer-generated r and om numbers provided by the statistician , with stratification for years postmenopause . The women in the hormonal replacement group took conjugated equine estrogens ( Premarin , Wyeth-Ayerst Laboratories , Inc. ; Philadelphia , Pennsylvania ) , 0.625 mg daily for 25 days of the month along with medroxyprogesterone ( Provera , Upjohn ; Kalamazoo , Michigan ) , 10 mg from days 16 to 25 . All women received 400 IU of vitamin D daily in the form of a multivitamin , and calcium supplementation ( as Caltrate , Lederle ; Clifton , New Jersey ) was provided to the two treatment groups . The duration of the study was 2.9 1.1 years ( mean SD ) . A 7-day dietary history was review ed with a nutritionist every 2 months ; calcium was provided as calcium carbonate , 600 mg ( Caltrate ) , and used to supplement the diet to approximate a total daily intake of 1700 mg of elemental calcium ( the mean + 2 SD found by Heaney and colleagues [ 7 ] to result in zero calcium balance in estrogen-deprived women ) . The calcium supplements were taken with meals in divided doses . The placebo appeared identical to the calcium carbonate tablets . No patients took antacids or histamine-2 blockers . All women had a baseline mammogram . Measurements Routine laboratory studies included a complete blood count , urinalysis , and serum fasting calcium , phosphorus , urea nitrogen , creatinine , alkaline phosphatase , cholesterol , and aminotransferase measurements [ 19 , 20 ] . In addition , follicle-stimulating hormone , estradiol , parathyroid hormone , osteocalcin , free thyroxine , and bone alkaline phosphatase were measured , and a urine specimen was collected after an overnight fast for hydroxyproline , calcium , and creatinine determinations , following a 3-day low-hydroxyproline diet [ 21 - 23 ] . Total body calcium was measured annually in the participants , using the delayed neutron activation method at Brookhaven National Laboratory [ 24 , 25 ] . This method uses a whole-body counter to measure the characteristic rays emitted from the neutron capture of Calcium-48 ( natural abundance of 0.187 % ) in the body . The Brookhaven National Laboratory whole-body counter was up grade d in 1987 to use 32 NaI ( T1 ) detectors of 10 cm 10 cm 46 cm positioned symmetrically above and below the patient [ 25 ] . The activated isotope , Calcium-49 , decays with a half-life of 8.72 minutes , emitting a 3.08 MeV characteristic line . More than 99.5 % of the body calcium is contained in the bone [ 26 ] . The method provides total body calcium with a coefficient of variation of about 1.5 % when no substantial change in the body weight occurs during the period of repeated studies . The measurements were made annually . The bone mineral density of the distal radius site was measured using a Lunar Radiation ( Madison , Wisconsin ) single-photon absorptiometer ( SP2 ) .  Bone mineral density of the spine ( L2-L4 ) and femur ( neck , trochanter , and Ward triangle ) was measured using a Lunar Radiation DP4 dual-photon absorptiometer . The software version used for the analysis of scans was DP4 Lunar Corporation Version 1.1 . All scans were analyzed using the same software version , which corrects for source decay . Instruments were calibrated daily , and the radioactive source was changed annually . Each measurement was done every 6 months . The coefficient of variation of these measurements was 2 % , except for the Ward triangle ( 2.5 % ) . Activity was measured using  activity monitors  ( large-scale integrated monitors ) , which were worn about the waist [ 27 ] . The average of 2 weekdays and 1 weekend day was used as an activity score . Activity was measured at baseline and at one other point during the study to ensure that differences among the groups were not due to varied levels of exercise . Statistical Analysis Total body calcium was selected as the primary criterion for efficacy for the following reasons : It measures mass rather than density per unit area ; it measures calcium balance precisely and accurately in the free living state and may be better related to previous studies using the balance technique ; it is more precise than the other measurements ; and it avoids sampling error by measuring the entire skeleton rather than a specific region of the appendicular or axial skeleton . The rate of change in bone mineral was calculated for each woman at each of the sites used in the study . St and ard linear regression procedures were used to estimate the rate of bone mineral change for each woman , and the regression intercept was used as the best estimate of the baseline value . Because some women terminated their participation in the study before others , the rate-of-change data were weighted by the inverse variance to reflect the fit of the regression line for each woman [ 28 ] . Analyses of covariance were done using body mass index , activity scores , cigarette smoking , calcium intake , age , and years postmenopause as covariates . The data reported in this article are based on all women who provided at least three observations for a particular skeletal site . We considered other criteria , such as using data only from women who had participated in the study for at least 2 years , and all data analyses were done for this subgroup as well . The results of these analyses were invariably similar to those reported here and therefore are not presented separately . The mean rates of change in bone mineral for each condition at each site were characterized in terms of both raw units and percentages ; separate analyses were carried out for each . The two indices were similar . Evidence from recent research is substantial that estrogen replacement therapy is effective , whereas the efficacy of calcium supplements is question able . Our expectation was that our data would confirm the efficacy of estrogen-progesterone-calcium therapy , and the critical question was whether or not a beneficial effect of calcium supplements given alone could be shown . A separate one-way analysis of covariance was done for each of the bone mineral measurements to compare the mean rates of change in bone mineral for each of the three conditions . We used two a priori contrasts : the first contrasting women taking estrogen with those receiving calcium and the second comparing women receiving calcium supplements with those on placebo . All P values reported are two-tailed . Results Baseline data for historical data and bone mineral measurements and chemical studies are given in Table 1 . Analysis of variance showed no significant differences in the baseline variables . The initial and final activity scores did not differ significantly . Table 1 . Baseline Values for Patient Characteristics , Bone Mineral Measurements , and Chemical 
    Output:
    
agent
Calcium was more effective than placebo in reducing rates of bone loss after two or more years of treatment .
REVIEW ER 'S CONCLUSIONS Calcium supplementation alone has a small positive effect on bone density .
The data show a trend toward reduction in vertebral fractures , but it is unclear if calcium reduces the incidence of non vertebral fractures
***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 effects of calcium supplementation ( as calcium citrate malate , 1000 mg elemental Ca/d ) with and without the addition of zinc ( 15.0 mg/d ) , manganese ( 5.0 mg/d ) and copper ( 2.5 mg/d ) on spinal bone loss ( L2-L4 vertebrae ) was evaluated in healthy older postmenopausal women ( n = 59 , mean age 66 y ) in a 2-y , double-blind , placebo-controlled trial . Changes ( mean + /- SEM ) in bone density were -3.53 + /- 1.24 % ( placebo ) , -1.89 + /- 1.40 % ( trace minerals only ) , -1.25 + /- 1.46 % ( calcium only ) and 1.48 + /- 1.40 % ( calcium plus trace minerals ) . Bone loss relative to base-line value was significant ( P = 0.0061 ) in the placebo group but not in the groups receiving trace minerals alone , calcium alone , or calcium plus trace minerals . The only significant group difference occurred between the placebo group and the group receiving calcium plus trace minerals ( P = 0.0099 ) . These data suggest that bone loss in calcium-supplemented , older postmenopausal women can be further arrested by concomitant increases in trace mineral intake Three hundred ten normal postmenopausal volunteers were invited to enter a controlled trial of the effects of calcium supplementation on forearm mineral content ( FMC ) ; 269 entered the study and 210 completed it . Of those who completed the study , 158 were allocated to one of three calcium-supplemented treatment regimes and 52 were allocated to a control group . Twenty-two of the subjects allocated to the treatment group were unable to take supplementary calcium but agreed to remain in the study as additional controls . There were therefore 136 treated subjects , 52 strict controls and 74 controls altogether . During the initial observation period of 9 mo , there was a highly significant loss of bone in all groups ( P less than 0.001 ) . During the 9-mo period of treatment , there was a highly significant reduction in the rate of bone loss in the treated subjects ( P less than 0.001 ) , a just significant reduction in the strict controls ( P less than 0.05 ) and a nonsignificant reduction in the rate of loss in all controls . The difference between the treated and strict controls in the second period was not significant but the difference between the treated and all controls in the second period was significant ( P less than 0.025 ) . When the analysis was applied only to women within 10 yr of menopause , the difference between the treated and strict control groups in period 2 was significant ( P less than 0.025 ) and the difference between the treated and all controls was highly significant ( P less than 0.001 ) During a two-year study , we examined the effect of calcium supplementation on postmenopausal bone loss in 43 women in the early postmenopausal period who were assigned to one of three treatment groups : percutaneous 17 beta-estradiol ( combined with progesterone during the second year ) , oral calcium ( 2000 mg daily ) , and placebo . All participants were examined every three months . Bone mineral content in the forearm ( measured by single-photon absorptiometry ) and in the entire body and spine ( measured by dual-photon absorptiometry ) remained constant in the estrogen-treated group but decreased significantly in the groups receiving calcium and placebo . In the calcium-treated group , we observed a tendency toward a slowed loss of compact bone ( in the proximal forearm and total skeleton ) as compared with the placebo group , while the rate of loss of trabecular bone ( the distal forearm and spine ) was the same as in the placebo group . Our preliminary data suggest that calcium supplementation in the dosage we used is not as effective as estrogen therapy for the prevention of early postmenopausal bone loss .  Calcium supplementation may have had a minor effect on the loss of cortical bone , but it had no effect on the trabecular bone Postmenopausal bone loss is a major factor in the increasing prevalence of osteoporotic fractures . Evidence is abundant that hormonal replacement therapy prevents the bone loss that follows natural or surgical menopause and reduces the prevalence of osteoporotic fractures in later life [ 1 - 4 ] . However , only about 10 % of American women elect to receive replacement therapy because of attitudes of physicians and patients , the undesirability of menstrual bleeding , and unresolved questions about the relation of the use of estrogen to breast cancer [ 5 ] . Moreover , the duration of hormonal therapy may need to be prolonged because bone loss recurs when therapy is discontinued , yet the incidence of some adverse effects increases with the duration of estrogen use . Safer alternatives to estrogen use have been sought . Epidemiologic and cross-sectional studies have suggested that increasing calcium intake might prevent postmenopausal bone loss , and prospect i ve studies have yielded conflicting results [ 6 - 17 ] . Moreover , some investigators have suggested that effects differ on the various skeletal sites used to determine the rate of bone loss [ 18 ] . We compared the efficacy of calcium augmentation in early postmenopause with calcium augmentation plus hormonal replacement therapy and with placebo . The study had a three-arm , r and omized , parallel design . The patients receiving hormonal replacement therapy were obviously not blinded nor were their physicians , whereas the placebo and calcium groups were double blinded . Methods Healthy , white women between 6 months and 6 years after a natural menopause were recruited to participate in the study . The protocol was approved by the Human Investigation Review Committees of Winthrop-University Hospital and Brookhaven National Laboratory ; written informed consent was obtained from each participant . Participants were recruited by announcements in the local press and in hospital and university publications and through a direct mail campaign . All participants had a history and physical examination . Exclusion characteristics included any disorder known to affect bone metabolism such as glucocorticoid use , gastrointestinal disease , or any chronic illness . Previous or current malignancy was an exclusion characteristic as were absolute contraindications to estrogen replacement or calcium supplements . Absolute contraindications to estrogen replacement therapy included estrogen-dependent neoplasm ( breast or uterus ) , undiagnosed vaginal bleeding , thrombophlebitis or thromboembolism , and acute liver disease .  Women with the following problems considered by some investigators to be relative contraindications to estrogen therapy were also excluded : gallbladder disease , history of liver disease , first-degree relatives with breast cancer , and hypertension . Calcium urolithiasis was also an exclusion factor . Women with known osteoporosis or with a vertebral compression fracture were not eligible for the study . One hundred eighteen women entered the study . The women were r and omly assigned to three groups : 1 ) hormonal replacement [ estrogen-progesterone-calcium carbonate ] , 2 ) calcium carbonate , or 3 ) placebo . Assignment to the groups was based on computer-generated r and om numbers provided by the statistician , with stratification for years postmenopause . The women in the hormonal replacement group took conjugated equine estrogens ( Premarin , Wyeth-Ayerst Laboratories , Inc. ; Philadelphia , Pennsylvania ) , 0.625 mg daily for 25 days of the month along with medroxyprogesterone ( Provera , Upjohn ; Kalamazoo , Michigan ) , 10 mg from days 16 to 25 . All women received 400 IU of vitamin D daily in the form of a multivitamin , and calcium supplementation ( as Caltrate , Lederle ; Clifton , New Jersey ) was provided to the two treatment groups . The duration of the study was 2.9 1.1 years ( mean SD ) . A 7-day dietary history was review ed with a nutritionist every 2 months ; calcium was provided as calcium carbonate , 600 mg ( Caltrate ) , and used to supplement the diet to approximate a total daily intake of 1700 mg of elemental calcium ( the mean + 2 SD found by Heaney and colleagues [ 7 ] to result in zero calcium balance in estrogen-deprived women ) . The calcium supplements were taken with meals in divided doses . The placebo appeared identical to the calcium carbonate tablets . No patients took antacids or histamine-2 blockers . All women had a baseline mammogram . Measurements Routine laboratory studies included a complete blood count , urinalysis , and serum fasting calcium , phosphorus , urea nitrogen , creatinine , alkaline phosphatase , cholesterol , and aminotransferase measurements [ 19 , 20 ] . In addition , follicle-stimulating hormone , estradiol , parathyroid hormone , osteocalcin , free thyroxine , and bone alkaline phosphatase were measured , and a urine specimen was collected after an overnight fast for hydroxyproline , calcium , and creatinine determinations , following a 3-day low-hydroxyproline diet [ 21 - 23 ] . Total body calcium was measured annually in the participants , using the delayed neutron activation method at Brookhaven National Laboratory [ 24 , 25 ] . This method uses a whole-body counter to measure the characteristic rays emitted from the neutron capture of Calcium-48 ( natural abundance of 0.187 % ) in the body . The Brookhaven National Laboratory whole-body counter was up grade d in 1987 to use 32 NaI ( T1 ) detectors of 10 cm 10 cm 46 cm positioned symmetrically above and below the patient [ 25 ] . The activated isotope , Calcium-49 , decays with a half-life of 8.72 minutes , emitting a 3.08 MeV characteristic line . More than 99.5 % of the body calcium is contained in the bone [ 26 ] . The method provides total body calcium with a coefficient of variation of about 1.5 % when no substantial change in the body weight occurs during the period of repeated studies . The measurements were made annually . The bone mineral density of the distal radius site was measured using a Lunar Radiation ( Madison , Wisconsin ) single-photon absorptiometer ( SP2 ) .  Bone mineral density of the spine ( L2-L4 ) and femur ( neck , trochanter , and Ward triangle ) was measured using a Lunar Radiation DP4 dual-photon absorptiometer . The software version used for the analysis of scans was DP4 Lunar Corporation Version 1.1 . All scans were analyzed using the same software version , which corrects for source decay . Instruments were calibrated daily , and the radioactive source was changed annually . Each measurement was done every 6 months . The coefficient of variation of these measurements was 2 % , except for the Ward triangle ( 2.5 % ) . Activity was measured using  activity monitors  ( large-scale integrated monitors ) , which were worn about the waist [ 27 ] . The average of 2 weekdays and 1 weekend day was used as an activity score . Activity was measured at baseline and at one other point during the study to ensure that differences among the groups were not due to varied levels of exercise . Statistical Analysis Total body calcium was selected as the primary criterion for efficacy for the following reasons : It measures mass rather than density per unit area ; it measures calcium balance precisely and accurately in the free living state and may be better related to previous studies using the balance technique ; it is more precise than the other measurements ; and it avoids sampling error by measuring the entire skeleton rather than a specific region of the appendicular or axial skeleton . The rate of change in bone mineral was calculated for each woman at each of the sites used in the study . St and ard linear regression procedures were used to estimate the rate of bone mineral change for each woman , and the regression intercept was used as the best estimate of the baseline value . Because some women terminated their participation in the study before others , the rate-of-change data were weighted by the inverse variance to reflect the fit of the regression line for each woman [ 28 ] . Analyses of covariance were done using body mass index , activity scores , cigarette smoking , calcium intake , age , and years postmenopause as covariates . The data reported in this article are based on all women who provided at least three observations for a particular skeletal site . We considered other criteria , such as using data only from women who had participated in the study for at least 2 years , and all data analyses were done for this subgroup as well . The results of these analyses were invariably similar to those reported here and therefore are not presented separately . The mean rates of change in bone mineral for each condition at each site were characterized in terms of both raw units and percentages ; separate analyses were carried out for each . The two indices were similar . Evidence from recent research is substantial that estrogen replacement therapy is effective , whereas the efficacy of calcium supplements is question able . Our expectation was that our data would confirm the efficacy of estrogen-progesterone-calcium therapy , and the critical question was whether or not a beneficial effect of calcium supplements given alone could be shown . A separate one-way analysis of covariance was done for each of the bone mineral measurements to compare the mean rates of change in bone mineral for each of the three conditions . We used two a priori contrasts : the first contrasting women taking estrogen with those receiving calcium and the second comparing women receiving calcium supplements with those on placebo . All P values reported are two-tailed . Results Baseline data for historical data and bone mineral measurements and chemical studies are given in Table 1 . Analysis of variance showed no significant differences in the baseline variables . The initial and final activity scores did not differ significantly . Table 1 . Baseline Values for Patient Characteristics , Bone Mineral Measurements , and Chemical 
    Output:
    