***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: Raloxifene HCl , a selective estrogen receptor modulator , has been shown to increase bone mineral density ( BMD ) and decrease biochemical markers of bone turnover in postmenopausal women without stimulatory effects on the breast and uterus . However , it is not known whether the changes in BMD and bone turnover are associated with changes at the tissue level , nor how changes with raloxifene compare with estrogen . In this r and omized , double blind study , we evaluated the effects of raloxifene ( Evista , 60 mg/day ) or conjugated equine estrogens ( CEE ; Premarin , 0.625 mg/day ) on bone architecture , bone turnover , and BMD . Iliac crest bone biopsies were obtained at baseline and at the end of the study after double tetracycline labeling and were analyzed for st and ard histomorphometric indexes . Serum and urinary biochemical markers of bone turnover were measured at baseline and at 4 , 10 , 18 , and 24 weeks of treatment . Total body , lumbar spine , and hip BMD were measured at baseline and at the end of the study by dual energy x-ray absorptiometry . Activation frequency and bone formation rate/bone volume were significantly decreased from baseline in the CEE , but not in the raloxifene , group . Bone mineralization did not change in either group . Most markers of bone resorption and formation decreased in both groups , but to a greater degree in the CEE group ( P < .05 ) . Total body and lumbar spine BMD increased from baseline in both groups , with a greater increase in the CEE group ( P < 0.05 ) . Hip BMD significantly increased from baseline in the raloxifene group , but the change was not different from that in the CEE group . These results suggest that raloxifene reduces bone turnover and increases bone density , although to a lesser extent than CEE . Thus , raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women BACKGROUND Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption . In a phase 2 clinical trial , strontium ranelate , an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption , has been shown to reduce the risk of vertebral fractures and to increase bone mineral density . METHODS To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial , we r and omly assigned 1649 postmenopausal women with osteoporosis ( low bone mineral density ) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years . We gave calcium and vitamin D supplements to both groups before and during the study . Vertebral radiographs were obtained annually , and measurements of bone mineral density were performed every six months . RESULTS New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group , with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period ( relative risk , 0.59 ; 95 percent confidence interval , 0.48 to 0.73 ) . Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck ( P<0.001 for both comparisons ) . There were no significant differences between the groups in the incidence of serious adverse events . CONCLUSIONS Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures UNLABELLED An 18-month r and omized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 microg with alendronate 10 mg on bone histomorphometry . Biopsies were obtained from 42 patients .  Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment . INTRODUCTION Alendronate and teriparatide increased BMD , assessed by DXA , by different mechanisms of action , supported by changes in biochemical markers of bone turnover . The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment . MATERIAL S AND METHODS Patients were a cohort from a r and omized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 microg and alendronate 10 mg in postmenopausal women with osteoporosis . Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months ( n = 23 ) or 18 months ( n = 14 ) ; 5 additional patients were biopsied from contralateral sides at 6 and 18 months . Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months ( teriparatide , n = 8 ; alendronate , n = 9 ) and 15 patients at 18 months ( teriparatide , n = 8 ; alendronate , n = 7 ) . Data were analyzed by two- sample tests . RESULTS Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months , whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months . Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group , returning to levels comparable with untreated postmenopausal women . In the teriparatide group , the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen , a biochemical marker of bone formation . The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups . CONCLUSIONS These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide UNLABELLED The relationship between early changes in biochemical markers of bone turnover and the subsequent BMD response to daily teriparatide therapy in women with postmenopausal osteoporosis was studied . Changes in five biochemical markers , obtained from a subset of women enrolled in the Fracture Prevention Trial , were examined . Early increases in the PICP and the PINP were the best predictors of BMD response to teriparatide in this analysis . INTRODUCTION Early reductions in biochemical markers of bone turnover with antiresorptive therapy negatively correlate with subsequent increases in BMD . We undertook this analysis to determine if early changes in biochemical markers with teriparatide therapy predict subsequent increases in BMD . MATERIAL S AND METHODS In the Fracture Prevention Trial , 1637 postmenopausal women with osteoporosis were r and omized to receive daily , self-administered , subcutaneous injections of placebo , teriparatide 20 microg/day , or teriparatide 40 microg/day . Serum concentrations of two bone formation markers ( bone-specific alkaline phosphatase [ bone ALP ] and the carboxy-terminal extension peptide of procollagen type 1 [ PICP ] ) and urinary concentrations of two bone resorption markers ( free deoxypyridinoline [ DPD ] and N-terminal telopeptide [ NTX ] ) were assessed in a trial population subset ( n = 520 ) at baseline and at 1 , 3 , 6 , and 12 months . We also assessed serum concentrations of another bone formation marker , the amino-terminal extension peptide of procollagen type 1 ( PINP ) , in a subset of 771 women at baseline and 3 months . Lumbar spine ( LS ) BMD was measured by DXA at baseline and 18 months . Femoral neck BMD was measured at baseline and 12 months . RESULTS AND CONCLUSION Baseline bone turnover status correlated positively and significantly with BMD response . The highest correlations occurred for the LS BMD response to teriparatide 20 microg/day . Among all studied biochemical markers , increases in PICP at 1 month and PINP at 3 months correlated best with increases in LS BMD at 18 months ( 0.65 and 0.61 , respectively ; p < 0.05 ) . The relationships between these two biochemical markers and the LS BMD response were stronger than the corresponding relationships for the femoral neck BMD response . Using receiver operator curve analysis , we determined that the increases in PICP at 1 month and PINP at 3 months were the most sensitive and accurate predictors of the LS BMD response It has been previously shown that the level of circulating undercarboxylated osteocalcin ( ucOC ) is elevated in elderly women in comparison with young , healthy , premenopausal ones . To underst and the mechanism of the increase in the ucOC in the elderly and to assess its potential consequences on bone fragility , we have measured  ucOC  in the sera of 195 elderly institutionalized women 70 - 101 yr of age . In 45 women ( 23 % ) serum ucOC was above the upper limit of the normal range for young women . The level of ucOC was negatively correlated with 25OHD ( r = -0.32 , P < 0.001 ) even after excluding the effect of age , parathyroid hormone ( PTH ) , and creatinine by partial correlation ( r = -0.24 , P < 0.002 ) . During an 18-mo follow-up , 15 women sustained a hip fracture and their baseline ucOC level was higher ( P < 0.01 ) in women who subsequently sustained hip fracture than in the nonfracture group contrasting with no significant differences for serum calcium , phosphate , alkaline phosphatase , creatinine , PTH , 250HD , and total and carboxylated OC . The risk of hip fracture was increased in women with elevated ucOC ( relative ratio 5.9 , 99.9 % Cl 1.5 - 22.7 , P < 0.001 ) . During 1 yr of calcium/vitamin D2 treatment , ucOC decreased ( P < 0.05 ) , especially in those with the initially increased values ( from 2.22 + /- 0.35 to 1.41 + /- 0.29 ng/ml , P < 0.005 ) contrasting with an increase in the placebo group ( P < 0.05 ) . In conclusion , the increase in ucOC in the elderly reflects not only some degree of vitamin K deficiency but also their poor vitamin D status , suggesting that vitamin D may be important , either directly or indirectly through its effect on bone turnover , for achieving a normal gamma-carboxylation of OC . The ucOC , but not conventional calcium metabolism parameters , predicts the subsequent risk of hip fracture , suggesting that serum ucOC reflects some changes in bone matrix associated with increased fragility CONTEXT Denosumab is an investigational fully human monoclonal antibody against receptor activator of nuclear factor-kappaB lig and , a mediator of osteoclastogenesis and osteoclast survival . OBJECTIVE This study evaluated the ability of denosumab to increase bone mineral density ( BMD ) and decrease bone turnover markers ( BTMs ) in early and later postmenopausal women with low BMD . DESIGN AND SETTING This 2-yr r and omized , double-blind , placebo-controlled study was conducted in North America . PARTICIPANTS Subjects included 332 postmenopausal women with lumbar spine BMD T-scores between -1.0 and -2.5 . INTERVENTIONS SUBJECTS were r and omly assigned to receive denosumab sc , 60 mg every 6 months , or placebo . R and omization was stratified by time since onset of menopause ( < or = 5 yr or > 5 yr ) . MAIN OUTCOME MEASURES The primary end point was the percent change in lumbar spine BMD by dual-energy x-ray absorptiometry at 24 months . Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography ; percent change in BMD by dual-energy x-ray absorptiometry for the total hip , one-third radius , and total body ; hip structural analysis ; percent change in BTMs ; and safety . RESULTS Denosumab significantly increased lumbar spine BMD , compared with placebo at 24 months ( 6.5 vs. -0.6 % ; P<0.0001 ) with similar results for both strata . Denosumab also produced significant increases in BMD at the total hip , one-third radius , and total body ( P < 0.0001 vs. placebo ) ; increased distal radius volumetric BMD ( P < 0.01 ) ; improved hip structural analysis parameters ; and significantly suppressed serum C-telopeptide , tartrate-resistant acid phosphatase-5b , and intact N-terminal propeptide of type 1 procollagen . The overall incidence of adverse events was similar between both study groups . CONCLUSIONS Twice-yearly denosumab increased BMD 
    Output:
    
Results High levels of BTMs may predict fracture risk independently from bone mineral density in postmenopausal women .
Conclusion BTM hold promise in fracture risk prediction and for monitoring treatment .