HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Early postmenopausal bone loss is prevented by estrogen and partially by 1alpha-OH-vitamin D3: therapeutic effects of estrogen and/or 1alpha-OH-vitamin D3. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study. Treatment of postmenopausal osteoporosis with calcitriol or calcium. 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. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Effect of low-dose calcitriol and calcium therapy on bone histomorphometry and urinary calcium excretion in osteopenic women. Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60. Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Calcitriol in the treatment of postmenopausal osteoporosis. 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. Alfacalcidol reduces the number of fallers in a community-dwelling elderly population with a minimum calcium intake of more than 500 mg daily. Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial. Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women. Long-term effect of nandrolone decanoate, 1 alpha-hydroxyvitamin D3 or intermittent calcium infusion therapy on bone mineral content, bone remodeling and fracture rate in symptomatic osteoporosis: a double-blind controlled study. Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A randomized controlled study. Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design. Amelioration of hemiplegia-associated osteopenia more than 4 years after stroke by 1 alpha-hydroxyvitamin D3 and calcium supplementation. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NONOF) Study. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. Calcitriol treatment is not effective in postmenopausal osteoporosis. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. Superiority of alfacalcidol compared to vitamin D plus calcium in lumbar bone mineral density in postmenopausal osteoporosis. Clinical, biochemical and histological results of a double-blind trial with 1,25-dihydroxyvitamin D3, estradiol and placebo in post-menopausal osteoporosis. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. Effects of the combined use of calcitonin and 1 alpha-hydroxycholecalciferol on vertebral bone loss and bone turnover in women with postmenopausal osteopenia and osteoporosis: a prospective study of long-term and continuous administration with low dose calcitonin. Vitamin D3 and calcium to prevent hip fractures in the elderly women. Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation. Effects of 1 alpha-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis. Calcium plus vitamin D supplementation and the risk of fractures. Postmenopausal osteoporosis: no effect of three years treatment with 1,25-dihydroxycholecalciferol. Amelioration of osteopenia and hypovitaminosis D by 1alpha-hydroxyvitamin D3 in elderly patients with Parkinson's disease. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo-controlled trial. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. The effect of calcitriol on patients with postmenopausal osteoporosis with special reference to fracture frequency. Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation.
We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial.
                A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13,100) were randomized 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 years); (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.
                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-vertebral 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).
                This study is the first prospective 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. A total of 79 Japanese women who were within 5 years of menopause were randomly assigned 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] 1.0 microg/day, conjugated estrogens 0.625 mg/day, a combination of both, or control (no treatment). Lumbar spine and proximal femur bone mineral density (BMD) and biochemical indices were monitored over 2 years. In the 1alpha(OH)D3-treated group, there was a nonsignificant decrease in lumbar spine BMD compared with controls, and no significant loss in the femoral neck compared with controls. In the estrogen-treated group, there was a nonsignificant increase in spine BMD (+2.17% in the first year and +1.71% in the second year), and no loss in femoral neck BMD. The combination of conjugated estrogens +1alpha(OH)D3 was more effective in increasing BMD in the spine (+3. 68% in the first year and +3.63% in the second year) and femur (+2. 56% in the first year and +4.44% in the second year) BMD. There was a significant difference in lumbar spine BMD in both the first and second years between the combination-treated group and the 1alpha(OH)D3-treated and control groups (P < 0.01). Serum osteocalcin (OC) significantly decreased in the combination-treated group (-23.8% in the first year) and the estrogen-treated group (-37. 6% and -41.2% at 6 and 18 months, respectively), and serum alkaline phosphatase (Alp) decreased significantly in the first year in the combination-treated (-31.5%), estrogen-treated (-27.3%), and 1alpha(OH)D3-treated (-7.9%) groups, whereas serum OC increased (+45. 4% in the first year) in women without treatment. The results of this study indicate that early postmenopausal bone loss in the femoral neck is prevented by conjugated estrogens, 1alpha(OH)D3, or both, whereas bone loss in the spine is not prevented by 1alpha(OH)D3. Estrogen proves effective in preventing early postmenopausal bone loss by markedly inhibiting bone turnover. Moreover, a synergistic bone-sparing effect can be expected when estrogen is administered concomitantly with 1alpha(OH)D3 rather than when used alone. 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, randomized, 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) randomized 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. Osteoporosis is a common problem whose management is controversial. To evaluate the efficacy and safety of calcitriol (1,25-dihydroxyvitamin D3) in the treatment of postmenopausal osteoporosis, we conducted a three-year prospective, multicenter, single-blind study in 622 women who had one or more vertebral compression fractures. The women were randomly assigned to receive treatment with calcitriol (0.25 micrograms twice a day) or supplemental calcium (1 g of elemental calcium daily) for three years. New vertebral fractures were detected by means of lateral roentgenography of the spine each year, and calcium absorption was measured in 392 of the women.
                The women who received calcitriol had a significant reduction in the rate of new vertebral fractures during the second and third years of treatment, as compared with the women who received calcium (second year, 9.3 vs. 25.0 fractures per 100 patient-years; third year, 9.9 vs. 31.5 fractures per 100 patient-years; P less than 0.001). This effect was evident only in women who had had five or fewer vertebral fractures at base line (second year, 5.2 vs. 25.3 fractures per 100 patient-years; third year, 4.2 vs. 31.0 fractures per 100 patient-years; P less than 0.0001). The groups also differed significantly in the number of peripheral fractures; 11 such fractures occurred in 11 women in the calcitriol group, whereas 24 occurred in 22 women in the calcium group (P less than 0.05). There was no significant difference between the groups in the incidence of side effects requiring withdrawal of treatment (8.6 percent in the calcitriol group vs. 6.5 percent in the calcium group).
                Continuous treatment of postmenopausal osteoporosis with calcitriol for three years is safe and significantly reduces the rate of new vertebral fractures in women with this disorder. 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. To determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures.
                Prospective, double-blind trial.
                Community setting (Amsterdam and surrounding area).
                2578 persons (1916 women, 662 men) 70 years of age and older (mean age +/- SD, 80 +/- 6 years) living independently, in apartments for elderly persons, or in homes for elderly persons.
                Participants were randomly assigned to receive either vitamin D3, 400 IU in one tablet daily, or placebo for a maximum of 3.5 years.
                Dietary calcium intake and serum 25-hydroxyvitamin D [25(OH)D] were estimated in a subset of participants. During follow-up, attention was concentrated on hip fractures and other peripheral fractures. The maximal follow-up period was 4 years. The results were evaluated by survival analysis.
                Mean dietary calcium intake from dairy products was 868 mg/d. Mean serum 25(OH)D concentration in the third year of the study was 23 nmol/L in the placebo group and 60 nmol/L in the vitamin D group. Median follow-up was 3.5 years, and total follow-up was 8450 patient-years. During follow-up, 306 persons in the placebo group and 282 persons in the vitamin D group died (P = 0.20). Hip fractures occurred in 48 persons in the placebo group and 58 persons in the vitamin D group (P = 0.39, intention-to-treat analysis). Other peripheral fractures occurred in 74 persons in the placebo group and 77 persons in the vitamin D group (P = 0.86).
                Our results do not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation. We evaluated low-dose calcitriol (0.25 microgram b.i.d.) in combination with 1 g of supplemental calcium therapy as treatment for osteopenic women over 60 years of age (n = 4). Control patients (n = 6) received ergocalciferol (50,000 units twice a week) and 1 g of supplemental calcium. Bone biopsies and CT-determined bone mineral density were done initially and after 1 year of therapy. Bone mineral density increased from 77 +/- 18 to 88 +/- 9 mg/ml (NS) in the calcitriol-treated group and from 87 +/- 13 to 112 +/- 30 mg/ml (NS) in the ergocalciferol-treated group. There was also no significant change in bone volume, as determined by bone biopsy in either group. No compression fractures occurred in either treatment group. After 1 year of therapy, urinary calcium excretion was increased significantly above that observed in age-matched untreated women. Creatinine clearance did not change significantly. Hypercalcemia was rare. In summary, we found calcitriol was not superior to ergocalciferol in preventing progressive bone loss and fractures. Both therapies were associated with significant hypercalciuria. Dietary supplements that prevent bone loss at the hip and that can be applied safely in the elderly are likely to reduce hip fractures. A daily dietary supplement of 750 mg calcium or 15 microg 25OH vitamin D3 on bone loss at the hip and other sites, bone turnover and calcium-regulating hormones were studied over 4 yr in elderly volunteers using a randomized, double-blind, placebo-controlled trial. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone structure by radiographs. Calcium biochemistry and bone turnover markers were measured in blood and urine. The 316 women entering the trial had a mean age of 73.7 yr and the 122 men of 75.9 yr. Baseline median calcium intake was 546 mg/day, and median serum 25OH vitamin D3 was 59 nmol/L. On placebo, loss of BMD at total hip was 2% and femoral medulla expansion was 3% over 4 yr. Calcium reduced bone loss, secondary hyperparathyroidism, and bone turnover. 25OH vitamin D3 was intermediate between placebo and calcium. Fracture rates and drop-out rates were similar among groups, and there were no serious adverse events with either supplement. A calcium supplement of 750 mg/day prevents loss of BMD, reduces femoral medullary expansion, secondary hyperparathyroidism, and high bone turnover. A supplement of 15 microg/day 25OH vitamin D3 is less effective, and because its effects are seen only at low calcium intakes, suggests that its beneficial effect is to reverse calcium insufficiency. To assess the comparative effectiveness of several medications on bone mineral density, biochemical bone markers, and the incidence of vertebral fractures in postmenopausal women with osteoporosis.
                A total of 396 postmenopausal women, aged 50 to 75 years, were allocated randomly to six equal-sized groups: hormone replacement therapy, etidronate, eel calcitonin, alfacalcidol, vitamin K (menatetrenone), or control (no treatment). Thoracic and lumbar spine radiographs, bone mineral density at the distal radius, and markers of bone turnover were assessed at baseline and every 3 months during the 2-year study.
                Compared with baseline, the 2-year mean changes in bone mineral density were 2.0% for hormone replacement therapy, -0.5% for etidronate, 1.6% for calcitonin, -3.6% for alfacalcidol, -1.9% for vitamin K, and -3.3% for control. Seventeen (26%) of the 66 control patients developed new vertebral fractures. Compared with controls, the relative risks of vertebral fracture were 0.35 (95% confidence interval [CI]: 0.14 to 0.83) for hormone replacement therapy, 0.40 (95% CI: 0.17 to 0.92) for etidronate, 0.41 (95% CI: 0.17 to 0.93) for calcitonin, 0.56 (95% CI: 0.26 to 1.12) for alfacalcidol, and 0.44 (95% CI: 0.20 to 0.99) for vitamin K.
                We observed significant reductions in the incidence of vertebral fractures with hormone replacement therapy, etidronate, and calcitonin, and significant improvements in bone mineral density with hormone replacement therapy and calcitonin. Calcitriol was compared with placebo in the treatment of postmenopausal osteoporosis in a double-blind, randomized, 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. Osteoporosis in men is an emerging public health problem. As calcitriol reduces the rate of vertebral fractures in osteoporotic postmenopausal women, we conducted a prospective study of this treatment in men with primary osteoporosis. Our study was a 2-yr, randomized, 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. To study the effect of alfacalcidol (1alpha(OH)D3) on fall risk in community-dwelling elderly men and women.
                Randomized, double-blind, placebo-controlled intervention trial.
                Basel, Switzerland.
                Three hundred seventy-eight community-dwelling elderly (191 women/187 men).
                Participants were randomly assigned to receive 1 microg of alfacalcidol or matched placebo daily for 36 weeks.
                Serum 25-hydoxyvitamin D3 (25(OH) D,1,25-dihydroxyvitamin D3 (D-hormone), and intact parathormone (iPTH) levels were measured using radioimmunoassay at baseline and every 12 weeks. Numbers of fallers and falls were assessed using a questionnaire during each study site visit. Dietary calcium intake was assessed at baseline using a food frequency questionnaire.
                At baseline, participants had, on average, normal vitamin D and D-hormone serum levels. Over 36 weeks, alfacalcidol treatment was associated with fewer fallers (odds ratio (OR)=0.69, 95% confidence interval (CI)=0.41-1.16) than placebo. In a post hoc subgroups analysis by medians of total calcium intake, this reduction reached significance in alfacalcidol-treated subjects with a total calcium intake of more than 512 mg/d (OR=0.45, 95% CI=0.21-0.97, P=.042) but not in those who consumed less than 512 mg/d (OR=1.00, 95% CI= 0.47-2.11, P=.998). Alfacalcidol treatment was also, independent of total calcium intake, associated with a significant 37.9% reduction in iPTH serum levels (P<.0001). No cases of clinically relevant hypercalcemia were observed.
                Provided a minimal calcium intake of more than 512 mg/d, alfacalcidol treatment significantly and safely reduces number of fallers in an elderly community dwelling population. 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, methandienone 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 methandienone, 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 methandienone. Ergocalciferol (vitamin D(2)) supplementation plays a role in fall prevention, but the effect in patients living in the community in sunny climates remains uncertain. We evaluated the effect of ergocalciferol and calcium citrate supplementation compared with calcium alone on the risk of falls in older women at high risk of falling.
                A 1-year population-based, double-blind, randomized controlled trial of 302 community-dwelling ambulant older women aged 70 to 90 years living in Perth, Australia (latitude, 32 degrees S), with a serum 25-hydroxyvitamin D concentration of less than 24.0 ng/mL and a history of falling in the previous year. Participants were randomized to receive ergocalciferol, 1000 IU/d, or identical placebo (hereinafter, ergocalciferol and control groups, respectively). Both groups received calcium citrate, 1000 mg/d. Fall data were collected every 6 weeks.
                Ergocalciferol therapy reduced the risk of having at least 1 fall over 1 year after adjustment for baseline height, which was significantly different between the 2 groups (ergocalciferol group, 53.0%; control group, 62.9%; odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). When those who fell were grouped by the season of first fall or the number of falls they had, ergocalciferol treatment reduced the risk of having the first fall in winter and spring (ergocalciferol group, 25.2%; control group, 35.8%; OR, 0.55; 95% CI, 0.32-0.96) but not in summer and autumn, and reduced the risk of having 1 fall (ergocalciferol group, 21.2%; control group, 33.8%; OR, 0.50; 95% CI, 0.28-0.88) but not multiple falls.
                Patients with a history of falling and vitamin D insufficiency living in sunny climates benefit from ergocalciferol supplementation in addition to calcium, which is associated with a 19% reduction in the relative risk of falling, mostly in winter. A double-blind controlled study was performed in 60 patients with symptomatic osteoporosis with at least one vertebral crush fracture, comparing the effect of nandrolone decanoate, 1 alpha-hydroxyvitamin D3 and intermittent calcium infusions. Thirty-four out of 60 patients completed the 2 year observation period. Nandrolone decanoate statistically significantly increased the bone mineral content at the radius, reduced the endosteal bone loss at the metacarpals and statistically significantly reduced urinary calcium and hydroxyproline excretion. Calcium infusions and 1 alpha-hydroxyvitamin D3 inhibited further loss of bone mineral content, but endosteal bone loss continued. In the second year fracture rate was reduced in the nandrolone decanoate groups compared to the two other groups. We conclude that nandrolone decanoate is an active drug for increasing bone mineral content and reducing endosteal bone loss, while 1 alpha-hydroxyvitamin D3 and calcium infusions only stop further bone mineral loss at the radius but do not inhibit endosteal bone loss as measured at the metacarpals and that single photon absorptiometry and radiography are complementary in interpreting cortical bone mineral changes. To study the efficacy of synthetic 1,25 dihydroxyvitamin D3 (calcitriol) in the treatment of osteoporosis.
                Two-year, double-blind, randomized clinical trial.
                University medical center.
                Fifty postmenopausal women with vertebral fractures recruited by referral.
                Calcium intake was adjusted to 25 mmol/d (1000 mg/d) at baseline. Patients were then randomized 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).
                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.
                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. Dietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius.
                The putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age.
                Healthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables.
                Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049).
                These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation. In randomized trials there may be no overriding reason whether or not to have a placebo control.
                We assessed the effects of an open trial design (no placebo and people know what tablets they are given) compared with a blinded, placebo-controlled design on recruitment, compliance and retention within a randomized trial of secondary osteoporotic fracture prevention.
                We undertook a randomized controlled comparison nested within a placebo-controlled trial of nutritional supplementation amongst people aged 70 years or over who had previously sustained a fracture, recruited in a UK teaching hospital. Randomization was 2:1 in favour of the blinded, placebo-controlled trial design.
                From 180 eligible participants randomized to receive information based on the open trial design, 134 (74.4%) consented to take part, compared with 233 (65.1%) of 358 people randomized to the blinded, placebo-controlled design (difference 9.4%, 95% confidence interval 1.3-17.4%). Reluctance to take a placebo and the desire to know tablet allocation were reasons given for not taking part in the blinded, placebo-controlled design. There was no significant difference in tablet compliance. Open trial participants were more likely to remain in the trial for one year (difference 13.9%, 95% confidence interval 3.1-24.6%), mainly reflecting the high retention of the open trial no tablet group compared to the open trial tablet group (difference 23.6%, 95% confidence interval 11.9-35.2%). The odds ratio for reporting an adverse event in the open trial compared to the blinded, placebo-controlled design was 0.64 (95% confidence interval 0.28-1.49), and for reporting a fracture was 0.81 (0.36-1.85).
                We conclude that using an open trial design may enhance participant recruitment and retention and thus improve generalizability and statistical power, but withdrawal rates may differ between the study allocations and may threaten the internal validity of the trial. 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.
                In a randomized 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.
                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 randomization. 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).
                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-standing stroke. Treatment also may improve these indices on the intact side. Elderly people who have a fracture are at high risk of another. Vitamin D and calcium supplements are often recommended for fracture prevention. We aimed to assess whether vitamin D3 and calcium, either alone or in combination, were effective in prevention of secondary fractures.
                In a factorial-design trial, 5292 people aged 70 years or older (4481 [85%] of whom were women) who were mobile before developing a low-trauma fracture were randomly assigned 800 IU daily oral vitamin D3, 1000 mg calcium, oral vitamin D3 (800 IU per day) combined with calcium (1000 mg per day), or placebo. Participants who were recruited in 21 UK hospitals were followed up for between 24 months and 62 months. Analysis was by intention-to-treat and the primary outcome was new low-energy fractures.
                698 (13%) of 5292 participants had a new low-trauma fracture, 183 (26%) of which were of the hip. The incidence of new, low-trauma fractures did not differ significantly between participants allocated calcium and those who were not (331 [12.6%] of 2617 vs 367 [13.7%] of 2675; hazard ratio (HR) 0.94 [95% CI 0.81-1.09]); between participants allocated vitamin D3 and those who were not (353 [13.3%] of 2649 vs 345 [13.1%] of 2643; 1.02 [0.88-1.19]); or between those allocated combination treatment and those assigned placebo (165 [12.6%] of 1306 vs 179 [13.4%] of 1332; HR for interaction term 1.01 [0.75-1.36]). The groups did not differ in the incidence of all-new fractures, fractures confirmed by radiography, hip fractures, death, number of falls, or quality of life. By 24 months, 2886 (54.5%) of 5292 were still taking tablets, 451 (8.5%) had died, 58 (1.1%) had withdrawn, and 1897 (35.8%) had stopped taking tablets but were still providing data for at least the main outcomes. Compliance with tablets containing calcium was significantly lower (difference: 9.4% [95% CI 6.6-12.2]), partly because of gastrointestinal symptoms. However, potentially serious adverse events were rare and did not differ between groups.
                The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people. Randomized 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 randomized controlled trial. Residents from 51 nursing homes were allocated randomly 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 subsample. 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. To determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community.
                Randomised double blind controlled trial of 100 000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every four months over five years.
                2686 people (2037 men and 649 women) aged 65-85 years living in the general community, recruited from the British doctors register and a general practice register in Suffolk.
                Fracture incidence and total mortality by cause.
                After five years 268 men and women had incident fractures, of whom 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population.
                Four monthly supplementation with 100 000 IU oral vitamin D may prevent fractures without adverse effects in men and women living in the general community. 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 randomized double blind, placebo-controlled trial. Women were randomized 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 clinically 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. survivors of hip fracture are at 5- to 10-fold risk of a second hip fracture. There is little consensus about secondary prevention. Many are given calcium and vitamin D, but the evidence supporting this is circumstantial.
                to compare the effects of different calcium and vitamin D supplementation regimens on bone biochemical markers, bone mineral density and rate of falls in elderly women post-hip fracture.
                randomised controlled trial.
                orthogeriatric rehabilitation ward.
                150 previously independent elderly women, recruited following surgery for hip fracture, were assigned to receive a single injection of 300,000 units of vitamin D(2), injected vitamin D(2) plus 1 g/day oral calcium, 800 units/day oral vitamin D(3) plus 1 g/day calcium, or no treatment. Follow-up was one year, with measurement of 25-hydroxyvitamin D, parathyroid hormone, bone mineral density, and falls.
                mean 25-hydroxyvitamin D increased and mean parathyroid hormone was suppressed in all the actively treated groups, more so in the group receiving combined oral vitamin D and calcium. Twenty per cent of participants injected with vitamin D were deficient in 25-hydroxyvitamin D a year later. Bone mineral density showed small but statistically significant differences of up to 4.6% between actively treated groups and placebo. Relative risk of falling in the groups supplemented with vitamin D was 0.48 (95% CI 0.26-0.90) compared with controls.
                Vitamin D supplementation, either orally or with injected vitamin D, suppresses parathyroid hormone, increases bone mineral density and reduces falls. Effects may be more marked with calcium co-supplementation. The 300,000 units of injected vitamin D may not last a whole year. Long-term vitamin D and calcium supplementation is effective in reducing nonvertebral fractures in elderly people. Increased bone fragility caused by secondary hyperparathyroidism (sHPT) and impaired balance are known risk factors for hip fractures. The hypothesis is that short-term therapy with calcium and vitamin D may improve body sway as well as sHPT more effectively than calcium monotherapy. The effects of 8 weeks of supplementation with vitamin D (cholecalciferol) and calcium on body sway and biochemical measures of bone metabolism were measured. The sample consisted of 148 women (mean [+/-SD] age, 74 +/- 1 years) with a 25-hydroxycholecalciferol level below 50 nmol/liter. They received either 1200 mg of calcium plus 800 IU of vitamin D or 1200 mg of calcium per day. We measured intact parathyroid hormone (PTH), markers of bone turnover, and body sway before and after treatment. Falls and fractures among the participants were followed over a 1-year period. Compared with calcium mono, supplementation with vitamin D and calcium resulted in an increase in serum 25-hydroxyvitamin D of 72% (p < 0.0001), a decrease in the serum PTH of 18% ( p = 0.0432), and a decrease in body sway of 9% (p = 0.0435). The mean number of falls per subject during a 1-year follow-up period was 0.45 for the calcium mono group and 0.24 for the calcium and vitamin D group (p = 0.0346). Short-term supplementation with vitamin D and calcium improves sHPT and body sway and therefore may prevent falls and subsequent nonvertebral fractures in elderly women. To determine whether vitamin D supplementation can reduce the incidence of falls and fractures in older people in residential care who are not classically vitamin D deficient.
                Randomized, placebo-controlled double-blind, trial of 2 years' duration.
                Multicenter study in 60 hostels (assisted living facilities) and 89 nursing homes across Australia.
                Six hundred twenty-five residents (mean age 83.4) with serum 25-hydroxyvitamin D levels between 25 and 90 nmol/L.
                Vitamin D supplementation (ergocalciferol, initially 10,000 IU given once weekly and then 1,000 IU daily) or placebo for 2 years. All subjects received 600 mg of elemental calcium daily as calcium carbonate.
                Falls and fractures recorded prospectively in study diaries by care staff.
                The vitamin D and placebo groups had similar baseline characteristics. In intention-to-treat analysis, the incident rate ratio for falling was 0.73 (95% confidence interval (CI)=0.57-0.95). The odds ratio for ever falling was 0.82 (95% CI=0.59-1.12) and for ever fracturing was 0.69 (95% CI=0.40-1.18). An a priori subgroup analysis of subjects who took at least half the prescribed capsules (n=540), demonstrated an incident rate ratio for falls of 0.63 (95% CI=0.48-0.82), an odds ratio (OR) for ever falling of 0.70 (95% CI=0.50-0.99), and an OR for ever fracturing of 0.68 (95% CI=0.38-1.22).
                Older people in residential care can reduce their incidence of falls if they take a vitamin D supplement for 2 years even if they are not initially classically vitamin D deficient. To determine if calcitriol is an effective treatment in postmenopausal osteoporosis.
                Double-blind, randomized clinical trial of 2 years' duration.
                University medical center with patients recruited by media announcements.
                Eighty-six postmenopausal women with vertebral compression fractures.
                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.
                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.
                Calcitriol is not an effective treatment for established postmenopausal osteoporosis. Inadequate dietary intake of calcium and vitamin D may contribute to the high prevalence of osteoporosis among older persons.
                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.
                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).
                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. In a randomized multicenter, double-blind, double-dummy, parallel group study a comparison of the efficacy and safety of 1 microg alfacalcidol to 880 IU vitamin D plus calcium carbonate (1 g calcium) once daily per os was performed on 148 postmenopausal osteoporotic Caucasian patients with normal vitamin D serum levels for 18 months. Bone mineral density (BMD) was measured at baseline, 12 and 18 months. Safety parameters were followed during the entire study period. Sixty-nine (90.8%) in the alfacalcidol group and 67 (93.1%) in the vitamin D group were included in the ITT analysis. Lumbar BMD in the alfacalcidol group increased by 0.017 g/cm2 (2.33%) and 0.021 g/cm2 (2.87%) from baseline (P<0.001) at 12 and 18 months, respectively, whereas in the vitamin D plus calcium group the increase was 0.005 g/cm2 (0.70%) from baseline (N.S.) at both 12 and 18 months. The higher changes from baseline in the alfacalcidol group, as compared to the changes in the vitamin D plus calcium group at both 12 and 18 months, were found to be statistically significant (P=0.018, 0.005). A small increase of mean femoral BMD was achieved in both groups (N.S.). Adverse events were similar in both groups. No significant differences were noted between the groups in serum calcium. In conclusion, alfacalcidol was found to be superior in significantly increasing lumbar BMD as compared to vitamin D plus calcium while safety characteristics were found to be similar in both treatments. Twenty-eight women with postmenopausal osteoporosis were studied in a double-blind trial aimed 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. To assess whether supplementation with calcium and cholecaliferol (vitamin D3) reduces the risk of fracture in women with one or more risk factors for fracture of the hip.
                Pragmatic open randomised controlled trial.
                Practice nurse led clinics in primary care.
                3314 women aged 70 and over with one or more risk factors for hip fracture: any previous fracture, low body weight (< 58 kg), smoker, family history of hip fracture, or fair or poor self reported health.
                Daily oral supplementation using 1000 mg calcium with 800 IU cholecaliferol and information leaflet on dietary calcium intake and prevention of falls, or leaflet only (control group).
                Primary outcome measure was all clinical fractures and secondary outcome measures were adherence to treatment, falls, and quality of life (measured with the SF-12).
                69% of the women who completed the follow-up questionnaire at 24 months were still taking supplements (55% with inclusion of randomised participants known to be alive). After a median follow-up of 25 months (range 18 to 42 months), clinical fracture rates were lower than expected in both groups but did not significantly differ for all clinical fractures (odds ratio for fracture in supplemented group 1.01, 95% confidence interval 0.71 to 1.43). The odds ratio for hip fracture was 0.75 (0.31 to 1.78). The odds of a woman having a fall at six and 12 months was 0.99 and 0.98, respectively. Quality of life did not significantly differ between the groups.
                We found no evidence that calcium and vitamin D supplementation reduces the risk of clinical fractures in women with one or more risk factors for hip fracture. Registration ISRCTN26118436, controlled trials registry. The present study investigates the effect of long-term and continuous treatment with low dose calcitonin in combination with 1 alpha-hydroxycholecalciferol on vertebral bone mass in early postmenopausal women.
                A total of 202 postmenopausal women between 53 and 58 years of age were recruited individually and randomly assigned to one of four groups. Comparisons were made among groups of women receiving calcitonin alone (10 IU i.m. twice a month), 1 alpha-hydroxycholecalciferol alone (0.5 microg orally twice daily), a combination of the above two agents, or no treatment. Bone mineral density (BMD) of lumber spine (L2-4) was determined using Dual Energy X-ray Absorptiometry. The study was carried out prospectively over a 2-year period.
                We observed a significant increase in vertebral bone mass in the combined treatment regimen of calcitonin and 1 alpha-hydroxycholecalciferol (3.44% at 12 months in the combination group vs 1.40,0.92, and -0.70% in the calcitonin alone, 1 alpha-hydroxycholecalciferol alone, and control groups, respectively; 4.51% at 24 months in the combination group vs 2.21,1.04, and -3.61% in the calcitonin alone, 1 alpha-hydroxycholecalciferol alone, and control groups, respectively). Serum PTH, osteocalcin levels and alkaline phosphatase activity decreased significantly within 12 months whereas urinary pyridinoline/creatinine ratio decreased at 24 months in the combination group. We observed mild adverse effects in 25.0% (7/28) and 30.0% (6/20) of combination regimen and calcitonin treatment cases, respectively.
                The results of the study suggest that the combination treatment regimen increased vertebral bone loss in early postmenopausal women to a greater extent than did calcitonin alone or 1 alpha-hydroxycholecalciferol alone. Hypovitaminosis D and a low calcium intake contribute to increased parathyroid function in elderly persons. Calcium and vitamin D supplements reduce this secondary hyperparathyroidism, but whether such supplements reduce the risk of hip fractures among elderly people is not known.
                We studied the effects of supplementation with vitamin D3 (cholecalciferol) and calcium on the frequency of hip fractures and other nonvertebral fractures, identified radiologically, in 3270 healthy ambulatory women (mean [+/- SD] age, 84 +/- 6 years). Each day for 18 months, 1634 women received tricalcium phosphate (containing 1.2 g of elemental calcium) and 20 micrograms (800 IU) of vitamin D3, and 1636 women received a double placebo. We measured serial serum parathyroid hormone and 25-hydroxyvitamin D (25(OH)D) concentrations in 142 women and determined the femoral bone mineral density at base line and after 18 months in 56 women.
                Among the women who completed the 18-month study, the number of hip fractures was 43 percent lower (P = 0.043) and the total number of nonvertebral fractures was 32 percent lower (P = 0.015) among the women treated with vitamin D3 and calcium than among those who received placebo. The results of analyses according to active treatment and according to intention to treat were similar. In the vitamin D3-calcium group, the mean serum parathyroid hormone concentration had decreased by 44 percent from the base-line value at 18 months (P < 0.001) and the serum 25(OH)D concentration had increased by 162 percent over the base-line value (P < 0.001). The bone density of the proximal femur increased 2.7 percent in the vitamin D3-calcium group and decreased 4.6 percent in the placebo group (P < 0.001).
                Supplementation with vitamin D3 and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women. To determine whether vitamin D supplementation reduces the risk of fracture or falls in elderly people in care home accommodation.
                A randomised controlled trial of cluster design.
                223 Residential units (mainly identical 30-bedded units), within 118 homes for elderly people throughout Britain, with 3,717 participating residents (76% women, average age 85 years). The units provided mainly or entirely residential care (35% of residents), nursing care (42%) or care for elderly mentally infirm (EMI) residents (23%).
                Participants were randomly allocated by residential unit (cluster design) to a treated group offered ergocalciferol 2.5 mg every 3 months (equivalent to a daily dose of 1,100 IU), or to a control group. Fractures were reported by staff and confirmed in hospital, and routinely collected data on reported falls were obtained.
                After median follow-up of 10 months (interquartile range 7-14 months), 64 (3.6%) of 1,762 vitamin D-treated residents and 51 (2.6%) of 1,955 controls had one or more non-vertebral fractures, and 24 (1.3%) and 20 (1.0%), respectively, had a hip fracture. The proportion reporting at least one fall was 44% in vitamin D-treated and 43% in control residents. The differences between the vitamin D and control groups were not statistically significant. The incidence of all non-vertebral fractures in the care homes (3.2% per year) and of hip fractures (1.1% per year) was low, similar to rates in elderly people in sheltered accommodation, and the pre-treatment serum 25-hydroxy vitamin D concentration was high [median 47 nmol/l, measured in a 1% (n = 18) sample].
                We found no evidence that vitamin D prevents fractures or falls in elderly people in care home accommodation. The effects of 1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] on bone mineral density, fracture incidence, and bone metabolism were evaluated by a double-blind, placebo-controlled study. Eighty postmenopausal osteoporotic Japanese women (71.9 +/- 7.3 years, mean +/- SD) were randomly assigned to 1 microgram of 1 alpha(OH)D3 daily or inactive placebo for 1 year. All patients were given supplemental calcium (300 mg of elemental calcium daily). Lumbar (L2-L4) bone mineral density (BMD) determined by dual energy X-ray absorptiometry increased 0.65% with 1 alpha(OH)D3 treatment and decreased 1.14% with placebo (P = 0.037). BMD in both the femoral neck and Ward's triangle did not yield any significant differences between the two groups, whereas trochanter BMD in the 1 alpha(OH)D3-treated group increased 4.20% and decreased 2.37% with placebo (P = 0.055). X-ray analysis demonstrated that new vertebral fractures occurred in two patients with 1 alpha(OH)D3 and in seven patients with placebo. The vertebral fracture rate in the treated group was significantly less (75/1000 patient years) than in the control group (277/1000 patient years; P = 0.029). Hypercalcemia (12.1 mg/100 ml) occurred in one patient receiving 1 alpha(OH)D3; however, the serum calcium level in this patient promptly decreased to the reference range after cessation of the treatment. There were no significant changes in serum creatinine level in either group. A significant increase in urinary excretion of calcium was found but there was no significant change in urinary excretion of hydroxyproline in the treated group. The serum level of bone-derived alkaline phosphatase activity significantly decreased by -26 +/- 26 (mU/ml) after the treatment (P = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS) The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal.
                We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental [corrected] calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers.
                Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels.
                Among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones. (ClinicalTrials.gov number, NCT00000611.).
                Copyright 2006 Massachusetts Medical Society The therapeutic effect of 1,25-dihydroxycholecalciferol (1,25(OH)2D3) in postmenopausal osteoporosis was tested in a single blind, randomized prospective 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. 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 1alpha-hydroxyvitamin D3 (1alpha(OH)D3; an active form of vitamin D) was evaluated for maintaining bone mass and reducing the incidence of hip and other nonvertebral fractures in patients with Parkinson's disease.
                In a double blind, randomised trial, 86 elderly patients with Parkinson's disease (mean Hoehn and Yahr stage, 3; mean age 70.6 years) were randomised to receive either 1 microg 1alpha(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 nonvertebral fractures was recorded.
                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).
                By increasing serum 1, 25-[OH]2D concentrations, treatment with 1alpha(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. Low trauma fractures in older people incur enormous physical, social and economic costs. Previous research indicates that an annual intramuscular injection of vitamin D may reduce fracture rates in this group. This strategy requires validation in a population setting.
                Randomized, double-blind, placebo-controlled trial of 300,000 IU intramuscular (i.m.) vitamin D2 (ergocalciferol) injection or matching placebo every autumn over 3 years. 9440 people (4354 men and 5086 women) aged 75 yrs and over were recruited from general practice registers in Wessex, England. Primary outcome measure was all non-vertebral fracture. Secondary outcomes were hip and wrist fractures, and all falls.
                585 subjects had incident non-spine fractures (hip 110, wrist 116, ankle 37). Hazard ratios (HRs) for fracture in the vitamin D group were: 1.09 [95% confidence interval (CI) 0.93-1.28, P = 0.29] for any first fracture, 1.49 (95% CI 1.02-2.18, P = 0.04) for hip and 1.22 (95% CI 0.85-1.76, P = 0.28) for wrist. There was no effect on falls: HR 0.98 (0.93-1.04). No protective effect was observed in any subgroup when the cohort was stratified by sex, age, previous fracture or mobility.
                An annual i.m. injection of 300,000 IU vitamin D2 is not effective in preventing non-vertebral fractures among elderly men and women resident in the general population. Specific receptors for vitamin D have been identified in human muscle tissue. Cross-sectional studies show that elderly persons with higher vitamin D serum levels have increased muscle strength and a lower number of falls. We hypothesized that vitamin D and calcium supplementation would improve musculoskeletal function and decrease falls. In a double-blind randomized controlled trial, we studied 122 elderly women (mean age, 85.3 years; range, 63-99 years) in long-stay geriatric care. Participants received 1200 mg calcium plus 800 IU cholecalciferol (Cal+D-group; n = 62) or 1200 mg calcium (Cal-group; n = 60) per day over a 12-week treatment period. The number of falls per person (0, 1, 2-5, 6-7, >7 falls) was compared between the treatment groups. In an intention to treat analysis, a Poisson regression model was used to compare falls after controlling for age, number of falls in a 6-week pretreatment period, and baseline 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations. Among fallers in the treatment period, crude excessive fall rate (treatment - pretreatment falls) was compared between treatment groups. Change in musculoskeletal function (summed score of knee flexor and extensor strength, grip strength, and the timed up&go test) was measured as a secondary outcome. Among subjects in the Cal+D-group, there were significant increases in median serum 25-hydroxyvitamin D (+71%) and 1,25-dihydroxyvitamin D (+8%). Before treatment, mean observed number of falls per person per week was 0.059 in the Cal+D-group and 0.056 in the Cal-group. In the 12-week treatment period, mean number of falls per person per week was 0.034 in the Cal+D-group and 0.076 in the Cal-group. After adjustment, Cal+D-treatment accounted for a 49% reduction of falls (95% CI, 14-71%; p < 0.01) based on the fall categories stated above. Among fallers of the treatment period, the crude average number of excessive falls was significantly higher in the Cal-group (p = 0.045). Musculoskeletal function improved significantly in the Cal+D-group (p = 0.0094). A single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49% compared with calcium alone. Over this short-term intervention, recurrent fallers seem to benefit most by the treatment. The impact of vitamin D on falls might be explained by the observed improvement in musculoskeletal function. nan Osteoporotic fractures in older people are a major and increasing public health problem. We examined the effect of vitamin D supplementation on fracture rate in people living in sheltered accommodation.
                In a pragmatic double blind randomised controlled trial of 3 years duration, we examined 3,440 people (2,624 women and 816 men) living in residential or care home. We used four-monthly oral supplementation using 100,000 IU vitamin D(2) (ergocalciferol). As a main outcome measure, we used the incidence of first fracture using an intention to treat analysis. This was a multicentre study in 314 care homes or sheltered accommodation complexes in South Wales, UK.
                The vitamin D and placebo groups had similar baseline characteristics. In intention-to-treat analysis, 205 first fractures occurred in the intervention group during a total of 2,846 person years of follow-up (7 fractures per 100 people per year of follow-up), with 218 first fractures in the control group over 2,860 person years of follow-up. The hazard ratio of 0.95 (95% confidence interval 0.79-1.15) for intervention compared to control was not statistically significant.
                Supplementation with four-monthly 100,000 IU of oral vitamin D(2) is not sufficient to affect fracture incidence among older people living in institutional care.
Frail older people confined to institutions may sustain fewer hip fractures if given vitamin D with calcium. Vitamin D alone is unlikely to prevent fracture. Overall there is a small but significant increase in gastrointestinal symptoms and renal disease associated with vitamin D or its analogues. Calcitriol is associated with an increased incidence of hypercalcaemia.