***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 Severe osteogenesis imperfecta is a disorder characterized by osteopenia , frequent fractures , progressive deformity , loss of mobility , and chronic bone pain . There is no effective therapy for the disorder . We assessed the effects of treatment with a bisphosphonate on bone resorption . METHODS In an uncontrolled observational study involving 30 children who were 3 to 16 years old and had severe osteogenesis imperfecta , we administered pamidronate intravenously ( mean [ + /-SD ] dose , 6.8+/-1.1 mg per kilogram of body weight per year ) at 4-to-6-month intervals for 1.3 to 5.0 years . Clinical status , biochemical characteristics reflecting bone turnover , the bone mineral density of the lumbar spine , and radiologic changes were assessed regularly during treatment . RESULTS Administration of pamidronate result ed in sustained reductions in serum alkaline phosphatase concentrations and in the urinary excretion of calcium and type I collagen N-telopeptide . There was a mean annualized increase of 41.9+/-29.0 percent in bone mineral density , and the deviation of bone mineral density from normal , as indicated by the z score , improved from -5.3+/-1.2 to -3.4+/-1.5 . The cortical width of the metacarpals increased by 27+/-20.2 percent per year . The increases in the size of the vertebral bodies suggested that new bone had formed . The mean incidence of radiologically confirmed fractures decreased by 1.7 per year ( P<0.001 ) . Treatment with pamidronate did not alter the rate of fracture healing , the growth rate , or the appearance of the growth plates . Mobility and ambulation improved in 16 children and remained unchanged in the other 14 . All the children reported substantial relief of chronic pain and fatigue . CONCLUSIONS In children with severe osteogenesis imperfecta , cyclic administration of intravenous pamidronate improved clinical outcomes , reduced bone resorption , and increased bone density BACKGROUND Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospect i ve study . METHODS We assessed potential risk factors , including bone mass , in 9516 white women 65 years of age or older who had had no previous hip fracture . We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture . All reports of hip fractures were vali date d by review of x-ray films . RESULTS During the follow-up period , 192 women had first hip fractures not due to motor vehicle accidents . In multivariable age-adjusted analyses , a maternal history of hip fracture doubled the risk of hip fracture ( relative risk , 2.0 ; 95 percent confidence interval , 1.4 to 2.9 ) , and the increase in risk remained significant after adjustment for bone density . Women who had gained weight since the age of 25 had a lower risk . The risk was higher among women who had previous fractures of any type after the age of 50 , were tall at the age of 25 , rated their own health as fair or poor , had previous hyperthyroidism , had been treated with long-acting benzodiazepines or anticonvulsant drugs , ingested greater amounts of caffeine , or spent four hours a day or less on their feet . Examination findings associated with an increased risk included the inability to rise from a chair without using one 's arms , poor depth perception , poor contrast sensitivity , and tachycardia at rest . Low calcaneal bone density was also an independent risk factor . The incidence of hip fracture ranged from 1.1 ( 95 percent confidence interval , 0.5 to 1.6 ) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 ( 95 percent confidence interval , 20 to 34 ) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age . CONCLUSIONS Women with multiple risk factors and low bone density have an especially high risk of hip fracture . Maintaining body weight , walking for exercise , avoiding long-acting benzodiazepines , minimizing caffeine intake , and treating impaired visual function are among the steps that may decrease the risk Bisphosphonates are potent inhibitors of bone resorption and are widely used in the treatment of bone diseases . One of the side effects of administered aminobisphosphonates is transient fever and some biological changes that are suggestive of an acute phase response . Pamidronate [ (3-amino-1-hydroxypropylidene).1 , 1-bisphosphonate ] and ib and ronate [ 1-hydroxy-3-(methylpentylamino ) propylidenebisphosphonate ] incubated in heparinized whole blood at doses of 10(-4 ) and 10(-5 ) mol/L , induced the production of tumor necrosis factor alpha ( TNFalpha ) . Moreover , pamidronate was found to slightly stimulate interleukin-6 IL-6 production . In contrast , clodronate ( dichloromethylenebisphosphonate ) did not increase IL-6 or TNFalpha . To investigate these phenomena in vivo , acute phase reaction was assessed in patients with malignant disease treated with 60 mg of pamidronate ( n = 29 ) , 1500 mg of clodronate ( n = 8) , or 0.5 - 2 mg of ib and ronate ( n = 6 ) , all given intravenously . A significant decrease in lymphocyte and leukocyte count was observed in the pamidronate group . In the same group , seven patients ( 24 % ) showed a transient increase of body temperature above 37 degrees C with an increase > or = 0.5 degrees C at 24 h. These changes were not found in the patients treated with clodronate or ib and ronate . Plasma IL-6 and TNFalpha levels increased significantly after pamidronate treatment , whereas no change was seen after clodronate infusion . The peak of IL-6 level ( 53.7 + /- 14.1 [ SEM ] pg/mL ) was observed at 24 h , and that of TNFalpha level ( 26.9 + /- 3.4 pg/mL ) at 48 h after the beginning of pamidronate administration ( values before treatment , respectively : 28.6 + /- 7.1 pg/mL , p < 0.006 ; and 13.1 + /- 1.5 pg/mL , p = 0.0001 ) . The peak of C-reactive protein ( CRP ) level was found at 48 h ( 41.0 + /- 7.8 vs. 25.5 + /- 5.6 mg/L before treatment , p < 0.01 ) and CRP levels were strongly correlated with IL-6 levels ( p = 0.65,p < 0.001 ) . Only one patient treated with ib and ronate showed an increase in IL-6 and CRP levels . Patients treated with pamidronate , whose body temperatures were increased at 24 h , had a greater increases of circulating IL-6 , TNFalpha , and CRP at 24 h and 48 h than patients without temperature increase . These results suggest that pamidronate treatment , but not clodronate and possibly not ib and ronate at the doses used , induced an increase in the plasma levels of IL-6 and TNFalpha , which may be responsible for the acute phase reaction observed clinical ly OBJECTIVES Osteoporosis is a frequent complication of rheumatoid arthritis ( RA ) . We therefore investigated the effect of oral pamidronate therapy as a specific bone-sparing agent in RA . METHODS The study design was a 3-year r and omized , double-blind trial of 300 mg oral pamidronate/day compared with placebo in 105 RA patients .  Bone mineral density ( BMD ) measured at 12-month intervals was the primary efficacy parameter . RESULTS In 3 years , lumbar spine and forearm BMD increased significantly in the pamidronate-treated group ( by 8.4 + /- 6.9 % [ mean = /- SEMI ] [ P < 0.00011 and 5.2 = /- 6.5 % [ P < 0.005 ] , respectively ) , compared with nonsignificant changes in the placebo-treated patients ( increase of 0.6 = /- 5.2 % and decrease of 1.2 = /- 5.8 % , respectively ) . Femoral neck BMD increased in the pamidronate-treated group ( by 2.6 = /- 8.6 % ) and decreased significantly in the placebo-treated group ( by 4.0=/- 1.3 % [ P < 0.005 ] ) . The changes in BMD with time at all 3 measurement sites were significantly different between the treatment groups ( P < 0.0001 ) . Changes in radiographic signs of joint damage and in disease activity were similar in the 2 groups . CONCLUSION The present study provides the first evidence that long-term treatment with an orally administered bisphosphonate overcomes bone loss and increases bone mass when compared with placebo . This finding may have significance with regard to the treatment of patients with RA AIMS Glucocorticoids suppress the release of tumour necrosis factor-alpha ( TNF-alpha ) by macrophages in vitro and cause monocytopaenia in vivo . These actions may contribute to anti-inflammatory and immunosuppressant effects . We therefore examined relationships between prednisolone concentration , suppression of monocyte TNF-alpha release , monocytopaenia and suppression of total cortisol concentration in healthy volunteers treated with a single dose ( 1.5 mg kg-1 ) of the glucocorticoid , prednisolone .  METHODS Monocyte numbers , total cortisol concentration and prednisolone concentration were measured in blood sample s collected over 48 h after the dose . Plasma from these sample s was also tested for its capacity to suppress lipopolysaccharide-induced TNF-alpha release from monocytes in autologous whole blood cultures . RESULTS At 4 h after the dose , monocyte numbers in peripheral blood had fallen to a mean of 18 % of the pre-dose level whilst plasma total cortisol had fallen to 9 % of the pre-dose concentration . Monocyte numbers recovered in concordance with elimination of prednisolone and there was a significant relative monocytosis at 24 h. The recovery of plasma cortisol was delayed in comparison , with cortisol remaining significantly suppressed at 24 h. Plasma sample s taken at 2 h after the dose ( corresponding to peak plasma prednisolone concentration ) suppressed the lipopolysaccharide-stimulated production of TNF-alpha by autologous blood monocytes to 27 % of pre-dose control . Plasma collected at intervals over the 48 h from dosing also suppressed monocyte TNF-alpha release in relation to the prednisolone concentration therein . Suppression was largely reversed by the glucocorticoid antagonist , mifepristone . A similar relationship between prednisolone concentration and TNF-alpha suppression was observed when prednisolone was added to blood sample s collected from the volunteers when they were drug-free . CONCLUSIONS Blood concentration of prednisolone achieved after a dose of 1.5 mg kg-1 are sufficient to suppress monocyte TNF-alpha release and cause a biphasic change in peripheral blood monocyte numbers . Suppression of TNF-alpha is principally a direct glucocorticoid effect , rather than a consequence of other prednisolone-induced changes to blood composition Background : Low bone mineral density ( BMD ) is recognised in individuals with cystic fibrosis ( CF ) although the pathogenesis remains unclear . The aims of this study were to compare BMD over a broad continuum of Australian individuals with CF with healthy controls and to examine the relationship between BMD and clinical parameters including physical activity , nutrition , and vitamin D levels . Methods : BMD of the lumbar spine ( LS ) , total body ( TB ) , femoral neck ( FN ) , cortical wrist ( R33 % ) , and distal wrist ( RUD ) was examined in 153 individuals with CF aged 5.3–55.8 years ( 84 males ) and in 149 local controls aged 5.6–48.3 years ( 66 males ) using dual energy x ray absorptiometry .  Anthropometric variables , body cell mass , markers of disease severity , corticosteroid usage , measures of physical activity , dietary calcium and caloric intake and serum vitamin D  were assessed and related to BMD . Results : Compared with controls , mean BMD was not significantly different in children aged 5–10 years with CF . Adolescents ( females 11–18 years , males 11–20 years ) had reduced TB and R33 % BMD when adjusted for age , sex , and height ( difference in BMD ( g/cm2 ) adjusted means between control and CF : TB = 0.04 ( 95 % CI 0.01 to 0.07 ) ; R33 % = 0.03 ( 95 % CI 0.01 to 0.06 ) ) . BMD was reduced at all sites except R33 % in adults ( difference in BMD ( g/cm2 ) adjusted means between control and CF : TB = 0.05 ( 95 % CI 0.02 to 0.09 ) ; LS = 0.08 ( 95 % CI 0.03 to 0.14 ) ; FN = 0.09 
    Output:
    
Bone pain was the most common adverse event with intravenous agents .
Flu-like symptoms were also increased in those taking bisphosphonates .
In participants with a lung transplant ( one study ) , intravenous pamidronate did not change the number of new fractures .
Oral and intravenous bisphosphonates increase BMD in people with CF .
Severe bone pain and flu-like symptoms may occur with intravenous agents .