title: Combined Calcium and Vitamin D3 Supplementation in Elderly Women: Confirmation of Reversal of Secondary Hyperparathyroidism and Hip Fracture Risk: The Decalyos II Study Amelioration of osteopenia and hypovitaminosis D by 1α-hydroxyvitamin D3 in elderly patients with Parkinson’s disease Prevention of postmenopausal bone loss by low and conventional doses of calcitriol or conjugated equine estrogen. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. The necessity and safety of calcium and vitamin D in the elderly. Effect of ipriflavone on bone in elderly hemiplegic stroke patients with hypovitaminosis D. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Effect of withdrawal of calcium and vitamin D supplements on bone mass in elderly men and women. Calcium intake influences the association of protein intake with rates of bone loss in elderly men and women. Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women. Single-dose cholecalciferol suppresses the winter increase in parathyroid hormone concentrations in healthy older men and women: a randomized trial. Low-dose calcitriol versus calcium in established postmenopausal osteoporosis. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Comparison of methods for defining prevalent vertebral deformities: the Study of Osteoporotic Fractures. Vitamin D and Calcitonin Treatment in Patients with Femoral Neck Fracture: A Prospective Controlled Clinical Study Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women. Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial. Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A randomized controlled study. Effect of discontinuation of estrogen, calcitriol, and the combination of both on bone density and bone markers. The Association of Radiographically Detected Vertebral Fractures with Back Pain and Function: A Prospective Study Calcitriol treatment is not effective in postmenopausal osteoporosis. Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. TREATMENT OF POST MENOPAUSAL OSTEOPOROSIS. A CONTROLLED THERAPEUTIC TRIAL COMPARING OESTROGEN/GESTAGEN, 1,25‐DIHYDROXY‐VITAMIN D3 AND CALCIUM Do vitamin D supplements improve the physical capabilities of elderly hospital patients? Falls in the elderly: a prospective study of risk factors and risk profiles. The Effect of Season and Vitamin D Supplementation on Bone Mineral Density in Healthy Women: A Double-Masked Crossover Study
   Calcium and vitamin D supplements reduce tooth loss in the elderly. Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis Vitamin D-Fortified Liquid Milk: Benefits for the Elderly Community-Based Population Calcium and Vitamin D Supplementation Increases Spinal BMD in Healthy, Postmenopausal Women
   HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Clinical, biochemical and histological results of a double-blind trial with 1,25-dihydroxyvitamin D3, estradiol and placebo in post-menopausal osteoporosis. Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Administration of a supplement containing both calcium and vitamin D is more effective than calcium alone to reduce secondary hyperparathyroidism in postmenopausal women with low 25(OH)vitamin D circulating levels Vitamin D Supplementation and Fracture Incidence in Elderly Persons Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial. Effects of 2 years' treatment of osteoporosis with 1 alpha-hydroxy vitamin D3 on bone mineral density and incidence of fracture: a placebo-controlled, double-blind prospective study. Postmenopausal osteoporosis: no effect of three years treatment with 1,25-dihydroxycholecalciferol. Reduced occurrence of vertebral crush fractures in senile osteoporosis treated with 1 alpha (OH)-vitamin D3. Histomorphometric effects of calcium or calcium plus 25-hydroxyvitamin D3 therapy in senile osteoporosis. A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy. The Effect of Calcitriol on Patients with Postmenopausal Osteoporosis with Special Reference to Fracture Frequency Effects of calcitriol or calcium on bone mineral density, bone turnover, and fractures in men with primary osteoporosis: a two-year randomized, double blind, double placebo study. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. Effect of estrogen/gestagen and 24R,25-dihydroxyvitamin D3 therapy on bone formation in postmenopausal women. Functional improvement with vitamin D replenishment in a cohort of frail, vitamin D-deficient older people. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. Amelioration of hemiplegia-associated osteopenia more than 4 years after stroke by 1 alpha-hydroxyvitamin D3 and calcium supplementation. Role of calcitriol in the treatment of postmenopausal osteoporosis. Calcitriol in the treatment of postmenopausal osteoporosis. Prophylactic vitamin D in the elderly. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials
abstract: Vitamin D insufficiency and low calcium intake contribute to increase parathyroid function and bone fragility in elderly people .  Calcium and vitamin D supplements can reverse secondary hyperparathyroidism thus preventing hip fractures , as proved by Decalyos I. Decalyos II is a 2-year , multicenter , r and omized , double-masked , placebo-controlled confirmatory study . The intention-to-treat population consisted of 583 ambulatory institutionalized women ( mean age 85.2 years , SD = 7.1 ) r and omized to the  calcium – vitamin D3  fixed combination group ( n= 199 ) ; the calcium plus vitamin D3 separate combination group ( n= 190 ) and the placebo group ( n= 194 ) . Fixed and separate combination groups received the same daily amount of calcium ( 1200 mg ) and vitamin D3 ( 800 IU ) , which had similar pharmacodynamic effects . Both types of calcium-vitamin D3 regimens increased serum 25-hydroxyvitamin D and decreased serum intact parathyroid hormone to a similar extent , with levels returning within the normal range after 6 months . In a subgroup of 114 patients  , femoral neck bone mineral density ( BMD ) decreased in the placebo group ( mean = –2.36 % per year , SD = 4.92 ) , while remaining unchanged in women treated with calcium-vitamin D3 ( mean = 0.29 % per year , SD = 8.63 ) . The difference between the two groups was 2.65 % ( 95 % CI = –0.44 , 5.75 % ) with a trend in favor of the active treatment group . No significant difference between groups was found for changes in distal radius BMD and quantitative ultrasonic parameters at the os calcis . The relative risk ( RR ) of HF in the placebo group compared with the active treatment group was 1.69 ( 95 % CI = 0.96 , 3.0 ) , which is similar to that found in Decalyos I ( RR = 1.7 ; 95 % CI = 1.0 , 2.8 ) . Thus , these data are in agreement with those of Decalyos I and indicate that calcium and vitamin D3 in combination reverse senile secondary hyperparathyroidism and reduce both hip bone loss and the risk of hip fracture  in elderly institutionalized women OBJECTIVES A high prevalence of hip and other fractures in elderly patients with Parkinson ’s disease has been linked to reduced bone mass arising from a defect of renal synthesis of 1 , 25-dihydroxyvitamin D ( 1 , 25-[OH]2D ) . Treatment with 1α-hydroxyvitamin D3 ( 1α(OH)D3 ; an active form of vitamin D ) was evaluated for maintaining bone mass and reducing the incidence of hip and other non-vertebral fractures in patients with Parkinson ’s disease . METHODS In a double blind , r and omised trial , 86 elderly patients with Parkinson ’s disease ( mean Hoehn and Yahr stage , 3 ; mean age 70.6 years ) were r and omised to receive either 1 μg 1α(OH)D3 daily ( treatment group , n=43 ) or a placebo ( n=43 ) for 18 months . Bone mineral densities in the second metacarpals were determined by computed radiographic densitometry . Serum bone turnover indices were measured serially , and incidence of non-vertebral fractures was recorded . RESULTS Bone mineral densities decreased 1.2 % in the treatment group compared with 6.7 % in the placebo group during 18 months ( p<0.0001 ) . At baseline in both groups , the serum concentration of 1 , 25-[OH]2D was reduced . Parathyroid hormone was abnormally increased in 15 patients ( 17 % ) and correlated negatively with serum 25-hydroxyvitamin D , indicating compensatory hyperparathyroidism . Eight patients  sustained fractures ( six at the hip and two at other sites ) in the placebo group , and one hip fracture occurred among treated patients ( odds ratio 9.8 ; p=0.0028 ) . CONCLUSION By increasing serum 1 , 25-[OH]2D concentrations , treatment with 1α(OH)D3 can reduce the risk of hip and other non-vertebral fractures in osteoporotic elderly patients with Parkinson ’s disease by slowing the loss of bone mineral densities OBJECTIVES Estrogen deficiency is the most common cause of postmenopausal osteoporosis and estrogen replacement is well known to retard postmenopausal bone loss . Calcium supplement alone is generally considered to be insufficient for the prevention of bone loss associated with estrogen deficiency while the role of calcitriol is unclear . In the present study we examined the efficacy different doses of estrogen or calcitriol in the prevention of  postmenopausal bone loss in Thais . METHODS The subjects consisted of 146 Thai women no more than 6 years postmenopausal . The subjects were r and omly allocated to receive 750 mg supplemental calcium alone , calcium and conjugated equine estrogen ( CEE ) at 0.3 or 0.625 mg , calcium and calcitriol at 0.25 or 0.5 microg daily . Those receiving CEE also took 5 mg medrogestone for 12 days each month . BMD at L2 - 4 and femoral neck were measured at baseline 1 year and 2 years after treatments . Data were expressed as mean + /- S.E. RESULTS Subjects on supplemental calcium alone had approximately 2.5 % decreases in L2 - 4 ( P < 0.05 ) and femoral BMD ( P < 0.01 ) at 2 years . CEE ( 0.3 mg ) result ed in 3.20 + /- 1.2 % increase in vertebral BMD ( P < 0.05 ) while no significant change in BMD was demonstrated at the femoral neck . Likewise , 0.625 mg of CEE induced 5.4 + /- 1.4 % increase in vertebral BMD at 2 years ( P < 0.001 ) without change in the femoral BMD . In regard to calcitriol , no significant change in vertebral or femoral BMD was demonstrated with either 0.25 or 0.5 microg calcitriol . CONCLUSION We concluded that calcitriol is effective in the prevention of early postmenopausal bone loss in Thais . It represents an option for the prevention of osteoporosis in postmenopausal women who are contraindicated for estrogen replacement An unexplained loss of muscle strength occurs with aging . Vitamin D deficiency can cause myopathy and administration of 1,25-dihydroxyvitamin D3 [ 1,25-(OH2)D3 ] to persons with low serum concentrations can improve strength . To test the hypothesis that the weakness associated with aging is in part due to inadequate serum concentrations of [ 1,25-(OH2)D3 ] , we conducted a r and omized , controlled , double blinded trial in 98 men and women volunteers over 69 yr old . Treatment consisted of 0.25 micrograms 1,25-(OH)2D3 , orally , twice per day or identical placebo for 6 months .  Leg muscle strength of the quadriceps was measured with an isokinetic dynamometer . There was no difference between the two groups at 1 week , 1 month , or 6 months of treatment in any of the measures of muscle strength . We conclude that oral administration of 0.5 micrograms 1,25-(OH)2D3/day does not improve muscle strength in older persons . Further research is needed to determine the etiology of the decline in muscle strength associated with aging Estrogen deficiency and declining calcium absorption due to reduced calcitriol levels or intestinal resistance to calcitriol , are important factors in the pathogenesis of age-related bone loss . The main objective of this study was to examine the effect of estrogen and 1,25-dihydroxyvitamin D therapy given individually or in combination on  bone loss in elderly women . Four hundred eighty-nine elderly women with normal bone density for their age , aged 65 - 77 yr , were entered into a r and omized double blind , placebo-controlled trial . Women were r and omized to one of four groups : conjugated estrogens ( 0.625 mg , daily ) to women without a uterus ( estrogen replacement therapy ) plus medroxyprogesterone acetate ( 2.5 mg , daily ) to women with a uterus ( hormone replacement therapy ) , calcitriol ( 0.25 microg twice daily ) , a combination of hormone replacement therapy/estrogen replacement therapy plus calcitriol , or placebos for 3 yr . The primary outcome was the change in bone mineral density of the femoral neck and spine . In the intent to treat analysis , hormone therapy ( hormone replacement therapy/estrogen replacement therapy ) produced a mean ( + /-1 SD ) increase in bone mineral density of 2.98 % ( + /-5.45 % ) at the femoral neck ( P < 0.0001 ) and 4.36 % ( + /-6.42 % ) at the spine ( P < 0.0001 ) . There were parallel increases in total hip and trochanter bone mineral density . Calcitriol increased bone mineral density 0.10 % ( + /- 4.27 % ) at the femoral neck ( P = 0.57 ) and 1.65 % ( + /- 4.83 % ) at the spine ( P < 0.0124 ) . The combination of hormone replacement therapy/estrogen replacement therapy + calcitriol  increased bone mineral density 3.80 % ( + /-4.95 % ) at the femoral neck ( P < 0.001 ) , 4.91 % ( + /-6.0 % ) at the spine ( P < 0.0001 ) , and parallel changes at the total hip and trochanter . All three treatment groups differed significantly from placebo at the spine and for the hormone replacement therapy/estrogen replacement therapy groups at the femoral neck , spine , total hip and trochanter . There were no significant differences between combination therapy and hormone replacement therapy/estrogen replacement therapy alone on bone mineral density at any site in the intent to treat analysis . In a secondary analysis of the effect in women who were adherent to treatment , calcitriol had a more significant effect on spine ( P = 0.003 ) and total hip ( P = 0.004 ) . The increase in bone mineral density in the adherent groups of women was always higher compared with the intent to treat groups . Combination therapy compared with hormone replacement therapy/estrogen replacement therapy alone produced a significantly greater response in trochanter ( P = 0.007 ) and total hip bone mineral density ( P = 0.0017 ) . In summary , hormone replacement therapy/estrogen replacement therapy alone and in combination with calcitriol therapy was highly effective in reducing bone resorption and increasing bone mineral density at the hip and other clinical ly relevant sites in a group of elderly women , with normal bone density for their age . Calcitriol was effective in increasing spine bone mineral density . In the adherent women , combination therapy with hormone replacement therapy/estrogen replacement therapy and calcitriol increased bone mineral density significantly more in the total hip and trochanter than did hormone replacement therapy/estrogen replacement therapy alone The necessity and safety of an oral calcium ( Ca ) and vitamin D regimen was evaluated in a population of 66 independently living and 73 institutionalized elderly women over an 11-week winter period . The members of both groups were r and omly assigned into trial and control groups . Serum Ca , creatinine , and calcidiol levels were measured before and after the trial . The regimen consisted of 1.558 g of Ca and 45 micrograms ( equal to 1,800 IU ) of vitamin D administered daily in addition to the normal diet . The controls received no treatment . A majority of the elderly subjects living independently had ensured their Ca , and a quarter of them also their vitamin D intake on their own initiative . The mean serum calcidiol concentration before the trial was 24.1 nmol/L in the institutionalized and 38.5 nmol/L in the elderly subjects living independently ( P less than .001 ) . After the trial , serum calcidiol was 10.4 nmol/L in the institutionalized control subjects and had decreased ( P less than .001 ) in both control groups , but increased ( P less than .001 ) in both treatment groups . The safety indicators , serum Ca , creatinine , and calcidiol , did not indicate any group or individual side effect A significant reduction in bone mineral density occurs in stroke patients on the hemiplegic side , correlating with the degree of paralysis and vitamin D deficiency due to malnutrition , sunlight deprivation , and immobilization-induced hypercalcemia , and increases the risk of hip fracture . We evaluated the effect of ipriflavone and 1alpha-hydroxyvitamin D3 [ 1alpha(OH)D3 ; vitamin D3 ] administration on bone mineral density preservation as compared with untreated controls . In a r and omized and prospect i ve study of 103 patients with hemiplegia after stroke ( the mean duration of illness was 4.8 yr ) , 68 ( 34 patients in each group ) were given 600 mg ipriflavone or 1 microg vitamin D3 daily for 12 mo , whereas the remaining 35 patients received no drug .  Bone mineral density on the hemiplegic side decreased by 1.4 % in the ipriflavone group , 3.8 % in the vitamin D3 group , and 5.4 % in the control group ( P < .0001 , ipriflavone v vitamin D3 and control ) . At baseline , all three groups of patients showed a 25-hydroxyvitamin D insufficiency , increased serum ionized calcium , and low levels of 1 , 25-dihydroxyvitamin D , suggesting immobilization-induced hypercalcemia and inhibition of renal synthesis of 1 , 25-dihydroxyvitamin D. After treatment , the serum 1 , 25-dihydroxyvitamin D level increased by 139.9 % in the ipriflavone group and by 26.9 % in the vitamin D3 group . Significant decreases in the serum ionized calcium and pyridinoline cross-linked carboxyterminal telopeptide of type I collagen , and increases in parathyroid hormone and bone Gla protein were observed in the ipriflavone group , whereas no changes occurred in the other two groups . One patient in the untreated group suffered a hip fracture , compared with none in the ipriflavone and vitamin D3 groups . These results suggest that ipriflavone is more efficacious than vitamin D3 in the prevention of decreased bone mineral density in hemiplegic stroke patients because it decreases serum calcium levels through inhibition of bone resorption and cause a subsequent increase in 1 , 25-dihydroxyvitamin D concentration BACKGROUND The Food and Nutrition Board of the National Academy of Sciences states that 95 microg vitamin D/d is the lowest observed adverse effect level ( LOAEL ) . OBJECTIVE Our objective was to assess the efficacy and safety of prolonged vitamin D3 intakes of 25 and 100 microg ( 1000 and 4000 IU)/d . Efficacy was based on the lowest serum 25-hydroxyvitamin D [ 25(OH)D ] concentration achieved by subjects taking vitamin D3 ; potential toxicity was monitored by measuring serum calcium concentrations and by calculating urinary calcium-creatinine ratios . DESIGN Healthy men and women ( n = 61 ) aged 41 + /- 9 y ( mean + /- SD ) were r and omly assigned to receive either 25 or 100 microg vitamin D3/d for 2 - 5 mo , starting between January and February . Serum 25(OH)D was measured by radioimmunoassay . RESULTS Baseline serum 25(OH)D was 40.7 + /- 15.4 nmol/L ( mean + /- SD ) . From 3 mo on , serum 25(OH)D plateaued at 68.7 + /- 16.9 nmol/L in the 25-microg/d group and at 96.4 + /- 14.6 nmol/L in the 100-microg/d group . Summertime serum 25(OH)D concentrations in 25 comparable subjects not taking vitamin D3 were 46.7 + /- 17.8 nmol/L. The minimum and maximum plateau serum 25(OH)D concentrations in subjects taking 25 and 100 microg vitamin D3/d were 40 and 100 nmol/L and 69 and 125 nmol/L , respectively . Serum calcium and urinary calcium excretion did not change significantly at either dosage during the study . CONCLUSIONS The 100-microg/d dosage of vitamin D3 effectively increased 25(OH)D to high-normal concentrations in practically all adults and serum 25(OH)D remained within the physiologic range ; therefore , we consider 100 microg vitamin D3/d to be a safe intake BACKGROUND Supplementation with calcium and vitamin D reduces bone loss and prevents fractures in elderly people , but it is not known whether any lasting benefit remains if the supplements are discontinued . OBJECTIVE The objective was to determine whether gains in bone mineral density ( BMD ) induced by calcium and vitamin D supplementation persist after supplement withdrawal . DESIGN Two-hundred ninety-five healthy , elderly men and women ( aged > /=68 y ) who had completed a 3-y r and omized , placebo-controlled trial of calcium and vitamin D supplementation were followed for an additional 2 y during which no study supplements were given .  BMD was measured by dual-energy X-ray absorptiometry , and biochemical variables related to calcium metabolism and bone turnover were measured . RESULTS In the 128 men , supplement-induced increases in spinal and femoral neck BMD were lost within 2 y of supplement discontinuation , but small benefits in total-body BMD remained . In the 167 women , there were no lasting benefits in total-body BMD or at any bone site . Consistent with the observations on BMD , the bone turnover rates in both men and women ( as measured by serum osteocalcin concentrations ) returned to their original higher concentrations within the same 2-y period . CONCLUSION Discontinued calcium and vitamin D supplementation has limited cumulative effect on bone mass in men and women aged > /=68 BACKGROUND There is currently no consensus on the effect of dietary protein intake on the skeleton , but there is some indication that low calcium intakes adversely influence the effect of dietary protein on fracture risk . OBJECTIVE The objective of the present study was to determine whether supplemental calcium citrate malate and vitamin D influence any associations between  protein intake and change in bone mineral density ( BMD ) . DESIGN Associations between protein intake and change in BMD were examined in 342 healthy men and women ( aged > or = 65 y ) who had completed a 3-y , r and omized , placebo-controlled trial of calcium and vitamin D supplementation . Protein intake was assessed at the midpoint of the study with the use of a food-frequency question naire and  BMD  was assessed every 6 mo by dual-energy X-ray absorptiometry . RESULTS The mean ( + /-SD ) protein intake of all subjects was 79.1 + /- 25.6 g/d and the mean total calcium intakes of the supplemented and placebo groups were 1346 + /- 358 and 871 + /- 413 mg/d , respectively . Higher protein intake was significantly associated with a favorable 3-y change in total-body BMD in the supplemented group ( in a model containing terms for age , sex , weight , total energy intake , and dietary calcium intake ) but not in the placebo group . The pattern of change in femoral neck BMD with increasing protein intake in the supplemented group was similar to that for the total body . CONCLUSION Increasing protein intake may have a favorable effect on change in BMD in elderly subjects supplemented with calcium citrate malate and vitamin BACKGROUND Adequate intakes of calcium and vitamin D reduce bone loss and fracture risk in the elderly . Other nutrients also affect bone health , and adequate intakes may influence bone turnover and balance . OBJECTIVE We compared the long-term effects on bone turnover markers and calciotropic hormones of a multinutrient supplement , a calcium and vitamin D supplement , and dietary instruction aim ed at increasing calcium intake through foods . DESIGN Ninety-nine healthy postmenopausal women participated in a 3-y , r and omized trial , receiving either 1 ) supplemental calcium ( 1450 mg/d ) and vitamin D [ 10 microg ( 400 IU)/d ] , 2 ) calcium , vitamin D , and other nutrients ( multinutrient supplement ) , or 3 ) dietary instruction ( dietary control group ) . Data are from 83 subjects who completed the trial . RESULTS Increases over baseline in calcium intakes and serum 25-hydroxyvitamin D concentrations were sustained over 3 y in all treatment groups . Circulating parathyroid hormone concentrations were reduced at year 1 in all treatment groups but trended toward baseline thereafter . Bone turnover markers followed a similar pattern , and none of the changes in biochemical concentrations differed significantly between groups . CONCLUSIONS All 3 interventions offer long-term feasibility for increasing calcium intake and serum 25-hydroxyvitamin D concentrations . The dietary addition of micronutrients implicated in skeletal physiology confers no obvious bone-sparing effect in healthy postmenopausal women beyond that of calcium and vitamin D alone . The attenuation over time in suppression of parathyroid hormone and bone turnover might help explain why nutrient intervention tends to have less of a bone-sparing effect than do skeletally active medications such as estrogen or bisphosphonates A r and omized double-blind controlled trial of a single oral dose of 2.5 mg ( 100,000 IU ) cholecalciferol ( vitamin D3 ) was conducted in the winter in 189 healthy free-living men and women aged 63 - 76 y. The mean baseline serum concentration for 25-hydroxyvitamin D was 34.5 nmol/L and for parathyroid hormone 3.18 pmol/L. After 5 wk , mean serum 25-hydroxyvitamin D concentrations were 60 % higher in the treated than in the placebo group ( P < 0.001 ) . There was a 12 % difference in parathyroid hormone concentrations in the treated compared with the placebo group ( P < 0.001 ) . No differences in serum calcium were seen . Findings suggest that 25-hydroxyvitamin D has a physiological role in the regulation of parathyroid secretion independent of serum calcium in healthy elderly people .  Parathyroid concentrations rise and 25-hydroxyvitamin D concentrations decline with age . These results may have implication s for the prevention of osteoporotic fractures that occur with increased frequency in winter and in elderly people An ongoing r and omized clinical trial of 3 years duration is being undertaken to evaluate the recurrent fracture rate and safety profile associated with low-dose calcitriol versus calcium supplementation in women with at least 3 years postmenopausal osteoporosis who are under the age of 80 years . A total of 856 patients were su bmi tted for possible inclusion in the study by 123 primary care physicians , and 636 met all entry requirements . Each patient was r and omly allocated to receive either 0.25 micrograms of calcitriol twice daily or calcium supplementation of 1,000 mg/d . If significant hypercalcemia developed ( greater than 2.6 mmol/L ) or a deterioration in renal function was observed , the dose of trial medication was to be halved or stopped if laboratory values did not return to normal . Patients were given no specific instructions regarding dietary calcium intake . To date , 528 patient-years experience with calcitriol  and 527 patient-years experience with calcium the calcium supplementation have been accumulated . Thus far , low-dose calcitriol has not been observed to cause hypercalcemia , deterioration in renal function , or nephrocalcinosis . At 1 year , a loss in total anterior height ( P less than .05 ) has been detected in the calcium-treated group compared with the calcitriol-treated group . Thus , calcitriol appears to preserve spinal height . Long-term follow-up of all patients for 2 or 3 years will be continued The Women 's Health Initiative ( WHI ) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women , including cancer , cardiovascular disease , and osteoporotic fractures . The WHI was initiated in 1992 , with a planned completion date of 2007 . Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial ( CT ) that will include about 64,500 women or an observational study ( OS ) that will include about 100,000 women . The CT is design ed to allow r and omized controlled evaluation of three distinct interventions : a low-fat eating pattern , hypothesized to prevent breast cancer and colorectal cancer and , secondarily , coronary heart disease ; hormone replacement therapy , hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and , secondarily , to reduce the risk of hip and other fractures , with increased breast cancer risk as a possible adverse outcome ; and calcium and vitamin D supplementation , hypothesized to prevent hip fractures and , secondarily , other fractures and colorectal cancer . Overall benefit-versus-risk assessment is a central focus in each of the three CT components . Women are screened for participation in one or both of the components -- dietary modification ( DM ) or hormone replacement therapy (HRT)--of the CT , which will r and omize 48,000 and 27,500 women , respectively . Women who prove to be ineligible for , or who are unwilling to enroll in , these CT components are invited to enroll in the OS . At their 1-year anniversary of r and omization , CT women are invited to be further r and omized into the calcium and vitamin D ( CaD ) trial component , which is projected to include 45,000 women . The average follow-up for women in either CT or OS is approximately 9 years . Concerted efforts are made to enroll women of racial and ethnic minority groups , with a target of 20 % of overall enrollment in both the CT and OS . This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component . Some detail is provided on specific study design choices , including eligibility criteria , recruitment strategy , and sample size , with attention to the partial factorial design of the CT . Some aspects of the CT monitoring approach are also outlined . The scientific and logistic complexity of the WHI implies particular leadership and management challenges . The WHI organization and committee structure employed to respond to these challenges is also briefly described Women with vertebral deformities caused by osteoporosis have more back pain and disability and are at higher risk for subsequent vertebral deformities than women without deformities . Despite the importance of vertebral deformities , there has been a great deal of controversy about how to identify or define them . In order to compare methods for defining vertebral deformities , we studied  spinal radiographs from women in the Study of Osteoporotic Fractures ( SOF ) , a cohort study of 9704 non-black women over age 65 recruited from population -based listings in four clinical centers . Using radiographs obtained at the baseline exam , we compared five methods for defining vertebral deformities : one based on a semiquantitative reading by a radiologist and four using vertebral morphometry . The semiquantitative method was compared with the other methods in a r and om sample of 503 films , while the morphometric methods were compared with each other in a larger sample of 9575 films . We tested a system of " triage " in which only those films with evidence of deformity were assessed by morphometry . We compared the relationship between deformity , defined by each method , and a variety of clinical criteria including bone mineral density at the lumbar spine , height loss since age 25 , back pain , and incidence of subsequent deformity . Semiquantitative reading and three of the four morphometry-based methods provided similar relationships to clinical criteria . The fourth morphometry method ( based on ratios of each vertebral height to the corresponding height at T4 ) produced significantly weaker relationships for several of the clinical validation criteria . Triage of radiographs rarely result ed in missed deformities and did not reduce the performance of any of the methods . We conclude that use of any of the similar methods , with or without triage , provides a valid approach to defining vertebral deformities The effects on general and bone metabolism of femoral neck fracture patients of 0.25 μg α-calcoid given orally twice daily ( n=9 ) and 25 μg calcitonin given subcutaneously 30 times ( n=10 ) in 10 weeks were studied against a  control ( n = ll ) . Bone histology and histomorphometry showed non-age related osteoporosis in 30 % and osteomalacia in 22 % of the patients studied . Impaired serum vitamin D status was found in 47 – 88 % of patients , secondary hyperparathyroidism and increased serum parathyroid hormone in 59 % and decreased serum calcitonin levels in 69 % . On histology , normal findings and non-age related osteoporosis on histology were associated with low serum levels of 25-hydroxyvitamin D3,1,25- and 24,25-dihydroxy vitamin D3 . Very high serum levels of 1,25-dihydroxyvitamin D3 and low levels of 25-hydroxyvitamin D3 occurred in fracture patients with osteomalacia . Calcitonin improved calcium balance , reduced osteoporosis and increased the serum 1,25- and 24,25-dihydroxyvitamin D3 levels but had no effect on osteomalacia .  Vitamin  D reduced osteomalacia , slightly increased the serum 1,25-dihydroxyvitamin D3 concentration and decreased serum levels of parathyroid hormone . Both treatments gave a similar slight decrease in serum calcitonin concentrations . A mechanism of action for the treatments is suggested OBJECTIVES To investigate the therapeutic effect of combined use of vitamin K(2 ) and D(3 ) on vertebral bone mineral density in postmenopausal women with osteopenia and osteoporosis . SUBJECTS AND METHODS We enrolled 172 women with vertebral bone mineral density < 0.98 g/cm(2 ) ( osteopenia and osteoporosis ) as measured by dual-energy X-ray absorptiometry . In this study , we employed the criteria for diagnosis of osteopenia and osteoporosis using dual energy X-ray absorptiometry proposed by the Japan Society of Bone Metabolism in 1996 . Subjects were r and omized into four groups ( each having 43 subjects in vitamin K(2 ) therapy group , vitamin D(3 ) therapy group , vitamin K(2 ) and D(3 ) combined therapy group , or a control group receiving dietary therapy alone ) and treated with respective agents for 2 years , with bone mineral density was measured prior to therapy and after 6 , 12 , 18 , and 24 months of treatment . The bone metabolism markers analyzed were serum type 1 collagen carboxyterminal propeptide ( P1CP ) , serum intact osteocalcin , and urinary pyridinoline . Tests of blood coagulation function consisted of measurement of activated partial thromboplastin time ( APTT ) and analysis of concentrations of antithrombin III ( AT III ) , fibrinogen , and plasminogen . RESULTS Combined therapy with vitamin K(2 ) and D(3 ) for 24 months markedly increased bone mineral density ( 4.92 + /- 7.89 % ) , while vitamin K(2 ) alone increased it only 0.135 + /- 5.44 % . The bone markers measured , revealed stimulation of both bone formation and resorption activity . We observed an increase in coagulation and fibrinolytic activity that was within the normal range , suggesting that balance was maintained in the fibrinolysis-coagulation system . CONCLUSIONS Continuous combination therapy with vitamin K(2 ) and D(3 ) may be useful for increasing vertebral bone mass in postmenopausal women . Furthermore , the increase in coagulation function observed during this therapy was within the physiological range , and no adverse reactions were observed In a double-blind trial , 327 patients ( 57 men ) over 65 ( mean age 79.5 ) years received all possible combinations of calcium carbonate 3 g , vitamin D3 1000 iu , meth and ienone 2.5 mg and /or placebos daily for 9 months . The higher incidence of bone fractures in the placebo group was not significant . Serum calcium , phosphorus , creatinine , aspartate aminotransferase and alkaline phosphatase were followed : the greatest changes occurred with meth and ienone , which thus reduced osteoporotic activity and increased the muscular mass most effectively ; calcium carbonate had the poorest effect . Surprisingly , coronary mortality was higher among those taking all three active substances . With two treatments the increase was not significant , but when both the groups receiving a combination of any two of the treatments were compared with those taking only one or neither of these two treatments , a significant increase in coronary deaths was seen , most significant ( P less than 0.001 ) in those receiving vitamin D3 and meth and ienone OBJECTIVE To study the efficacy of synthetic 1,25 dihydroxyvitamin D3 ( calcitriol ) in the treatment of osteoporosis . DESIGN Two-year , double-blind , r and omized clinical trial . SETTING University medical center . PATIENTS Fifty postmenopausal women with vertebral fractures recruited by referral . INTERVENTION Calcium intake was adjusted to 25 mmol/d ( 1000 mg/d ) at baseline . Patients were then r and omized to treatment with either calcitriol or placebo . During the study , calcium intake was reduced to 15 mmol/d ( 600 mg/d ) and the dose of calcitriol was adjusted to maintain serum calcium less than 2.74 mmol/L ( less than 11.0 mg/dL ) or urine calcium less than 9.96 mmol/d ( less than 400 mg/d ) . MEASUREMENTS AND MAIN RESULTS After 2 years , the mean dose of calcitriol in the treated group was 0.62 micrograms/d . Bone mineral density of the spine increased 1.94 % with calcitriol therapy and decreased 3.92 % with placebo ( P = 0.001 ) . Total body calcium increased 0.21 % with calcitriol therapy and decreased 1.85 % with placebo ( P = 0.004 ) . Patients receiving placebo had significant decreases in spine density ( P = 0.0007 ) and total body calcium ( P = 0.0004 ) . There were no differences in vertebral fracture rates between the groups . Renal function studies were not statistically different between the groups after 2 years . CONCLUSION The treatment of postmenopausal osteoporotic women with synthetic calcitriol for 2 years was associated with increases in spine density and total body calcium . No adverse effects on renal function were seen after long-term calcitriol therapy In a 5-yr r and omized prospect i ve study we examined the treatment effect of estrogen replacement therapy/hormone replacement therapy ( ERT/HRT ) , calcitriol , ERT/HRT and calcitriol , or placebo for 3 yr and the effect of discontinuation of therapy for 2 more yr on bone mineral density ( BMD ) , calciotropic hormones , markers of bone remodeling , and calcium absorption in 489 elderly women . The treatment phase of the study was double-blinded . After discontinuing therapy for 2 yr , there was rapid bone loss in all 3 treatment groups , and most of the decrease in BMD occurred in the first year . In the ERT/HRT group , spine BMD increased 5.5 % in yr 3 , decreased 3.2 % in yr 4 , and decreased 0.7 % in yr 5 ; femoral neck BMD increased 3.7 % in yr 3 , decreased 2.5 % in yr 4 , and decreased 0.4 % in yr 5 ; total body BMD increased 2.1 % in yr 3 , decreased 1.4 % in yr 4 , and decreased 0.6 % in yr 5 . In the combination group , spine BMD increased 7.1 % in yr 3 , decreased 4.3 % in yr 4 , and decreased 0.3 % in yr 5 ; femoral neck BMD increased 4.5 % in yr 3 , decreased 3.0 % in yr 4 , and decreased 0.01 % in yr 5 ; total body BMD increased 2.2 % in yr 3 , decreased 1.5 % in yr 4 , and decreased 0.6 % in yr 5 . In the calcitriol group , spine BMD increased 1.8 % in yr 3 , decreased 1.8 % in yr 4 , and showed no change in yr 5 ; femoral neck BMD increased 0.2 % in yr 3 , decreased 0.2 % in yr 4 , and decreased 0.6 % in yr 5 ; total body BMD decreased 0.4 % in yr 3 , decreased 0.6 % in yr 4 , and decreased 0.4 % in yr 5 . Compared with placebo , all treated groups at yr 5 had significantly higher total body BMD ; only the combination group had significantly higher spine BMD ( 3.4 % ; P < 0.001 ) and total hip BMD ( 2.4 % ; P < 0.01 . ) compared with the placebo group . Compared with baseline , only spine BMD in the combination group was significantly higher ( 2.6 % ; P < 0.001 ) at yr 5 . The increase in calcium absorption and the decrease in serum PTH levels in the calcitriol groups were reversed after discontinuation of treatment , and the decrease in bone markers was reversed in the hormone-treated groups . These results suggest that discontinuation of ERT/HRT and /or calcitriol therapy  in elderly women leads to a decrease in much of the BMD gained on treatment ; however , in the combination group there was a statistically significant residual effect on spine BMD Radiographically detected vertebral fractures ( hereafter referred to as vertebral fractures ) are a hallmark of postmenopausal osteoporosis and an important end point in clinical trials of osteoporosis treatment . Women with vertebral fractures have low bone mass compared with women without these fractures and , independently of bone mass , have an increased risk for additional vertebral and other fractures [ 1 - 4 ] . Vertebral fractures are common : Five percent of 50-year-old white women and 25 % of 80-year-old women have had at least one vertebral fracture [ 5 ] . Surprisingly , however , the manner in which vertebral fractures affect health remains uncertain . Cross-sectional studies in community-derived sample s of older women have demonstrated only a modest association [ 6 - 8 ] or no association [ 9 - 11 ] between prevalent vertebral fractures and back pain or disability . Cross-sectional studies do not distinguish more recent fractures from older vertebral fractures and may fail to capture transient increases in pain or disability [ 12 ] , a limitation that may underestimate the clinical effect of these fractures [ 13 ] . Back pain is common among elderly women [ 14 ] , and frequent causes of back pain , such as degenerative disc disease , facet joint osteoarthritis , spinal stenosis , and scoliosis , may obscure the impact of vertebral fracture . Only about one third of new vertebral fractures come to medical attention [ 15 , 16 ] , suggesting that most vertebral fractures are asymptomatic . However , attitudes toward back pain in older women and access to health care may also play a role in determining whether vertebral fractures come to medical attention . We examined the effect of incident vertebral fractures on back pain and back-related functional limitations in a large community-based sample of elderly women who underwent serial spinal radiography and annual assessment s of back pain and disability over the same period . Methods Participants Study patients were participants in the Study of Osteoporotic Fractures , a cohort recruited from population -based listings in four U.S. metropolitan areas . Details of the design of this study are published elsewhere [ 17 ] .  Lateral spine radiographs were obtained for 9677 white women between the ages of 65 and 99 years ( median age , 70 years ) who underwent baseline examination between 1986 and 1988 . Repeated spinal radiographs suitable for morphometry were obtained for 7223 women ( 75 % of the original cohort ) at a follow-up clinic visit held an average of 3.7 years ( range , 1.3 to 5.1 years ) later . All participants gave informed consent . Vertebral Morphometry Lateral radiographs of the thoracic and lumbar spine were obtained in accordance with current guidelines [ 18 ] . Quantitative vertebral morphometry was performed using six-point digitization as described elsewhere [ 3 , 19 ] to calculate the anterior ( Ha ) , mid- ( Hm ) , and posterior ( Hp ) height for each vertebral body from T4 to L4 . A system of triage of radiographs , described elsewhere [ 3 , 20 ] , was used to reduce the number of radiographs requiring morphometric measurements . Briefly , trained technicians separated sets of radiographs into normal , uncertain , or probably fractured groups on the basis of a limited semiquantitative grading scheme that categorized women by the most abnormal vertebral level [ 20 ] . Uncertain grade s were further categorized by the study radiologist as normal or probably fractured . Morphometry was done on the radiograph pairs that were categorized as probably fractured ( 42 % ) . In a r and om sample of 503 women whose radiographs were triaged and then digitized , triage missed no incident fractures according to the study definition . Definition of Vertebral Fracture A vertebra was classified as having a prevalent fracture on the baseline radiograph if any of the following ratios were more than 3 SDs ( > 4 SDs for severe fractures ) below the normal mean for that vertebral level : ( Ha/Hp ) , ( Hm/Hp ) , or a combination of ( H/H [ ] 1 ) and ( Hai/Hai 1 ) [ 3 , 21 ] . A new ( incident ) fracture was identified if any of the three vertebral heights ( Ha , Hm , or Hp ) on follow-up radiographs decreased by 20 % or more and by at least 4 mm compared with the baseline height . Incident fractures identified by morphometry were review ed by a radiologist to exclude imaging artifacts or such conditions as osteophytosis and Scheuermann disease ; 7 % of vertebrae meeting the morphometric criteria for incident fracture were reclassified as not fractured . Incident Clinical Fractures We used previously described methods [ 22 ] to assess the occurrence of clinical fractures of any bone during follow-up . Women were considered to have a clinical vertebral fracture if they reported a new diagnosis of spinal fracture and a clinical radiology report confirmed that a vertebral fracture was present . Measurements of Pain , Disability , and Limited Activity We evaluated outcome measures by using a previously described question naire [ 7 , 23 ] that asked about back pain and back-related disability in the past 12 months and the number of days of limited activity due to back pain . The question naire was administered at baseline and at three annual follow-up contacts held before assessment of vertebral fractures . The third follow-up contact coincided with follow-up radiography . Back pain was assessed on scales of frequency ( 0 , never or rarely ; 1 , some of the time ; 2 , most of the time ; or 3 , all of the time ) and severity ( 0 , no pain ; 1 , mild pain ; 2 , moderate pain ; or 3 , severe pain ) . The two pain questions had high internal consistency ( Cronbach = 0.81 ) and were summed for a total score that could range from 0 to 6 . We defined clinical ly significant back pain as pain that was experienced most or all of the time or pain that was moderate or severe . Women without significant back pain at baseline were considered to have increased back pain if clinical ly significant pain had developed between any follow-up contacts . For women with clinical ly significant back pain at baseline , increased back pain was defined as an increase in total pain score of at least two points . Both types of increase had a similar association with incident fractures and thus were combined for a single outcome . Back-related disability was assessed with questions about the degree of difficulty ( 0 , no difficulty ; 1 , some difficulty ; 2 , much difficulty ; or 3 , unable to perform activity ) in six activities of daily living that involved the back ( bending down to pick up light-weight objects , lifting a 10-pound object from the floor , reaching for objects just above the head , putting on socks or stockings , getting in and out of an automobile , and st and ing for 2 hours ) . These measures were combined in a back-related disability score ranging from 0 to 18 . As reported elsewhere [ 7 ] , this scale has high internal consistency ( Cronbach = 0.82 ) and is highly correlated ( Spearman r = 0.73 ) with a more extensive instrument used to assess disability caused by low back pain [ 24 ] . We defined clinical ly significant disability as much difficulty or unable in one or more of the six activities . Women without significant disability at baseline were considered to have increased disability if clinical ly significant disability had developed between any follow-up contacts . For women with clinical ly significant disability at baseline , increased disability was defined as an increase in disability score of at least three points . Both types of increase had a similar association with incident fractures and thus were combined for a single outcome . We also asked participants if they had limited their activities because of back pain since the last contact ; if the answer was yes , we asked for the number of days they had stayed in bed and the number of days on which activity was limited ( not including days in bed ) because of back pain . Questions were adapted from previous surveys [ 25 , 26 ] . For all follow-up contacts , we summed the number of days of bed rest and , in a separate measure , the number of days of limited activity ; we then divided these numbers by the total years of follow-up to estimate the average number of affected days per year . Other Measurements The baseline question naire assessed potential confounding factors that may be associated with the risk for incident vertebral fracture and with back pain or disability  , including smoking ( current or past smoker ) ; inactivity , defined as walking less than one block daily ( yes or no ) ; a previous physician diagnosis of osteoporosis or spinal fracture ( yes or no ) ; current use of estrogen ( yes or no ) ; hip pain in the past 12 months ( yes or no ) ; and height at 25 years of age . At the baseline examination , we assessed height and weight and calculated body mass index ( kg/m2 ) . We assessed grip strength by using an isometric dynamometer ( Jamar Hydraulic H and Dynamometer , JA Preston , Jackson , Mississippi ) at baseline and at the follow-up examination and calculated change in grip strength between the two measurements . A r and om sample of 16 % of baseline spine radiographs was assessed for spinal disc degeneration by using previously published methods [ 27 ] . Statistical Analysis Unless otherwise indicated , analyses were done separately in groups stratified by the presence of one or more baseline prevalent vertebral fractures . Descriptive and bivariate associations were assessed by using the t-test for continuous variables and the chi-square test for dichotomous variables . The association between incident vertebral fractures and dichotomous outcomes ( increased back pain and increased back disability ) was analyzed with logistic regression techniques . We analyzed the association of incident vertebral fracture with days of bed rest and days of  limited activity per year by using Poisson regression . The distribution of days of bed rest ( mean SD , 0.44 5.15 ) and limited-activity days ( 16.3 53.7 ) indicate that considerable overdispersion is present . Poisson regression allowing for this overdispersion provides a good estimation and inferential scheme [ STUDY OBJECTIVE To determine if calcitriol is an effective treatment in postmenopausal osteoporosis . DESIGN Double-blind , r and omized clinical trial of 2 years ' duration . SETTING University medical center with patients recruited by media announcements . PATIENTS Eighty-six postmenopausal women with vertebral compression fractures . INTERVENTIONS Patients were treated with calcitriol or placebo . Mean dose was 0.43 micrograms/d . Dietary calcium was 1000 mg/d ( 24.9 mmol/d ) . The medication dose and dietary calcium were adjusted for hypercalciuria or hypercalcemia . MEASUREMENTS AND MAIN RESULTS No significant differences between placebo and control groups were seen in the percent change in total body calcium ( 0.4 % + /- 1.0 compared with 0.0 % + /- 0.9 ) , single photon absorptiometry ( -0.5 % + /- 1.2 compared with -3.1 % + /- 0.9 ) or dual photon absorptiometry ( 0.0 % + /- 1.7 compared with -1.0 % + /- 2.2 ) . New fractures were seen in 16 % of the placebo group and 26 % of the calcitriol groups , so the difference in percent fractures was 10 % ( 95 % CI , -5.7 % to 25.7 % ) . Bone biopsies did not show changes in either group . The calcitriol group had significantly higher serum and urine calcium values , but renal function was not worse than in the placebo group . CONCLUSIONS Calcitriol is not an effective treatment for established postmenopausal osteoporosis 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 A controlled therapeutic trial on seventy‐four 70‐year‐old women was carried out with the purpose of finding the optimal treatment for post menopausal osteoporosis .  The bone mineral content ( BMC ) was measured by 125I‐photonabsorptiometry at two sites in the distal part of the forearms , where the trabecular/cortical ratio is 0·25 and 1·5 , respectively . Radiographs were done on the right h and to measure the metacarpal bone mass ( cortical area/total area = CA/TA ) A r and omized double-blind controlled trial of the effect of vitamin D supplementation on the abilities of elderly hospital patients to carry out basic activities of daily life is described . Those patients included in the trial had plasma 25-hydroxyvitamin D concentrations which were low or low normal as judged by the normal range in young adults . After 2 to 9 months on the trial there was no significant difference in the performance of the control and treatment groups In this prospect i ve study , the authors determined intrinsic risk factors for falls and recurrent falls and constructed a risk profile that indicated the relative contribution of each risk factor and also estimated the probabilities of falls and recurrent falls . In 1992 , over a 28-week period , falls were recorded among 354 elderly subjects aged 70 years or over who were living in homes or apartments for the elderly in Amsterdam and the vicinity . During the study period , 251 falls were reported by 126 subjects ( 36 % ) , and recurrent falls ( > or = 2 falls ) were reported by 57 subjects ( 16 % ) . Associations of falls and recurrent falls with potential risk factors were identified in logistic regression models . Mobility impairment regarding one or more of the tested items ( i.e. , impairment of balance , leg-extension strength , and gait ) was associated with falls ( adjusted odds ratio ( OR ) = 2.6 ) and was strongly associated with recurrent falls ( OR = 5.0 ) . Dizziness upon st and ing was associated with falls ( OR = 2.1 ) and recurrent falls ( OR = 2.1 ) . However , several risk factors were associated with recurrent falls only : history of stroke ( OR = 3.4 ) , poor mental state ( OR = 2.4 ) , and postural hypotension ( OR = 2.0 ) . The authors constructed a risk profile for recurrent falls that included the five risk factors mentioned above . Inclusion of all risk factors in the profile implied an 84 % probability of recurrent falls over a period of 28 weeks , compared with 3 % when no risk factor was present . The probability of recurrent falls ranged only from 11 % to 29 % when predicted by number of falls occurring in the previous year . Physical activity , use of high-risk medication , and the use of vitamin D3 , which was r and omly allocated to the participants , were not strongly related to either falls or recurrent falls . In conclusion , a large range of probabilities of falls , especially of recurrent falls , was estimated by the risk profiles , in which mobility impairment was the major risk factor . Recurrent fallers may therefore be especially amenable to prevention based on mobility improvement Abstract : Vitamin D status is known to be an important determinant of bone mineral density ( BMD ) . There is a significant seasonal variation in serum vitamin D , and some studies have reported an associated seasonal variation in BMD . The present study was devised to investigate whether a seasonal variation in BMD could be detected in healthy normal subjects , along with associated variations in serum parathyroid hormone ( PTH ) , intestinal calcium absorption and biochemical markers of bone turnover . A second aim was to investigate whether , if such variations were identified , they could be suppressed by vitamin D supplementation . The subjects were 70 healthy female volunteers ( mean age 47.2 years , range 24–70 years ) recruited into a double-masked crossover study and followed over 2 years . During the first year 35 subjects received a daily oral supplement containing 800 IU ( 20 mg ) cholecalciferol ( group 1 ) and 35 subjects received a placebo preparation ( group 2 ) . During the second year the treatment each group received was reversed . Lumbar spine ( L1–L4 ) , left proximal femur and total body BMD were measured by DXA at 3-month intervals . Serum 25-hydroxyvitamin D ( 25-OHD ) , serum PTH , bone markers ( bone-specific ALP ( BSAP ) and urinary crosslinks ( DYPD/creatinine ) ) and calcium absorption were also measured at each visit . Cholecalciferol treatment increased serum 25-OHD by 25.4 nmol/l ( p < 0.001 ) , while a reciprocal decrease in serum PTH of 6.6 ng/l ( p = 0.011 ) was seen in subjects in the lowest quartile of baseline serum 25-OHD . The treatment had no significant effect on spine , femur or total body BMD , calcium absorption or bone markers . When Fourier analysis was used to analyze the data for seasonal effect ( defined as twice the amplitude of the 1-year period variation ) a highly significant effect for 25-OHD of 18 nmol/l ( p < 0.001 ) was found . However , no effect was found for BMD , PTH , calcium absorption or bone markers . The analysis set a 95 % confidence limit to the seasonal effect of less than 0.6 % for spine , total hip and total body BMD . It was concluded that in the population of healthy women studied there was no evidence of seasonal variation in spine , femur or total body BMD , serum PTH , calcium absorption or bone markers .  Vitamin D supplementation was found to have no effect on BMD PURPOSE Oral bone and tooth loss are correlated with bone loss at nonoral sites . Calcium and vitamin D supplementation slow the rate of bone loss from various skeletal sites , but it is not known if intake of these nutrients affects oral bone and , in turn , tooth retention . SUBJECTS AND METHODS Tooth loss was examined in 145 healthy subjects aged 65 years and older who completed a 3-year , r and omized , placebo-controlled trial of the effect of calcium and vitamin D supplementation on bone loss from the hip , as well as a 2-year follow-up study after discontinuation of study supplements . Teeth were counted at 18 months and 5 years . A comprehensive oral examination at 5 years included assessment of caries , oral hygiene , and periodontal disease . The odds ratio ( OR ) and 95 % confidence interval ( CI ) of tooth loss were estimated by stepwise multivariate logistic regression . Initial age ( mean + /- SD ) of subjects was 71 + /- 5 years , and the number of teeth remaining was 22 + /- 7 . RESULTS During the r and omized trial , 11 of the 82 subjects ( 13 % ) taking supplements and 17 of the 63 subjects ( 27 % ) taking placebo  lost one or more teeth ( OR = 0.4 ; 95 % CI : 0.2 to 0.9 ) . During the 2-year follow-up period , 31 of the 77 subjects ( 40 % ) with total calcium intake of at least 1000 mg per day lost one or more teeth compared with 40 of the 68 subjects ( 59 % ) who consumed less ( OR = 0.5 ; 95 % CI : 0.2 to 0.9 ) . CONCLUSION These findings suggest that intake levels of calcium and vitamin D aim ed at preventing osteoporosis have a beneficial effect on tooth retention Abstract The effect of the combined administration of vitamin D3 and vitamin K2 on bone mineral density ( BMD ) of the lumbar spine was examined in postmenopausal women with osteoporosis . Ninety-two osteoporotic women who were more than 5 years after menopause , aged 55–81 years , were r and omly divided into four administration groups : vitamin D3 ( 1α hydroxyvitamin D3 , 0.75 μg/day ) ( D group ; n = 29 ) , vitamin K2 ( menatetrenone , 45 mg/day ) ( K group ; n = 22 ) , vitamin D3 plus vitamin K2 ( DK group , n = 21 ) , and calcium ( calcium lactate , 2 g/day ) ( C group ; n = 20 ) . BMD of the lumbar spine ( L2–L4 ) was measured by dual energy X-ray absorptiometry at 0 , 1 , and 2 years after the treatment started . There were no significant differences in age , body mass index , years since menopause , and initial BMD among the four groups . One-way analysis of variance ( ANOVA ) with repeated measurements showed a significant decrease in BMD in the C group ( P < 0.001 ) . Two-way ANOVA with repeated measurements showed a significant increase in BMD in the D and K groups compared with that in the C group ( P < 0.05 and P < 0.001 , respectively ) , and a significant increase in BMD in the DK group compared with that in the C , D , and K groups ( P < 0.0001 , P < 0.05 and P < 0.01 , respectively ) . These findings indicate that combined administration of vitamin D3 and vitamin K2 , compared with calcium administration , appears to be useful in increasing the BMD of the lumbar spine in postmenopausal women with osteoporosis Abstract . To assess the efficacy and acceptability of vitamin D-fortified liquid milk in the management of hypovitaminosis D we carried out a double-blind , r and omized , controlled trial on 51 community-based , elderly subjects with serum 25 hydroxyvitamin D ( 25OHD ) levels of less than 12.9 ng/ml ( normal range 10–80 ng/ml ) . Each subject had a dietary assessment , mental test score , outdoor score , serum 25 hydroxyvitamin D level , and a general biochemical screening at baseline in April 1993 which was repeated in September 1993 , April 1994 , and September 1994 . All subjects received 500 ml of milk per day , delivered to their homes in specially manufactured , blank , tetrapak cartons , from June 1993 to June 1994 : 23 subjects received unfortified milk ( control group ) and 28 subjects received fortified milk ( active group ) . Our results showed a baseline mean 25OHD level in the active group of 9.6 ( range < 5.5–12.7 ) ng/ml and in the control group of 10.0 ( range < 5.5–12.9 ) ng/ml ( P < 0.4 ) . One year later the mean 25OHD level in the active group had risen significantly from its baseline to 18.5 ( range 9.6–26.7 ) ng/ml ( P < 0.001 ) and was significantly different from the control group with a 1-year mean of 12.7 ( range < 4–24.1 ) ng/ml ( P < 0.001 ) . Serum calcium levels in the active group also showed a significant rise over the 1-year period ( P < 0.001 ) whereas those in the control group did not . We conclude that vitamin D-fortified liquid milk is a safe , effective , and acceptable method of administering vitamin D to the elderly , community-based population Abstract : We undertook a double-masked , r and omized , placebo-controlled trial to evaluate the effect of a calcium and vitamin D supplement and a calcium supplement plus multivitamins on bone loss at the hip , spine and forearm . The study was performed in 240 healthy women , 58–67 years of age . Duration of treatment was 2 years . Bone mineral density ( BMD ) was measured at the lumbar spine , hip and forearm . A dietary question naire was administered twice during the study and revealed a fairly good calcium and vitamin D intake ( 919 mg calcium/day ; 3.8 mg vitamin D/day ) . An increase in lumbar spine BMD of 1.6 % was observed in the treatment group after 2 years ( p50.002 ) . In the placebo group no significant changes were observed during the 2 years . Lumbar spine BMD was significantly higher in the treatment group at both 1 ( p50.01 ) and 2 years ( p50.05 ) compared with the placebo group . Though not significant , the same trend was seen at the hip . No significant changes from baseline values were observed at the distal forearm in either the treatment or the placebo group . In conclusion , we found a significant increase in urinary calcium excretion in the treatment group compared with the placebo group . Together with significant changes in serum calcium and serum parathyroid hormone , this indicates that a long-term calcium and vitamin supplement of 1 g elementary calcium ( calcium carbonate ) and 14 mg vitamin D3 increases intestinal calcium absorption . A positive effect on BMD was demonstrated , even in a group of early postmenopausal age , with a fairly good initial calcium and vitamin D status OBJECTIVES We investigated the incidence of new  non-vertebral fractures  during HRT or low-dose vitamin ( Vit ) D3 supplementation in a 5-year prospect i ve trial . METHODS A total of 464 early postmenopausal women , ( a subgroup of the Kuopio Osteoporosis Study , n = 13100 ) were r and omized to four groups : ( 1 ) HRT , a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate ; ( 2 ) Vit D ( 300 IU/day and 100 IU/day during the fifth year ) ; ( 3 ) HRT + Vit D ; and ( 4 ) placebo .  Lumbar ( L2 - 4 ) and femoral neck bone mineral densities ( BMD ) were determined by dual X-ray absorptiometry ( DXA ) at baseline , after 2.5 and 5 years of treatment . All new symptomatic non-vertebral , radiographically defined fractures were recorded . RESULTS Altogether , 368 women ( 79 % ) completed the 5 year treatment . In all , 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up ( HRT 4 , Vit D 10 , HRT + Vit D 8 and placebo 17 ) . The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone ( P = 0.032 ) when adjusted by baseline BMD and previous fractures ; observed also with the intention-to-treat principle ( P = 0.048 ) . When the HRT groups were pooled , HRT showed a significantly lower incidence of new non-vertebral fractures ( P = 0.042 ) than women receiving placebo and also after adjusting as above ( P = 0.016 ) ; both in valid-case and in the intention-to-treat analysis . In the Vit D group , the fracture incidence was non-significantly decreased ( P = 0.229 ) in comparison with the placebo group . The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 ( 95 % CI , 0.10 - 0.90 ) and with Vit D 0.47 ( 95 % CI , 0.20 - 1.14 ) and with HRT + Vit D 0.44 ( 95 % CI , 0.17 - 1.15 ) , in comparison with the placebo group ( adjusted by femoral BMD and previous fractures ) . CONCLUSIONS This study is the first prospect i ve trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women . The effect of low-dose Vit D remains to be proved Twenty-eight women with postmenopausal osteoporosis were studied in a double-blind trial aim ed to compare the effects of a one-year treatment with 1,25-dihydroxyvitamin D3 ( 1,25(OH)2D3 ) , estradiol valerate ( E2 ) and placebo . Patients were divided into 4 groups : group 1 was given 1,25(OH)2D3 alone , group 2 was given E2 alone , group 3 was given 1,25(OH)2D3 + E2 , group 4 received a placebo . The evaluation of the effects of the treatments included clinical examination of patients , the measurement of a number of biochemical parameters , such as plasma and urinary calcium and phosphate , urinary hydroxyproline , serum alkaline phosphatase , the measurement of intestinal calcium absorption and bone mineral content ( BMC ) and a histomorphometric study of bone biopsies from the iliac crest . The best clinical results were obtained in the patients who were given 1,25(OH)2D3 alone ; appreciable results were also noticed in the patients who were given E2 alone or in combination with 1,25(OH)2D3 , while patients in the placebo group worsened . BMC decreased in the placebo group and increased , although non significantly , in the patients treated with 1,25(OH)2D3 or E2 or both . The histomorphometric study showed a significant increase in the mean trabecular diameter in patients treated with 1,25(OH)2D3 alone or in combination with E2 . Changes in the volume density of trabecular bone paralleled those in BMC . The results of the trial indicate that 1,25(OH)2D3 is an effective therapeutic agent in postmenopausal osteoporosis OBJECTIVES To determine whether relative vitamin D deficiency during the winter months contributes to age-related bone loss  and whether rates of change in hard- and soft-tissue mass vary during the year . DESIGN Double-blind , placebo-controlled , 1-year trial in 249 women in which equal numbers of women were r and omized to either placebo or 400 IU of vitamin D daily . All women received 377 mg/d of supplemental calcium largely as calcium citrate malate . PATIENTS Healthy , ambulatory postmenopausal women with usual intakes of vitamin D of 100 IU/d . MEASUREMENTS Duplicate spine and whole-body scans were done by dual energy x-ray absorptiometry at 6-month intervals that were timed to periods when 25-hydroxyvitamin D levels were highest and lowest . Period 1 was June-July to December-January and period 2 was December-January to the next June-July . Serum parathyroid hormone and plasma 25-hydroxyvitamin D levels were measured during periods 1 and 2 . MAIN RESULTS In the placebo group , spinal bone mineral density increased in period 1 , decreased in period 2 , and sustained no net change . Women treated with vitamin D had a similar spinal increase in period 1 ( 1.46 % compared with 1.40 % in placebo ) , less loss in period 2 ( -0.54 % compared with -1.22 % , CI for the difference , 0.05 % to 1.31 % , P = 0.032 ) and a significant overall benefit ( 0.85 % compared with 0.15 % , CI for the difference , 0.03 % to 1.37 % , P = 0.04 ) . In period 2 , 25-hydroxyvitamin D levels were lower and parathyroid hormone levels were higher in the placebo than in the vitamin D group . Whole-body lean and fat tissue and bone mineral density varied during the year but did not change overall . CONCLUSIONS At latitude 42 degrees , healthy postmenopausal women with vitamin D intakes of 100 IU daily can significantly reduce late wintertime bone loss and improve net bone density of the spine over one year by increasing their intake of vitamin D to 500 IU daily . A long-term benefit of preventing vitamin D insufficiency in the winter seems likely although it remains to be shown . Observed changes in bone as well as in fat and lean tissue appear to be related to season Background and aims : Supplementation of postmenopausal women with calcium alone or calcium-vitamin D association  was suggested to have positive effects on bone turnover and bone density , as well as to lower fracture incidence . The beneficial effect appears to be mediated by a reduction in parathyroid hormone secretion . Our aim was to compare the respective efficacy of calcium and calcium-vitamin D supplements in reducing serum parathyroid hormone levels in postmenopausal women with prevalent low 25(OH)vitamin D levels . Methods : One hundred consecutive ambulatory postmenopausal women with serum 25(OH)vitamin D levels below 18 ng/mL were included in a r and omized , prospect i ve , open label study . For a duration of 90 days , the women were r and omly assigned to a daily supplementation of either one tablet of calcium gluconolactate and carbonate ( 500 mg calcium ) , or one powder-pack of an association of calcium carbonate ( 500 mg calcium ) , citric acid ( 2.175 gr ) and cholecalciferol ( 200 IU ) . Changes observed during the 90 days of the study in circulating PTH levels were the primary endpoint , while changes in serum 25(OH)D levels were assessed as secondary endpoint . Results : A significant difference was observed between the calcium-vitamin D ( CaD ) and the calcium ( Ca ) only groups for changes occurring during the 90 days of the study in PTH ( −14.5±40 % and + 2.5±46 % ) ( p=0.009 ) and 25(OH)D ( + 67±77 % and + 18±55 % ) ( p<0.001 ) circulating levels . PTH changes between baseline and day 90 were significant in the CaD group , but not in the Ca group . The odds ratio for a patient in group Ca to experience an absolute ( < 12 ng/mL ) deficiency in circulating 25(OH)vitamin D levels , compared to a group CaD patient was statistically increased ( OR : 3.22 , 95 % CI : 1.33–7.80 ) . Conclusions : Our results support the recommendation of supplementing postmenopausal women with low circulating levels of 25(OH)vitamin D with a combination of calcium and vitamin D , rather than with calcium alone Vitamin D deficiency is common in elderly persons , especially those with hip fracture [ 1 , 2 ] . It is caused by low exposure to sunshine , decreased synthesis of vitamin D3 in the aging skin , and a diet low in vitamin D [ 3 , 4 ] . The mean vitamin D intake in elderly persons in the Netherl and s is about 100 IU/d , half that of elderly persons in the United States [ 5 ] . Most of this vitamin D comes from margarine , which is the only vitamin D-supplemented food in the Netherl and s ( 3 IU/g ) . In vitamin D deficiency , the low serum concentration of 25-hydroxyvitamin D [ 25(OH)D ] leads to a low 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] concentration and then to a higher serum parathyroid hormone concentration , especially in the winter [ 6 - 10 ] . Histologically , the increased parathyroid activity is associated with high bone turnover , leading to cortical bone loss and low density bone [ 5 , 11 ] , which may lead to hip fracture . We previously studied the effects of vitamin D supplementation in residents of a home for the elderly and residents of a nursing home [ 10 ] .  Vitamin D3 , 400 IU/d , led to an adequate increase of the serum 25(OH)D concentration , to a small but significant increase of the serum 1,25(OH)2D concentration , and to a decrease of the serum concentration of intact parathyroid hormone . It was recently observed [ 12 , 13 ] that bone mineral density at the hip is positively related to serum 25(OH)D concentration in postmenopausal and elderly women . Therefore , it might be expected that vitamin D supplementation would increase bone mineral density in elderly persons deficient in vitamin D. In line with this expectation , it was shown that vitamin D supplementation prevented bone loss from the spine during the winter in postmenopausal women [ 14 ] . These results suggest that vitamin D supplementation may reduce the incidence of hip fractures , because bone strength shows a strong correlation with bone mineral density [ 15 ] . However , increasing bone mineral density through a therapeutic intervention does not necessarily lead to increased bone strength , as has been shown with sodium fluoride [ 16 ] . Bone structure and bone quality are also determinants of bone strength [ 17 ] , and falls are a risk factor for hip fractures [ 18 ] . Therefore , hip fracture should be the outcome criterion in studies on the effect of vitamin D supplementation . Intervention studies on the prevention of osteoporotic fractures necessitate large numbers of patients , because the outcome has an annual incidence of 0.5 % to 4 % in the elderly population [ 19 ] . We report the results of a large-scale , prospect i ve study on the effect of vitamin D supplementation on the incidence of hip and other osteoporotic fractures . Methods Participants The study included 2578 persons ( 1916 women and 662 men ) 70 years of age and older ( mean age SD , 80 6 years ; range , 70 to 97 years ) . Participants were recruited from general practitioners , from apartment houses for elderly persons , and from homes for elderly persons in Amsterdam and its vicinity . Persons recruited from practitioners were living independently ; those recruited from apartment houses and homes were receiving some care , but less than they would have received in a nursing home . Participants had to be reasonably healthy and able to give informed consent . Persons with a history of hip fracture or total hip arthroplasty , known hypercalcemia , sarcoidosis , or recent urolithiasis ( < 5 years earlier ) were excluded . Patients who had diseases or who used medications that influence bone metabolism ( such as thyroid disease or glucocorticoid medication ) were not excluded . The spontaneous use of vitamin D supplements and multivitamins was discouraged , but the prescription practice s of the general practitioners were not altered . All vitamin use was carefully documented . The study was approved by the Ethical Review Board of the Vrije Universiteit Hospital , and all participants gave informed consent . Study Design After checking the inclusion and exclusion criteria and obtaining informed consent , the participants were r and omly assigned to receive either active treatment with vitamin D3 or placebo . The study was double-blind , and r and omization was done in blocks of 10 per general practice , apartment house , or home . R and omization lists were made using a computerized r and om-number generator . Lists in sealed envelopes were sent to the hospital pharmacy for assignment . Each participant took either one tablet per day that contained vitamin D3 , 400 IU , or one placebo tablet per day that was identical in appearance and taste to the vitamin tablet . After enrollment , the participants received the first container of tablets ( 210 tablets ) . The container was replaced every 6 months with a full container . All participants were also advised in writing to consume at least three servings of dairy products per day ( for example , 1 glass of milk , 1 cup of yogurt , and 1 slice of cheese ) to ensure a calcium intake of at least 800 to 1000 mg/d . The study was started in August 1988 . The last participant was enrolled in December 1990 , and all participants had stopped using study medication by December 1993 . The follow-up period had been planned to last no more than 3 years , but because the number of hip fractures during the study was lower than expected , a 6-month extension was planned . The study participants thus received medication for 3 to 3.5 years ; those who received it for 3.5 years were those who consented to the 6-month extension . Total follow-up was to a maximum of 4 years . Data collected at baseline included an  outdoor activity score  ( 1 equals going outdoors less than once a week ; 2 equals going outdoors 1 or 2 times per week ; and 3 equals going outdoors 3 times per week or more ) and a score for sunshine exposure ( when outside : 1 equals in the shade as much as possible ; 2 equals sometimes in sunshine ; 3 equals much exposure to sunshine ) . These scores show a positive relation with serum 25(OH)D concentration [ 3 ] . Mobility was estimated by a walking score that ranged from 1 ( unable to walk ) to 5 ( walks independently a fair distance on any surface ) [ 20 ] . The dietary calcium intake from dairy products was estimated in a subset of 348 women by using a question naire , as described previously [ 21 ] . The participants were evaluated annually with a question naire on hip fractures , other peripheral fractures , outdoor score , sunshine exposure score , use of vitamin supplements , and walking score . Each general practitioner or caretaker was asked to immediately report change of address , hip fracture , or death . Hip fracture and death were verified by the general practitioner . All participants were followed for the maximal period of 4 years if possible , even if they had stopped using the trial medication , had sustained a fracture , or had moved to another city . To investigate possible selection bias , 267 potential participants in a home for the elderly and its adjunct apartments ( all residents of the institution ) were studied for baseline characteristics , including age , sex , sunshine exposure score , outdoor score , walking score , and reasons for nonparticipation . Compliance was checked when the tablet containers were replaced ( every 6 months ) , by question naire ( every year ) , and by measurement of the serum 25(OH)D concentration . Serum 25(OH)D concentration was measured at baseline and after 1 year in 270 persons who participated in a sub study investigating the effect of vitamin D supplementation on bone mineral density and bone turnover variables . This sub study included a nonr and om sample of participants from several apartment houses and homes for the elderly and is described in detail elsewhere [ 21 ] . In the same sub study , dietary calcium intake from diary products was assessed . Serum 25(OH)D concentration was also estimated during the third year of the study in February and March in a r and om sample of 96 participants drawn from the remaining study population . These participants received a letter giving them an appointment within 10 days ; the blood sample s were drawn at home . Serum 25(OH)D concentration was measured by competitive protein binding assay after being purified by gradient high-pressure liquid chromatography . The intra- and interassay coefficients of variation were 5 % and 6 % , respectively [ 22 ] . Statistical Analysis Baseline data of the vitamin D group and the placebo group were compared using t-tests ( age , calcium intake ) , chi-square tests ( sex , residence ) , and Wilcoxon rank-sum tests ( scores ) . The serum 25(OH)D concentrations of both groups were compared using t-tests . Data on fractures and mortality were analyzed by survival analysis using log-rank tests , Cox proportional-hazards regression , and hazard rate ratios [ 23 ] . Hip fractures are presented using the Kaplan-Meier method . All participants were kept in the study as long as possible . The data were analyzed in two ways . The intention-to-treat analysis included all r and omly assigned participants for either the total follow-up period or until fracture , death , or loss to follow-up . The active treatment analysis included the participants as long as they stated that they were using the trial medication . Thus , the participants were included in the active treatment analysis until they stopped using the trial medication , regardless of whether a fracture occurred after they had stopped . Age , sex , and residence were added in both analyses as covariates to the Cox regression model . Because outdoor score , sunshine score , and walking score were interrelated ( correlation coefficients ranging from 0.21 to 0.59 ) and were likely to indicate general health or mobility , they were averaged over the years and added up to a sum score . For this purpose , the walking score was simplified ( 1 , 2 , or 3 equals 1 ; 4 equals 2 ; 5 equals 3 ) , because the lower walking scores applied to a few participants only . The result ing total score , ranging from 3 to 9 , was entered as a covariate in the model . The level of compliance ( weekly intake as reported on The long term effects of hormone replacement therapy ( HRT ) and vitamin D3 ( Vit D ) on bone mineral density ( BMD ) were studied . A total of 464 nonosteoporotic early postmenopausal women from the Kuopio Osteoporosis Study ( n = 13100 ) were r and omized to four groups : 1 ) HRT ( sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate , 2 ) Vit D3 ( 300 and 100 IU/day during the fifth year ) , 3 ) HRT and Vit D combined , and 4 ) placebo .  Lumbar ( L2-L4 ) and femoral neck BMD were determined by dual x-ray absorptiometry ( DXA ) at baseline and after 2.5 and 5 yr of treatment . Intention to treat analysis ( n = 464 ) showed that after 5 yr , lumbar BMD remained unchanged in the HRT and HRT plus Vit D groups [ + 0.2 % ( P = 0.658 ) and + 0.9 % ( P = 0.117 ) , respectively ] , whereas lumbar BMD decreased by 4.6 % in the Vit D group and by 4.5 % in the placebo group ( P < 0.001 in both ) . The loss of femoral neck BMD was less in the HRT ( -1.4 % ; P = 0.005 ) and HRT plus Vit D ( -1.3 % ; P = 0.003 ) groups than in the Vit D and placebo groups ( -4.3 % ; P < 0.001 in both ) . Among those 370 women who complied with the 5-yr treatment , the effect was more pronounced : lumbar BMD had increased by 1.5 % in the HRT ( P = 0.009 ) and by 1.8 % in the HRT plus Vit D group ( P = 0.005 ) , with a plateau after 2.5 yr , whereas lumbar BMD had decreased in both the Vit D and placebo groups ( 4.6 % and 4.7 % ; P < 0.001 , respectively ) . Femoral neck BMD decreased again less in the HRT ( -0.4 % ) and HRT plus Vit D ( -0.6 % ) groups than in the Vit D and placebo groups ( -4.4 % in both ) . This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis . The data suggest that low dose vitamin D3 supplementation does not prevent  bone loss in healthy , nonosteoporotic , early postmenopausal women , and it confers no benefit additional to that of HRT alone A two-year double-blind study monitored and evaluated the effects of 1 alpha-hydroxy vitamin D3 ( 1 alpha(OH)D3 ) on the lumbar ( L2 - 4BMD ) and total body bone mineral densities ( TBBMD ) and occurrence of fracture in 113 female osteoporotic patients receiving 0.75 micrograms/day of 1 alpha(OH)D3 ( n = 57 ) or a placebo ( n = 56 ) with calcium supplementation in both groups .  L2 - 4BMD increased 1.81.% and 2.32 % after one and 2 years in the 1 alpha (OH)D3 group , but decreased 1.89 % ( P < 0.05 ) and 0.28 % in the placebo group . A significant difference ( P < 0.01 ) existed between the two groups after one year . TBBMD decreased significantly in the placebo group by 3.34 % ( P < 0.01 ) and 3.52 % after one and 2 years . Six new fractures occurred in the control group , but only two in the 1 alpha(OH)D3 group ( Odd 's ratio = 0.343 , 95 % confidence range ; 0.0648 - 1.815 ) . There were no serious adverse effects of the 1 alpha(OH)D3 treatment . It was concluded that two-year treatment with 1 alpha(OH)D3 increased the lumbar BMD and inhibited the decrease in TBBMD . Although it was not significant , new fracture occurrence in the 1 alpha(OH)D3 group was around 1/3 of that in the control group The therapeutic effect of 1,25-dihydroxycholecalciferol ( 1,25(OH)2D3 ) in postmenopausal osteoporosis was tested in a single blind , r and omized prospect i ve study . Thirty-nine women , 50 - 65 years of age , were treated for three years with 0.5 microgram 1,25(OH)2D3 daily . In a control group , 37 women were given 400 IU vitamin D3 daily . There was no significant difference in annual bone loss from the distal or proximal forearm between the groups . New vertebral fractures were evaluated , and in the treatment group , the annual increase in vertebral fractures was 0.18 + /- 0.387 and in the control group 0.13 + /- 0.330 . New long bone fractures were 7 and 5 , respectively . None of the observed differences were statistically significant . In the 1,25(OH)2D3 group , 28 % had to reduce the dose because of slight hypercalcaemia . We conclude that 1,25(OH)2D3 as used in this study is not effective in the treatment of osteoporosis To examine whether the administration of 1 alpha (OH)-vitamin D3 ( 1 alpha (OH)D3 ) could prevent the occurrence of vertebral crush fractures in senile osteoporosis , crush fractures of the thoracic or lumbar spine in senile osteoporosis treated with 1 alpha (OH)D3  , 1.0 microgram/day ( 22 cases ) , 1 alpha (OH)D3 1.0 microgram/day + Ca 1.0 g/day ( 16 cases ) or Ca 1.0 g/day ( 23 cases ) were compared with those in non-treated controls ( 25 cases ) . The average treatment periods were 1.7 + /- 0.7 years in the 1 alpha (OH)D3 group , 2.1 + /- 1.0 years in the 1 alpha (OH)D3 + Ca group and 1.7 + /- 0.9 years in the Ca group . Occurrence of spinal crush fractures per 1000 patient years was significantly less in the 1 alpha (OH)D3 + Ca group ( P less than 0.01 ) than in the non-treated control group . These findings suggest that administration of 1 alpha (OH)D3 is effective in preventing the occurrence of pathological fractures in senile osteoporosis To evaluate the effects of calcium and 25-OHD in the therapy of senile osteoporosis , we studied a group of 39 women aged 69 + /- 7 ( st and ard deviation , SD ) years with severe osteoporosis . The group was characterized histomorphometrically by depressed bone remodeling rates without hyperosteoidosis . No subject had risk factors for osteopenia other than their age and postmenopausal status , and no subject was receiving therapy for bone disease at the onset of the study . Subjects were followed for 2 years after r and omization to receive either 1200 mg/day of calcium ( as calcium carbonate ) and 40 micrograms/day of 25-OHD ( calcium-25-OHD group ) , or 1200 mg/day of calcium plus placebo ( calcium-placebo group ) . Calcium-25-OHD result ed in a clear increase in 25-OHD levels ( p less than 0.001 ) and an increase in calcium absorption as indicated by urinary calcium excretion . Nevertheless , there was no significant change in fasting serum calcium , phosphorus , alkaline phosphatase , PTH , or 1,25-(OH)2D in either group . Radial and phalangeal bone mineral content and trabecular bone volume in the biopsied patients remained stable in both groups over the 2 year period . Unexpectedly , repeat bone biopsies revealed a clear improvement in the rate of mineralization in both groups , presumably as a result of the calcium supplementation alone . In summary , calcium-placebo and calcium-25-OHD treatment were both associated with stable appendicular bone mineral content in women with senile osteopenia . The finding of an effect of calcium supplementation on the rate of mineralization indicates that relative calcium deficiency may impair the mineralization phase of remodeling . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVES To investigate the effect of vitamin K2 treatment for a year on spinal bone mineral density ( BMD ) in postmenopausal women , comparing with vitamin D3 hormone replacement therapy and to determine the factors which affect the efficacy of vitamin K2 therapy . SUBJECTS AND METHODS Seventy-two postmenopausal women were r and omized into four groups and treated with respective agents . Before the therapy , 6 and 12 months after the treatment , their lumbar spine BMD were measured by dual energy X-ray absorptiometry . The rates of change in BMD ( delta BMD ) were calculated . Correlations of BMD with age , year since menopause and the initial BMD were determined . RESULTS Vitamin K2 suppressed the decrease in spinal BMD as compared with no treatment group . BMD in women treated with vitamin K2 was inversely correlated with their age ( r = -0.54 ; P < 0.05 ) . CONCLUSIONS Vitamin K2 therapy may be a useful method for preventing postmenopausal spinal bone mineral loss . In addition , the therapy should be started early in postmenopausal period Malabsorption of calcium is a common finding in patients with postmenopausal osteoporosis ( 1 , 2 ) . In a number of studies serum 1,25 dihydroxyvitamin D levels were found to be significantly lower in osteoporotic patients , which could account for the calcium absorptive defect ( 3–6 ) . Based on these findings , we studied the effects of synthetic calcitriol ( Rocaltrol ) in women with osteoporosis . We showed that calcitriol , 0.25 μg twice daily , improved and normalized the absorption of calcium in all patients and improved calcium balance ( 7 ) . Urine hydroxyproline , which is a measure of bone resorption , decreased significantly after 2 years of treatment with Rocaltrol . Because of these preliminary findings , further clinical studies were carried out at two centers using a variable dose of Rocaltrol . In these studies we focused on the effectiveness of Rocaltrol in preventing vertebral fractures in patients with spinal osteoporosis . Methods The results from two centers have been analyzed both as separate groups and as one combined group . One study was performed at the Mayo Clinic ( Protocol 861 ) and the other at Creighton University ( Protocol 860 ) . In both centers the studies performed were double blind and r and omized , and compared the effect of placebo against Rocaltrol for a period of 1 year . At the end of 1 year all patients on placebo were crossed over to treatment with Rocaltrol and followed for 2 more years . Patients initially treated with Rocaltrol were followed for an additional 2 years , thus yielding treatment data extending to 3 years in a number of patients . In the study design , patients were given Rocaltrol at a starting dose of 0.25 μg twice daily , if hypercalcemia and hypercalciuria did not occur the dose then was increased to 0.75 μg or 1.0 μg daily at the discretion of the investigator Osteoporosis in men is an emerging public health problem . As calcitriol reduces the rate of vertebral fractures in osteoporotic postmenopausal women , we conducted a prospect i ve study of this treatment in men with primary osteoporosis . Our study was a 2-yr , r and omized , double masked , double placebo-controlled trial of calcitriol ( 0.25 microg twice daily ) or calcium ( 500 mg twice daily ) in 41 men with primary osteoporosis and at least 1 baseline fragility fracture . Thirty-three men ( 85 % ) completed the study . There were no differences in baseline characteristics . Spinal and femoral neck bone mineral densities at 2 yr were unchanged in both groups . Serum osteocalcin decreased in both groups by 30 % ( P < 0.05 ) , whereas urine N-telopeptide cross-links decreased only in the calcium group by 30 % ( P < 0.05 ) . After 2 yr , fractional calcium absorption increased by 34 % ( P < 0.01 ) in the calcitriol group . Nineteen incident fragility fractures occurred ( 14 vertebral and 5 nonvertebral ) in 7 men . Over 2 yr , the number of men with vertebral fractures ( 6 vs. 1 ; P = 0.097 ) was similar in both groups . In conclusion , the efficacy of calcitriol remains unproven as a single agent for the treatment of osteoporosis in men R and omized controlled trials have shown that a combination of vitamin D and calcium can prevent  fragility fractures in the elderly . Whether this effect is attributed to the combination of vitamin D and calcium or to one of these nutrients alone is not known . We studied if an intervention with 10 microg of vitamin D3 per day could prevent hip fracture and other osteoporotic fractures in a double-blinded r and omized controlled trial . Residents from 51 nursing homes were allocated r and omly to receive 5 ml of ordinary cod liver oil ( n = 569 ) or 5 ml of cod liver oil where vitamin D was removed ( n = 575 ) . During the study period of 2 years , fractures and deaths were registered , and the principal analysis was performed on the intention-to-treat basis . Biochemical markers were measured at baseline and after 1 year in a sub sample . Forty-seven persons in the control group and 50 persons in the vitamin D group suffered a  hip fracture . The corresponding figures for all nonvertebral fractures were 76 persons ( control group ) and 69 persons ( vitamin D group ) . There was no difference in the incidence of hip fracture ( p = 0.66 , log-rank test ) , or in the incidence of all nonvertebral fractures ( p = 0.60 , log-rank test ) in the vitamin D group compared with the control group . Compared with the control group , persons in the vitamin D group increased their serum 25-hydroxyvitamin D concentration with 22 nmol/liter ( p = 0.001 ) . In conclusion , we found that an intervention with 10 microg of vitamin D3 alone produced no fracture-preventing effect in a nursing home population of frail elderly people The effect of two different estrogen/gestagen regimens and 24R,25-(OH)2-cholecalciferol on bone formation was studied in a r and omized trial with 144 healthy postmenopausal women .  Urinary excretion ( UE ) of 99m-technetium-diphosphonate and serum alkaline phosphatase ( AP ) was determined before and then once a year for 2 years of treatment . Both estimates of bone formation showed highly significant decreases ( p less than .001 ) to normal premenopausal levels in women receiving unopposed 17 beta-estradiol or in a sequential combination with progestagen , whereas unchanged high values were found in the groups receiving 24R,25-(OH)2D3 and placebo . The data show that bone turnover increases in early postmenopausal women concomitantly with the loss of bone mass , and that hormonal substitutional therapy normalizes the total skeletal turnover as well as preventing bone loss OBJECTIVE To evaluate functional improvement in a population of frail , homebound older persons with low vitamin D status as vitamin D stores improve . DESIGN R and omized , controlled intervention study . SETTING Subjects ' homes and a nursing facility in Baltimore , Maryl and . PARTICIPANTS The first 32 subjects ( community-dwelling , homebound older subjects from the Johns Hopkins Elder Housecall Program and nursing home residents from the Johns Hopkins Geriatrics Center ) entered in a longitudinal study of vitamin D replacement . MEASUREMENTS Baseline 25-hydroxyvitamin D levels were measured and repeated at least 1 month after therapy with either placebo or vitamin D ( ergocalciferol ) . Subjects were also administered the Frail Elderly Functional Assessment ( FEFA ) question naire , an instrument demonstrated to be reliable , valid , and sensitive to small increments of functional change in this population . MAIN RESULTS All subjects started with 25-hydroxyvitamin D levels less than 15 ng/mL. Those subjects whose levels improved by at least 3 ng/mL ( > assay coefficient of variation ) also demonstrated improvement in FEFA score . Regression analysis between change in FEFA score compared with change in 25-hydroxyvitamin D was significant ( r = .4 ; P = .02 ) . CONCLUSIONS In this cohort of homebound older people , improvement in vitamin D status was associated with functional improvement as measured by the FEFA question naire BACKGROUND Inadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons . METHODS We studied the effects of three years of dietary supplementation with calcium and vitamin D on bone mineral density , biochemical measures of bone metabolism , and the incidence of nonvertebral fractures in 176 men and 213 women 65 years of age or older who were living at home . They received either 500 mg of calcium plus 700 IU of vitamin D3 ( cholecalciferol ) per day or placebo .  Bone mineral density was measured by dual-energy x-ray absorptiometry , blood and urine were analyzed every six months , and cases of nonvertebral fracture were ascertained by means of interviews and verified with use of hospital records . RESULTS The mean ( + /-SD ) changes in bone mineral density in the calcium-vitamin D and placebo groups were as follows : femoral neck , + 0.50+/-4.80 and -0.70+/-5.03 percent , respectively ( P=0.02 ) ; spine,+2.12+/-4.06 and + 1.22+/-4.25 percent ( P=0.04 ) ; and total body , + 0.06+/-1.83 and -1.09+/-1.71 percent ( P<0.001 ) . The difference between the calcium-vitamin D and placebo groups was significant at all skeletal sites after one year , but it was significant only for total-body bone mineral density in the second and third years . Of 37 subjects who had nonvertebral fractures , 26 were in the placebo group and 11 were in the calcium-vitamin D group ( P=0.02 ) . CONCLUSIONS In men and women 65 years of age or older who are living in the community , dietary supplementation with calcium and vitamin D moderately reduced bone loss measured in the femoral neck , spine , and total body over the three-year study period and reduced the incidence of nonvertebral fractures BACKGROUND AND PURPOSE It has been demonstrated that bone mass was significantly reduced on the hemiplegic side of stroke patients , which might increase their risk of hip fracture . We evaluated the efficacy of 1 alpha-hydroxyvitamin D3 [ 1 alpha (OH)D3 ] and supplemental elemental calcium in maintaining bone mass and decreasing the incidence of hip fractures after hemiplegic stroke . METHODS In a r and omized study , 64 patients with hemiplegia after stroke with a mean duration of illness of 4.8 years received either 1 microgram 1 alpha (OH)D3 daily ( treatment group , n = 30 ) or an inactive placebo ( placebo group , n = 34 ) for 6 months and were observed for this duration . Both groups received 300 mg of elemental calcium daily . The bone mineral density ( BMD ) and metacarpal index ( MCI ) in the second metacarpals were determined by computed x-ray densitometry . The incidence of hip fractures in these patients was recorded . RESULTS BMD on the hemiplegic side decreased by 2.4 % in the treatment group and 8.9 % in the placebo group ( P = .0021 ) , while BMD on the intact side increased by 3.5 % and decreased by 6.3 % in the treated and placebo groups , respectively ( P = .0177 ) . In the treatment group , the difference in BMD between hemiplegic and nonhemiplegic sides decreased significantly compared with that before r and omization . This difference increased in the placebo group . We observed a similar improvement in MCI in the treatment group but not in the placebo group . Four patients in the placebo group suffered a hip fracture compared with none in the treatment group ( P = .0362 ) . CONCLUSIONS Treatment with 1 alpha (OH)D3 and supplemental elemental calcium can reduce the risk of hip fractures and can prevent further decreases in BMD and MCI on the hemiplegic side of patients with a long-st and ing stroke . Treatment also may improve these indices on the intact side Treatment with 1,25-(OH)2D3 ( calcitriol ) was compared with placebo in a double-blind , r and omized , parallel clinical trial of 24 months ' duration . Subjects were white women with postmenopausal osteoporosis . The study was completed by 15 patients who received placebo and 12 patients who received calcitriol .  Positive slopes were observed in the active treatment group for total body calcium , bone mineral content of the radius , bone mineral density of the lumbar spine , and radiographic absorptiometry of the middle phalanges . In contrast , negative slopes were observed for the bone mineral measurements in the placebo group . Measurement of urinary hydroxyproline and of serum alkaline phosphatase and osteocalcin suggested that the mechanism of action of 1,25-(OH)2D3 involved reduction of bone resorption . Hypercalciuria occurred regularly and preceded hypercalcemia by about 2 weeks . A decline in creatinine clearance was observed in two patients , one of whom had nephrolithiasis on sonography . Calcitriol is effective in preventing bone loss , but must be used with caution Calcitriol was compared with placebo in the treatment of postmenopausal osteoporosis in a double-blind , r and omized , parallel clinical trial of 24 months ' duration . Adjustment was made in dietary calcium to maximize the dose of calcitriol . The study was completed by 15 patients who received placebo and 12 patients who received calcitriol .  The calcitriol group had positive slopes ( compared with negative slopes for the placebo group ) for total body calcium , bone mineral content of the radius , bone mineral density of the lumbar spine , and radiographic absorptiometry of the middle phalanges . The difference between the two groups was statistically significant for each of these measurements . The fracture rate in the treatment group was 250 per 1,000 patient-years as compared with 333 for the placebo group . The mean dose of calcitriol was 0.8 micrograms per day . Hypercalcemia , hypercalciuria , and perhaps nephrolithiasis were observed as complications of treatment . Calcitriol increased bone mineral density by decreasing bone resorption , but not by increasing bone formation . Future studies should concentrate on treatment with oral calcitriol in lower doses . It would also be of interest to examine parenteral administration of calcitriol . It is possible that bone formation can be increased by achieving higher serum levels of the drug , whereas complications may be avoided by using a non-oral route of administration A cross-section of an elderly population was assessed in a double-blind trial for the effects of prophylactic vitamin D. The subjects who completed the trial were assessed clinical ly , by physiotherapy tests of muscle function and by biochemical analysis , before and after a course of vitamin D or placebo . A significant fall in serum phosphate was found in the placebo group but not in the vitamin D group . The fall was maximal between the months of October and March which correspond to maximum and minimum amounts of circulating 25-hydroxy-vitamin D during the year . No difference in muscle function between treated and untreated groups was shown . Two out of 63 individuals on vitamin D  developed hypercalcaemia . It is concluded that , although there appears to be improvement in the phosphate status of treated patients over the short term of this trial , hypercalcaemia after vitamin D administration precludes the continuous prophylactic use of vitamin D at the levels employed in this trial To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results
target: Two regimens , each represented by one large trial , which showed limited evidence of efficacy in reducing the incidence of hip or other appendicular skeleton fractures were : 1 ) Oral Vitamin D when accompanied by calcium supplementation .
  2 ) 1,25 dihydroxy Vitamin D ( calcitriol ) .
  This appeared more effective than calcium in a direct comparison .
  Hypercalcaemia and gastro-intestinal symptoms , reported in less than 5 % of participants , were slightly more common when Vitamin D analogues were taken .
  However , the risk of death was marginally less .
  REVIEW ER 'S CONCLUSIONS Uncertainty remains about the efficacy of regimens which include Vitamin D or its analogues in fracture prevention .
  Particularly if co-supplementation of calcium is required , significant cost differences are likely to exist between regimens .
background: BACKGROUND Due to their known effects on bone metabolism , Vitamin D and related compounds have been proposed for the prevention of osteoporosis and fractures .
  OBJECTIVES To determine the effects of supplementation with Vitamin D or a Vitamin D analogue in the prevention of fractures of the axial and appendicular skeleton in elderly men or women with involutional or post-menopausal osteoporosis .