Prevention of hip fractures by correcting calcium and vitamin D insufficiencies in elderly people. Calcium, vitamin D, milk consumption, and hip fractures: a prospective study among postmenopausal women. Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60. Vitamin K intake and hip fractures in women: a prospective study. Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence 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. Vitamin D Supplementation and Fracture Incidence in Elderly Persons Vitamin A intake and the risk of hip fracture in postmenopausal women: the Iowa Women’s Health Study Vitamin D3 and calcium to prevent hip fractures in elderly women. Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. Smoking, antioxidant vitamins, and the risk of hip fracture. Combined Calcium and Vitamin D3 Supplementation in Elderly Women: Confirmation of Reversal of Secondary Hyperparathyroidism and Hip Fracture Risk: The Decalyos II Study Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Calcium intake influences the association of protein intake with rates of bone loss in elderly men and women. Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study. Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women. Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. Prevention of bone loss and vertebral fractures in patients with chronic epilepsy--antiepileptic drug and osteoporosis prevention trial. Nutritional factors that influence change in bone density and stress fracture risk among young female cross-country runners.
For a 50-year old caucasian woman today , the risk of a hip fracture over her remaining lifetime is about 17 % . Tomorrow the situation will clearly be worse because the continual increase in life expectancy will cause a 3-fold rise in worldwide fracture incidence over the next 60 years , particularly in women , but also in men . In addition , a secular increase in the incidence of hip fractures in individuals of the same age has been noted in both sexes by several investigators , and the cost of hip fractures is expected to dramatically increase in the next decades . Consequently , preventive strategies are urgently required . A great deal has been learned in recent years about the risk factors for hip fracture , the pathophysiology of this fracture , and the prediction of fracture risk , particularly through bone mass measurements on the hip and biochemical evaluations of parathyroid and vitamin D status . The two main determinants of hip fractures are falls and bone loss leading to an intrinsic femoral fragility . A substantial femoral bone loss continues throughout the old age , with a continuous and exponential increase in the risk of hip fracture , and any reduction or arrest of this loss will induce an important reduction in the incidence of hip fractures . A preventive effect on the risk of hip fracture may be partly achieved by using long term estrogen replacement therapy after menopause , but also by using vitamin D and calcium supplements for a late prevention in elderly people .  Vitamin D insufficiency and deficit in calcium intake are very common in elderly people living either in institutions or at home , particularly in Europe where dairy products are not fortified with vitamin D. The cumulative response to this deficit in calcium intake and low vitamin D status is a negative calcium balance which stimulates parathyroid hormone secretion . In 300 residents of nursing homes , we recently found a significant negative correlation between serum 25 OHD and log serum PTH after age-adjustment . In addition , in 446 elderly women living at home in 5 French cities and selected from the voting lists , we also found an age-adjusted relationship between serum 25 OHD and PTH concentrations . This senile secondary hyperparathyroidism is one of the determinants of femoral bone loss and can be reversed by calcium and vitamin D supplements . We have shown in a 3-year controlled prospect i ve study that the daily use of these supplements ( 1.2 g of calcium and 800 IU of vitamin D3 ) given in a large population of 3270 elderly ambulatory women living in nursing homes reduced of 23 % ( intention-to-treat analysis ) the number of hip fractures and other non vertebral fractures . In parallel , serum perathyroid hormone concentration was reduced of 28 % and low serum 25-hydroxyvitamin D concentration returned to normal values . After 18 months of treatment the bone density of the total proximal femoral region had increased 2.7 % the vitamin D3-calcium group and decreased 4.6 % in the placebo group ( p < 0.001 ) . This prevention is safe and can be recommended in people living in institutions . It could be also useful in other elderly subjects particularly at risk because of a low calcium intake , an absence of solar exposure and a previous history of falls . From the data of our study we assessed the economic consequences in terms of medical cost of this prevention . In case of treatment of all women living in nursing homes in France , this would saved FF 150000000 per year , the economic balance of prevention becoming positive as soon as the age of the beginning of the prevention reaches 73.5 years . It is now possible to partly stop bone loss in elderly people and it is never too late to prevent hip fractures with calcium and vitamin D supplements BACKGROUND Short trials of calcium supplementation show that it reduces loss of bone density in postmenopausal women ; longer observational studies do not generally find a lower risk of hip fracture with higher-calcium diets . Fewer studies have focused on vitamin D in preventing postmenopausal osteoporosis or fractures . OBJECTIVE We assessed relations between postmenopausal hip fracture risk and calcium , vitamin D , and milk consumption . DESIGN In an 18-y prospect i ve analysis in 72 337 postmenopausal women , dietary intake and nutritional supplement use were assessed at baseline in 1980 and up date d several times during follow-up . We identified 603 incident hip fractures result ing from low or moderate trauma .  Relative risks ( RRs ) from proportional hazards models were controlled for other dietary and nondietary factors . RESULTS Women consuming > or = 12.5 microg vitamin D/d from food plus supplements had a 37 % lower risk of hip fracture ( RR = 0.63 ; 95 % CI : 0.42 , 0.94 ) than did women consuming < 3.5 microg/d . Total calcium intake was not associated with hip fracture risk ( RR = 0.96 ; 95 % CI : 0.68 , 1.34 for > or = 1200 compared with < 600 mg/d ) . Milk consumption was also not associated with a lower risk of hip fracture ( P for trend = 0.21 ) . CONCLUSIONS An adequate vitamin D intake is associated with a lower risk of osteoporotic hip fractures in postmenopausal women . Neither milk nor a high-calcium diet appears to reduce risk . Because women commonly consume less than the recommended intake of vitamin D , supplement use or dark fish consumption may be prudent It has been reported that vitamin K supplementation effectively prevents fractures and sustains bone mineral density in osteoporosis . However , there are only limited reported data concerning the association between vitamin K nutritional status and bone mineral density ( BMD ) or fractures in Japan . The objectives were to evaluate the association between plasma phylloquinone ( K1 ) or menaquinone ( MK-4 and MK-7 ) concentration and BMD or fracture in Japanese women prospect ively . A total of 379 healthy women aged 30–88 years ( mean age , 63.0 years ) were consecutively enrolled .  Plasma K1 , MK-4 , MK-7 , and serum undercarboxylated osteocalcin ( ucOC ) concentrations , BMD , and incidence of vertebral fractures were evaluated . In stepwise multiple linear regression analyses , L2–4 BMD and a bone turnover marker , log K1 , concentrations were independently correlated with vertebral fracture incidence . When subjects were divided into low and high K1 groups by plasma K1 concentration , the incidence of vertebral fracture in the low K1 group ( 14.4 % ) was significantly higher than that in the high K1 group ( 4.2 % ) , and its age-adjusted RR was 3.58 ( 95 % CI , 3.26–3.93 ) . L2–4 BMD was not different between the two groups . These results suggest that subjects with  vitamin K1 insufficiency in bone have increased susceptibility for vertebral fracture independently from BMD Low vitamin K status is associated with low BMD and increased fracture risk . Additionally , a specific menaquinone , menatetrenone ( MK4 ) , may reduce fracture risk . However , whether vitamin K plays a role in the skeletal health of North American women remains unclear . Moreover , various K vitamers ( e.g. , phylloquinone and MK4 ) may have differing skeletal effects . The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic , postmenopausal , North American women . In this double-blind , placebo-controlled study , 381 postmenopausal women received phylloquinone  ( 1 mg daily ) , MK4 ( 45 mg daily ) , or placebo for 12 mo . All participants received daily calcium and vitamin D(3 ) supplementation . Serum bone-specific alkaline phosphatase ( BSALP ) and n-telopeptide of type 1 collagen ( NTX ) were measured at baseline and 1 , 3 , 6 , and 12 mo . Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo . At baseline , the three treatment groups did not differ in demographics or study endpoints . Compliance with calcium , phylloquinone , and MK4  treatment was 93 % , 93 % , and 87 % , respectively . Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX . No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed . This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy , postmenopausal , North American women receiving calcium and vitamin D supplementation Osteoporosis is a major public health issue leading to significant morbidity , loss of independence and excess loss of life . It has been estimated that 13 to 17 million postmenopausal women have low bone mass or osteoporosis ( 1 , 2 ) . This is associated with almost 1.5 million fractures annually , including 300,000 hip fractures ( 2 , 3 ) . A review of the evidence by Cumming in 1990 ( 4 ) and subsequently published r and omized clinical trials have shown that calcium and /or vitamin D supplements may play a role in the prevention and treatment of osteoporosis by slowing the rates of bone loss in postmenopausal and elderly women ( 5–9 ) . However , there are a limited number of calcium and /or vitamin D trials ( 10–13 ) and observational studies [ review of evidence by Cumming and Nevitt ( 14 ) and Kanis ( 15 ) ] , to support a role for calcium and vitamin D supplementation in the reduction of hip and other fractures . It has also been suggested that calcium and vitamin D supplementation may play a role in the reduction of colorectal cancer incidence ( 16–21 ) . To address these major health concerns of postmenopausal women , the Calcium-Vitamin D ( CaD ) trial of the Women ’s Health Initiative ( WHI ) was design ed to test the primary hypothesis that women who are r and omized to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and secondarily , a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo . The objective of this paper is 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 r and omized , 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 BACKGROUND Vitamin K mediates the gamma-carboxylation of glutamyl residues on several bone proteins , notably osteocalcin . High serum concentrations of undercarboxylated osteocalcin and low serum concentrations of vitamin K are associated with lower bone mineral density and increased risk of hip fracture . However , data are limited on the effects of dietary vitamin K. OBJECTIVE We investigated the hypothesis that high intakes of vitamin K are associated with a lower  risk of hip fracture in women . DESIGN We conducted a prospect i ve analysis within the Nurses ' Health Study cohort . Diet was assessed in 72327 women aged 38 - 63 y with a food-frequency question naire in 1984 ( baseline ) . During the subsequent 10 y of follow-up , 270 hip fractures result ing from low or moderate trauma were reported . RESULTS Women in quintiles 2 - 5 of vitamin K intake had a significantly lower age-adjusted relative risk ( RR : 0.70 ; 95 % CI : 0.53 , 0.93 ) of hip fracture than women in the lowest quintile ( < 109 microg/d ) . Risk did not decrease between quintiles 2 and 5 and risk estimates were not altered when other risk factors for osteoporosis , including calcium and vitamin D intakes , were added to the models . Risk of hip fracture was also inversely associated with lettuce consumption ( RR : 0.55 ; 95 % CI : 0.40 , 0.78 ) for one or more servings per day compared with one or fewer servings per week ) , the food that contributed the most to dietary vitamin K intakes . CONCLUSIONS Low intakes of vitamin K may increase the  risk of hip fracture in women . The data support the suggestion for a re assessment of the vitamin K requirements that are based on bone health and blood coagulation Summary Vitamin K2 may preserve bone strength and reduce fracture risk . In this r and omised double-blind placebo-controlled trial among healthy postmenopausal Norwegian women , 1 year supplementation of vitamin K2 in the form of Natto capsules had no effect on bone loss rates . Introduction Japanese studies indicate that vitamin K2 ( menaquinone-7 ( MK-7 ) ) intake may preserve bone strength , but this has not been documented in Europeans . The aim of this study was to assess the effect of MK-7 on bone mineral density ( BMD ) changes in postmenopausal Norwegian women . Methods Three hundred thirty-four healthy women between 50 and 60 years , 1–5 years after menopause , were recruited to a r and omised double-blind placebo-controlled trial . The participants were r and omly assigned into two groups , one receiving 360 µg MK-7 in the form of Natto capsules and the other the same amount of identical-looking placebo capsules containing olive oil . BMD was measured at total hip , femoral neck , lumbar spine and total body at baseline and 12 months together with serum levels of bone-specific alkaline phosphatase , Crosslaps , total osteocalcin ( N-mid OC ) , carboxylated ( cOC ) and under-carboxylated osteocalcin ( ucOC ) . Results After 12 months , there were no statistical differences in bone loss rates between the groups at the total hip or any other measurement site . Serum levels of cOC increased and ucOC decreased in the treatment versus the placebo group ( p < 0.001 ) . Conclusion MK-7 taken as Natto over 1 year reduced serum levels of ucOC but did not influence bone loss rates in early menopausal women Background Osteoporosis is a major health problem , and the economic burden is expected to rise due to an increase in life expectancy throughout the world . Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk . As vitamin B12 and folate intake and status play a large role in homocysteine metabolism , it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration . Methods / Design The B-PROOF ( B-Vitamins for the PRevention Of Osteoporotic Fractures ) study is a r and omized double-blind placebo-controlled trial . The intervention comprises a period of two years , and includes 2919 subjects , aged 65 years and older , independently living or institutionalized , with an elevated homocysteine concentration ( ≥ 12 μmol/L ) . One group receives daily a tablet with 500 μg vitamin B12 and 400 μg folic acid and the other group receives a placebo tablet . In both tablets 15 μg ( 600 IU ) vitamin D is included . The primary outcome of the study is osteoporotic fractures . Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers , physical performance and physical activity including falls , nutritional intake and status , cognitive function , depression , genetics and quality of life . This large multi-center project is carried out by a consortium from the Erasmus MC ( Rotterdam , the Netherl and s ) , VUmc ( Amsterdam , the Netherl and s ) and Wageningen University , ( Wageningen , the Netherl and s ) , the latter acting as coordinator . Discussion To our best knowledge , the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population . We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013 . The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures . Trial Registration The B-PROOF study is registered with the Netherl and s Trial ( NTR NTR1333 ) and with Clinical Trials.gov ( NCT00696514 ) BACKGROUND 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 . OBJECTIVE 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 . DESIGN r and omised controlled trial . SETTING orthogeriatric rehabilitation ward . METHODS 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 . RESULTS 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 . CONCLUSION 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 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 Excessive intake of vitamin A is postulated to have a detrimental effect on bone by inducing osteoporosis . This may lead to an increased risk of fracture , particularly in persons who are already at risk of osteoporosis . However , few studies have specifically examined the association of vitamin A intake through diet and supplement use , with fractures in a cohort of older , community-dwelling women . We prospect ively followed a cohort of 34,703 postmenopausal women from the Iowa Women ’s Health Study to determine if high levels of vitamin A and retinol intake through food and supplement use were associated with an increased risk of hip or all fractures . A semiquantitative food frequency question naire was used to obtain the participants ’ baseline vitamin A and retinol intake . Participants were followed for a mean duration of 9.5 years for incident self-reported hip and nonhip fractures . After multivariate adjustment , it was revealed that users of supplements containing vitamin A had a 1.18-fold increased risk of incident hip fracture ( n=525 ) compared with nonusers ( 95 % CI , 0.99 to 1.41 ) , but there was no evidence of an increased risk of all fractures ( n=6,502 ) among supplement users . There was also no evidence of a dose-response relationship in hip fracture risk with increasing amounts of vitamin A or retinol from supplements . Furthermore , our results showed no association between vitamin A or retinol intake from food and supplements , or food only , and the risk of hip or all fractures . In conclusion , we found little evidence of an increased risk of hip or all fractures with higher intakes of vitamin A or retinol among a cohort of older , postmenopausal women BACKGROUND 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 . METHODS 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 . RESULTS 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 ) . CONCLUSIONS Supplementation with vitamin D3 and calcium reduces the risk of hip fractures and other nonvertebral fractures among elderly women We attempted to investigate whether vitamin K2 ( menatetrenone ) treatment effectively prevents the incidence of new fractures in osteoporosis . A total of 241 osteoporotic patients were enrolled in a 24-month r and omized open label study . The control group ( without treatment ; n = 121 ) and the vitamin K2-treated group ( n = 120 ) , which received 45 mg/day orally vitamin K2 , were followed for lumbar bone mineral density ( LBMD ; measured by dual-energy X-ray absorptiometry [ DXA ] ) and occurrence of new clinical fractures . Serum level of Glu-osteocalcin ( Glu-OC ) and menaquinone-4 levels were measured at the end of the follow-up period . Serum level of OC and urinary excretion of deoxypyridinoline ( DPD ) were measured before and after the treatment . The background data of these two groups were identical . The incidence of clinical fractures during the 2 years of treatment in the control was higher than the vitamin K2-treated group ( chi2 = 10.935 ; p = 0.0273 ) . The percentages of change from the initial value of LBMD at 6 , 12 , and 24 months after the initiation of the study were -1.8 + /- 0.6 % , -2.4 + /- 0.7 % , and -3.3 + /- 0.8 % for the control group , and 1.4 + /- 0.7 % , -0.1 + /- 0.6 % , and -0.5 + /- 1.0 % for the vitamin K2-treated group , respectively . The changes in LBMD at each time point were significantly different between the control and the treated group ( p = 0.0010 for 6 months , p = 0.0153 for 12 months , and p = 0.0339 for 24 months ) . The serum levels of Glu-OC at the end of the observation period in the control and the treated group were 3.0 + /- 0.3 ng/ml and 1.6 + /- 0.1 ng/ml , respectively ( p < 0.0001 ) , while the serum level of OC measured by the conventional radioimmunoassay ( RIA ) showed a significant rise ( 42.4 + /-6.9 % from the basal value ) in the treated group at 24 months ( 18.2 + /- 6.1 % for the controls;p = 0.0081 ) . There was no significant change in urinary DPD excretion in the treated group . These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures , although the vitamin K2-treated group failed to increase in LBMD . Furthermore , vitamin K2 treatment enhances gamma-carboxylation of the OC molecule Smoking increases the concentrations of free radicals , which have been suggested to be involved in bone resorption . We examined whether the dietary intake of antioxidant vitamins may modify the increased hip fracture risk associated with smoking . We prospect ively studied 66,651 women who were 40 - 76 years of age . Forty-four of the cohort members who sustained a first hip fracture within 2 - 64 months of follow-up ( n = 247 ) and 93 out of 873 age-matched controls were current smokers . Information on diet was obtained by a vali date d food-frequency question naire . The relative risk of hip fracture for current versus never smokers was analyzed in relation to the dietary intake of antioxidant vitamins stratified into two categories ( low/high ) , where median intakes among the controls were used as cut-off points . After adjustment for major osteoporosis risk factors , the odds ratio ( OR ) for hip fracture among current smokers with a low intake of vitamin E was 3.0 ( 95 % confidence interval 1.6 - 5.4 ) and of vitamin C 3.0 ( 1.6 - 5.6 ) . In contrast , the OR decreased to 1.1 ( 0.5 - 2.4 ) and 1.4 ( 0.7 - 3.0 ) with high intakes of vitamin E and C , respectively . This effect was not seen for beta-carotene , selenium , calcium , or vitamin B6 . In current smokers with a low intake of both vitamins E and C , the OR increased to 4.9 ( 2.2 - 11.0 ) . The influence of the intake of these two antioxidant vitamins on hip fracture risk was less pronounced in former smokers . Our results suggest a role for oxidant stress in the adverse effects on the skeleton of smoking , and that an insufficient dietary intake of vitamin E and C may substantially increase the risk of hip fracture in current smokers , whereas a more adequate intake seems to be protective 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 Vitamin K is a cofactor in the production of blood coagulation factors ( in the liver ) , osteocalcin ( in bone ) , and matrix Gla protein ( cartilage and vessel wall ) . Accumulating evidence suggests that for optimal bone and vascular health , relatively high intakes of vitamin K are required . The synthetic short-chain vitamin K(1 ) is commonly used in food supplements , but recently the natural long-chain menaquinone-7 ( MK-7 ) has also become available as an over-the-counter ( OTC ) supplement . The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K(1 ) and MK-7 .  Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity . Both K(1 ) and MK-7 were absorbed well , with peak serum concentrations at 4 hours after intake . A major difference between the 2 vitamin K species is the very long half-life time of MK-7 , result ing in much more stable serum levels , and accumulation of MK-7 to higher levels ( 7- to 8-fold ) during prolonged intake . MK-7 induced more complete carboxylation of osteocalcin , and hematologists should be aware that preparations supplying 50 mug/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinical ly relevant way 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 INTRODUCTION Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3 ) have yielded conflicting results . The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D ( 25-OH D ) , bone turnover markers , bone mineral density ( BMD ) , radius bone loss and incidence of fracture in postmenopausal women . METHODS 669 postmenopausal women ( mean age : 62.2 years ) belonging to a population -based cohort were followed prospect ively for a median of 11.2 years . At baseline , 25-OH D levels , BMD , bone turnover markers and clinical risk factors of osteoporosis were assessed . BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs . RESULTS 73 % and 35 % of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention . 11 % of women had levels below 30 nmol/l . Serum 25-OH D correlated modestly with intact PTH ( r(2)=0.023 , p<0.0001 ) , but not with bone turnover markers or BMD at the hip and radius after adjustment for age . When levels of 25-OH D were considered as a continuous variable , there was no significant association between 25-OH D levels and radius BMD loss or fracture risk . After adjustment for age , there was no significant difference in incidence of fracture , BMD , radius BMD loss , bone turnover markers , grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75 , 50 or 30 nmol/l . CONCLUSIONS In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency , vitamin D status may not be an important determinant of bone health 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 BACKGROUND Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures . Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk . OBJECTIVE This study [ B-vitamins for the PRevention Of Osteoporotic Fractures ( B-PROOF ) ] aim ed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals . DESIGN This was a double-blind , r and omized , placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations ( 12 - 50 μmol/L ) . Participants were assigned to receive daily 500 μg vitamin B-12 plus 400 μg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3 . The primary endpoint was time to first osteoporotic fracture . Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per- protocol principles . RESULTS Osteoporotic fractures occurred in 61 persons ( 4.2 % ) in the intervention group and 75 persons ( 5.1 % ) in the placebo group . Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses ( HR : 0.84 ; 95 % CI : 0.58 , 1.21 ) or per- protocol analyses ( HR : 0.81 ; 95 % CI : 0.54 , 1.21 ) . For persons aged > 80 y , in per- protocol analyses , osteoporotic fracture risk was lower in the intervention group than in the placebo group ( HR : 0.27 ; 95 % CI : 0.10 , 0.74 ) . The total number of adverse events ( including mortality ) did not differ between groups . However , 63 and 42 participants in the intervention and placebo groups , respectively , reported incident cancer ( HR : 1.56 ; 95 % CI : 1.04 , 2.31 ) . CONCLUSIONS These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population . Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged > 80 y. However , treatment was also associated with increased incidence of cancer , although the study was not design ed for assessing cancer outcomes . Therefore , vitamin B-12 plus folic acid supplementation can not be recommended at present for fracture prevention in elderly people . The B-PROOF study was registered with the Netherl and s Trial Register ( trialregister.nl ) as NTR1333 and at clinical trials.gov as NCT00696414 PURPOSE To evaluate whether use of a bisphosphonate ( risedronate ) in addition to calcium and vitamin D in male veterans with epilepsy who were taking antiepileptic drugs ( AEDs ) long term can prevent the loss of bone mass ( BMD , bone mineral density ) associated with AED use compared to patients who were treated with a placebo plus calcium and vitamin D. As a secondary end point we studied the incidence of new morphometric vertebral and nonvertebral fractures . METHODS Antiepileptic drug and osteoporosis prevention trial ( ADOPT ) was design ed as a prospect i ve 2-year double-blind , r and omized placebo controlled study involving 80 male veterans with epilepsy who were being treated with AEDs such as phenytoin , phenobarbital , sodium valproate , or carbamazepine for a minimum of 2 years . All enrolled participants received calcium and vitamin D supplementation , and were r and omized to risedronate or matching placebo .  Total body , bilateral proximal femora , and anteroposterior ( AP ) lumbar spine BMDs in addition to morphometric lateral vertebral assessment s ( LVAs ) were evaluated by a dual energy x-ray absorptiometry ( DXA ) instrument . Comparisons of BMDs were made between baseline , 1 year , and after 2 years of enrollment in the study . The incidence of new vertebral and nonvertebral fractures was secondary end point . KEY FINDINGS Of the 80 patients initially enrolled in the study , 53 patients completed the study . Baseline characteristics of the two groups were similar . At the end of the study , in the placebo plus calcium and vitamin D group , we observed a significant improvement in BMD at any of the evaluated sites when compared to their baseline scans in 69 % ( 18/26 ) of the participants . In the risedronate plus calcium and vitamin D group , we observed significant improvement of BMDs in 70 % ( 19/27 ) of the participants . At the end of the study , the risedronate group experienced a significant increase of BMD at the lumbar spine L1 - 4 ( 1.267 - 1.332 g/cm(2 ) ) , which was significantly larger than that seen in the placebo group ) ( 1.229 g/cm(2 ) vs. 1.245 g/cm(2 ) ; p = 0.0066).There were nonsignificant differences between the two groups regarding changes of total body BMD or at the proximal bilateral femora . Five new vertebral fractures and one nonvertebral fracture were observed only in the placebo group . SIGNIFICANCE Calcium and vitamin D supplementation or calcium and vitamin D supplementation in addition to risedronate improved BMD in more than 69 % of male veterans with epilepsy who were taking AEDs . In the group receiving risedronate plus calcium and vitamin D there was a significant improvement of BMD at the lumbar spine as compared to the placebo group , which also received calcium and vitamin D. The use of risedronate plus calcium and vitamin D prevented the incidence of new vertebral fractures and one nonvertebral fracture in this cohort OBJECTIVE To identify nutrients , foods , and dietary patterns associated with stress fracture risk and changes in bone density among young female distance runners . DESIGN AND SETTING Two-year , prospect i ve cohort study . Observational data were collected in the course of a multicenter r and omized trial of the effect of oral contraceptives on bone health . PARTICIPANTS One hundred and twenty-five female competitive distance runners ages 18 - 26 years . ASSESSMENT OF RISK FACTORS Dietary variables were assessed with a food frequency question naire . MAIN OUTCOME MEASUREMENTS Bone mineral density and content ( BMD/ BMC ) of the spine , hip , and total body were measured annually by dual x-ray absorptiometry ( DEXA ) .  Stress fractures were recorded on monthly calendars , and had to be confirmed by radiograph , bone scan , or magnetic resonance imaging . RESULTS Seventeen participants had at least one stress fracture during follow-up . Higher intakes of calcium , skim milk , and dairy products were associated with lower rates of stress fracture . Each additional cup of skim milk consumed per day was associated with a 62 % reduction in stress fracture incidence ( P < .05 ) ; and a dietary pattern of high dairy and low fat intake was associated with a 68 % reduction ( P < .05 ) . Higher intakes of skim milk , dairy foods , calcium , animal protein , and potassium were associated with significant ( P < .05 ) gains in whole-body BMD and BMC . Higher intakes of calcium , vitamin D , skim milk , dairy foods , potassium , and a dietary pattern of high dairy and low fat were associated with significant gains in hip BMD . CONCLUSIONS In young female runners , low-fat dairy products and the major nutrients in milk ( calcium , vitamin D , and protein ) were associated with greater bone gains and a lower stress fracture rate . Potassium intake was also associated with greater gains in hip and whole-body BMD
This systematic review suggests that supplementation with phytonadione and menaquinone-4 reduces bone loss .
In the case of the latter , there is a strong effect on incident fractures among Japanese patients
BACKGROUND Observational and some experimental data suggest that low intake of vitamin K may be associated with an increased risk of fracture .
OBJECTIVE To assess whether oral vitamin K ( phytonadione and menaquinone ) supplementation can reduce  bone loss  and prevent fractures .