Can Vitamin D Supplementation Reduce the Risk of Fracture in the Elderly? A Randomized Controlled Trial ABSTRACT

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1 JOURNAL OF BONE AND MINERAL RESEARCH Volume 17, Number 4, American Society for Bone and Mineral Research Can Vitamin D Supplementation Reduce the Risk of Fracture in the Elderly? A Randomized Controlled Trial HAAKON E. MEYER, 1,2 GURO B. SMEDSHAUG, 1,2 ELISABETH KVAAVIK, 1,2 JAN A. FALCH, 3 AAGE TVERDAL, 1 and JAN I. PEDERSEN 2 ABSTRACT 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 g of vitamin D 3 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 g of vitamin D 3 alone produced no fracture-preventing effect in a nursing home population of frail elderly people. (J Bone Miner Res 2002;17: ) Key words: frail elderly, hip fracture, osteoporosis, randomized controlled trial, vitamin D INTRODUCTION HIP FRACTURE constitutes a large health problem in the elderly, and nursing home residents are especially prone to these fractures. (1,2) Vitamin D deficiency may be one important contributing risk factor for osteoporotic fracture in old people, partly because of reduced food intake, reduced sun exposure, and a decline in the capacity of producing vitamin D in the skin. (3) The authors have no conflict of interest. In observational studies, low vitamin D intake and status has been associated with increased risk of hip fracture, and intake of cod liver oil has been associated with reduced risk of hip fracture. (4,5) It also has been shown that vitamin D supplementation reduces bone loss from the femoral neck in postmenopausal women. (6,7) However, the effectiveness of vitamin D in the prevention of osteoporotic fractures is not clear. (8) In both a French and an American randomized controlled trial a combined intervention with vitamin D 3 and calcium significantly reduced the number of hip fractures (9) and the number of all nonvertebral fractures, (9,10) 1 National Health Screening Service, Oslo, Norway. 2 Institute for Nutrition Research, University of Oslo, Oslo, Norway. 3 Hormone Laboratory and Department of Internal Medicine, Aker University Hospital, Oslo, Norway. 709

2 710 MEYER ET AL. TABLE 1. BASELINE CHARACTERISTICS OF THE 1144 STUDY PARTICIPANTS Characteristic Control group (n 575) whereas in a Dutch randomized controlled trial supplementation with vitamin D 3 alone did not reveal a protective effect. (11) Further investigation is required to study whether vitamin D alone can prevent osteoporotic fractures. (8) The objective of this randomized controlled trial was to study the effectiveness (8,12) of vitamin D in the prevention of osteoporotic fractures in a population of frail elderly people, that is, would an intervention with 10 g of vitamin D 3 per day lead to reduced rates of hip fracture and all nonvertebral fractures in a large, unselected group of institutionalized elderly people compared with a similar placebo group. We also planned to do subgroup analyses to study the effect of vitamin D supplementation stratified on dietary calcium intake and vitamin D intake at baseline. MATERIALS AND METHODS Subjects (study population) Vitamin D group (n 569) Age (year) a Female (%) Weight (kg) a Height (cm) a BMI (kg/m 2 ) a Calcium intake from milk and cheese (mg) a Vitamin D supplementation (%) b Calcium supplementation (%) At least one fall during the last 3 months (%) Previous hip fracture (%) No Yes Do not know Dependent on gait support (%) No Yes, cane or crutch Wheelchair-user a Mean values SD. b At baseline, usually in the form of a multivitamin supplement. We aimed to include as many as possible of the nursing home residents in two Norwegian cities. Fifty-one out of 106 institutions were able and willing to participate. The participation rate at the individual institution was on average 22.4% and somewhat higher at the wards because, frequently, not all wards at the institutions participated. The study comprised 1144 residents. Mean age at baseline was 84.7 years (SD 7.4 years) and 75% of these were women (Table 1). To be eligible, the residents should have a life expectancy of more than half a year, should not be permanently bedridden, and should not have difficulties in taking medicine. Persons already taking vitamin D supplements (usually in the form of a multivitamin supplement) were included as long as this supplementation did not exceed 10 g/day. We found it unethical to require discontinuation of the supplementation in this population of frail elderly people. However, at the start of the study the use of vitamin D supplements was registered carefully. The study was approved by the regional ethics committee, Norwegian Board of Health and the Data Inspectorate. Oral consent was considered satisfactory for this study with cod liver oil, which has been used as a vitamin supplement in the Norwegian population for decades. As described elsewhere, (13) permission also was given to include mentally impaired persons in the study, a group that constitutes an important part of the nursing home population. Conduct of the trial and supplements The study started up at the different institutions over a 3-year period from autumn After careful instruction, the staff at the institutions included study participants. (13) Lists with all residents who were eligible and willing to participate were returned to the coordinating office. The intended complete record on those not included was not reported in a satisfactory way. Before the study started, the days of the month (1 31 days) were divided randomly into group A and group B, and based on the day of birth, a participant was placed automatically in group A or group B when registered in the study database. The nursing staff was not aware of the details in the allocation procedures. At baseline, a simple questionnaire was filled in for each participant by the nursing staff, including questions concerning calcium intake from cheese and milk, the use of vitamin D and calcium supplements, height and weight, previous hip fracture, fall during the preceding 3 months, and mobility status (use of cane, wheel chair, etc.). Cod liver oil is rich in vitamins D and A. Vitamin D given in oily suspensions generally is considered to be absorbed almost completely. Approximately 80% of this fat-soluble vitamin is incorporated into the chylomicron fraction and absorbed through the lymphatic system. (14) Cod liver oil also is a natural source of very long chain -3 fatty acids. The intervention was ordinary cod liver oil, whereas the placebo was ordinary cod liver oil in which vitamin D had been removed (Peter Møller, avd. av Orkla ASA, Oslo, Norway). Vitamin D was extracted from the cod liver oil using the techniques of bleaching earth, deodorization, and molecular distillation. Because vitamin A also was removed by this process, it was later added in the form of retinyl palmitate to obtain the same levels of vitamin A as in untreated cod liver oil. Retinyl palmitate is the naturally occurring form of vitamin A in cod liver oil. In the cod liver oil in which vitamin D was not removed, the levels of vitamins A and D were controlled by the producer. There were no differences in taste, smell, or color, and the levels of vitamin A, -3 fatty acids, and energy were similar in the two types of cod liver oil. Control analyses of the vitamin content by high-performance liquid chromatography

3 CAN VITAMIN D SUPPLEMENTATION PREVENT FRACTURE 711 showed trace amounts of vitamin D 3 in the treated cod liver oil ( g/ml) compared with 2.2 g/ml in the untreated, that is, a difference of 10 g per 5-ml dose. During the 2 year study period, the intervention group received 5 ml ordinary cod liver oil daily, whereas the control group received 5 ml cod liver oil daily in which vitamin D had been removed. The individual participants either received group A cod liver oil or group B cod liver oil. The study was double-blinded because neither the participants nor the nursing staff or the investigators were aware of which group contained vitamin D. In general, the daily dose of cod liver oil was delivered together with other medicines by the staff. A person from the coordinating office visited each ward several times during the study and had regular contact by telephone. Follow-up All participants were followed with respect to hip fractures, other nonvertebral fractures, and death during the 2-year study period. (13) Only fractures verified via hospital discharge letters or X-ray descriptions were included in the analysis. Follow-up with respect to fractures also was done for withdrawals. At the end of the study, vital status (and date of death when applicable) for all participants was checked in the Norwegian registry of vital statistics. To validate the reporting of hip fractures at the institutions and to ensure a complete follow-up, the computerized discharge registers in all hospitals serving the included institutions were checked against the study database to see if participants were admitted for hip fractures. Unverified hip fractures were confirmed in the participant s medical records at the hospitals. The person responsible for this checking was not otherwise involved in the study and had no knowledge about the study participants. 22 hip fractures were identified in this way, which constitute 22.5% of all identified hip fractures. We were not able to follow 26 participants for all fractures when they moved to other institutions. However, they were followed for hip fracture using hospital registers. When withdrawal occurred, the active-treatment period was from the date at entry to the date of withdrawal. Biochemical measurements Because the Data Inspectorate required written consent from all persons in whom a blood sample was drawn, mentally impaired persons were excluded from this procedure. In general, it was difficult to recruit persons for blood tests, and we ended up with a smaller than intended group, which was on average 2.2 years younger (p 0.02) and had a lower mortality during the study period (p 0.000) compared with the rest. The blood samples were analyzed for 25-hydroxyvitamin D (calcidiol), osteocalcin, parathyroid hormone (PTH), and ionized calcium. All analyses were performed by the Hormone Laboratory, Aker Hospital, Oslo, Norway. The methods are described elsewhere. (15) The blood samples were drawn at baseline and at 1 year after the study started ( 1 month), regardless of whether they still took the treatment or not. Statistical analyses Based on previous studies, (5,13,16) we conservatively estimated that 6% of the nursing home population of Oslo sustained a new hip fracture annually. A sample size of 1113 participants in each group thus would give the study 80% power to detect a reduction in hip fracture incidence by 30% at the 5% significance level. If hip fractures constitute 50% of all nonvertebral fractures in such a population, (9) the study would have similar power to detect a 20% reduction in all nonvertebral fractures. Differences between the two groups in baseline characteristics and in treatment status were tested by the 2 test for categorical variables and by the independent samples t-test for means. Concerning changes in biochemical markers from baseline to year 1, differences between the two groups were tested by the independent samples t-test. In those instances in which the criteria for normal distribution were not fulfilled, the variables were log-transformed, and the significance test was repeated. Because they gave similar results, they were not reported. Two types of fracture endpoints were defined in the protocol: hip fracture (defined as cervical or trochanteric fracture) and all nonvertebral fractures (including hip fracture). The principal analysis of fracture data was made on the intention-to-treat basis (12) using Kaplan-Meier analyses. The two groups were compared by the log-rank test. (12) Unadjusted and multivariate-adjusted hazard rate ratios, in the text called relative risks, were calculated by the Cox proportional hazards regression. In the multivariate model controlling for potential confounding variables, all variables listed in Table 1 except weight and height were included. Censoring of data occurred only for people who died and people lost to follow-up. Because of matching to hospital registers, we had a complete follow-up of hip fracture. Active-treatment analysis also was performed wherein all persons were followed as long as they took the cod liver oil. The two groups were compared by the log-rank test. Finally, an analysis including only the people treated and followed for the whole study period was undertaken, comparing the two groups by the 2 test. The effects of the intervention on fractures and biochemical tests were evaluated before unblinding of the data. In the protocol it also was planned to do subgroup analyses stratifying on total calcium intake from cheese and milk as registered in the questionnaire at the start of the study (higher or lower than median intake of 400 mg/day) and the use of vitamin D supplements at the start of the study (yes/no). People treated for the whole study period were labeled treated for 2 years. This group also includes 34 persons who were included so late that they had not participated for 2 years when the study ended in the summer of RESULTS Five-hundred seventy-five residents were allocated to the control group and 569 residents were allocated to the vitamin D group. There were no statistically significant differ-

4 712 MEYER ET AL. TABLE 2. TREATMENT STATUS (1144 PARTICIPANTS) Control group n (%) Vitamin D group n (%) Treated for 2 years 186 (32.3) 197 (34.6) Cessation of treatment Death a 163 (28.3) 169 (29.7) Other reasons b,c 226 (39.3) 203 (35.7) Total a Treated on average 10.2 months. b Treated on average 9 months. c Reasons for cessation of treatment: no longer wanted to receive the treatment (n 184); the ward discontinued to participate in the study (n 87); the participant stopped taking the treatment because of illness; poor appetite; nausea, etc. (n 117); the participant not taking vitamin D supplements at entry started to take vitamin D supplements during the study (n 7); the participant moved to an other institution (n 26). For 8 persons the exact reason for withdrawal was not stated. ences between the two groups in baseline characteristics (Table 1). Of those included in the study, 383 persons received cod liver oil throughout the study period, 332 persons discontinued the treatment because of death (after an average treatment period of 10.2 months), and 429 persons stopped taking the treatment for a variety of other reasons (after an average treatment period of 9 months; Table 2). Of these 429 persons, 159 died after they had stopped taking the treatment and before end of follow-up. There was no difference in mortality between the control group and the vitamin D group (p 0.87, log-rank test), and there was no significant difference in the proportions who stopped taking the treatment for other reasons and in the proportions who were treated for 2 years. The study participants were followed for 1728 person-years (intention-to-treat), and they received cod liver oil for a period of 1365 person-years or in 79% of the observation time. Results from serum biochemical tests at baseline and after 1 year are shown in Table 3. One-third had a serum concentration of 25-hydroxyvitamin D 30 nmol/liter, and 15% had 20 nmol/liter at baseline. During the first year of the study, persons in the intervention group increased their 25-hydroxyvitamin D concentration by 22 nmol/liter (95% CI, ) compared with the control group. There was no statistical significant difference between the two groups concerning change in serum PTH, serum ionized calcium, or serum osteocalcin. During follow-up, 99 hip fractures were identified in 97 persons and 169 nonvertebral fractures (hip fractures included) were identified in 145 persons. 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 in the control group and 69 persons in the vitamin D group (Table 4). There was no difference in the incidence of hip fracture between the control group and the vitamin D group according to the intention-to-treat analysis (Fig. 1). The relative risk of hip fracture in the vitamin D group versus the control group was 1.09 (95% CI, ), and multivariate adjustment did not change this estimate. Similar results were found for active-treatment analysis (p 0.55, log-rank test) and in the analysis restricted to participants treated for the whole study period (p 0.97, 2 test). There was no effect of the intervention with vitamin D on all nonvertebral fractures (Fig. 1). Thus, the relative risk of any nonvertebral fracture was 0.92 (95% CI, ) in the vitamin D group versus the control group, and multivariate adjustment had negligible effect on the estimate. Similar results were found for active-treatment analysis (p 0.67, log-rank test) and in the analysis restricted to participants treated for the whole study period (p 0.41, 2 test). Concerning hip fracture, subgroup analyses showed that an effect of the intervention with vitamin D was evident neither in those with a higher than median intake (p 0.60, log-rank test) nor in those with a lower than median intake of calcium at baseline (p 0.31, log-rank test). Likewise, there was no effect in those not taking (p 0.18, log-rank test) or in those taking (p 0.30, log-rank test) a vitamin D supplement at the start of the study. Similar results were found for all nonvertebral fractures. For example, in those not taking vitamin D supplements at baseline, 42 persons in the control group and 40 persons in the vitamin D group were identified with any nonvertebral fracture during follow-up, with a corresponding relative risk of 0.93 (95% CI, , vitamin D group vs. control group). DISCUSSION In this study, performed in a population of frail nursing home residents, an intervention with 10 g (400 IU) of vitamin D neither prevented hip fracture nor all nonvertebral fractures. Subgroup analyses stratified on dietary calcium intake and vitamin D intake at baseline gave similar results. Our study is in concert with a large Dutch randomized controlled trial intervening with 10 g of vitamin D/day alone as tablets over years in a somewhat healthier study population than ours (mean age, 80 years; participants living independently, in apartments or homes for the elderly). (11) In contrast to the lack of effect of vitamin D alone reported in these studies, a fracturepreventing effect of an intervention with vitamin D and calcium combined has been reported in a large French randomized controlled trial over 18 months (9) and a smaller American randomized controlled trial over 3 years. (10) The participants in the French study were institutionalized and on average 84 years old, whereas the participants in the American study were on average 71 years old and were living in the community. In both studies, a higher dose of vitamin D was used ( g/day), and the calcium supplementation ranged from 500 to 1200 mg/day. Although it cannot be excluded that the higher vitamin D dose is responsible for these differences, a study in elderly women and men showed that a daily supplementation with 10 g of vitamin D clearly increased 25-hydroxyvitamin D in serum, whereas only a marginal additional effect was seen in those randomized to receive a dose of 20 g/day. (17)

5 CAN VITAMIN D SUPPLEMENTATION PREVENT FRACTURE 713 TABLE 3. SERUM BIOCHEMICAL VALUES IN THE CONTROL GROUP AND VITAMIN DGROUP AT BASELINE AND AFTER 1YEAR A Baseline 1 Year Change (1 year baseline) Serum 25-hydroxyvitamin D (nmol/liter) Control group (n 31) Vitamin D group (n 34) * Serum PTH (pmol/liter) Control group (n 34) Vitamin D group (n 36) Serum ionized calcium (mmol/liter) Control group (n 26) Vitamin D group (n 31) Serum osteocalcin (nmol/liter) Control group (n 33) Vitamin D group (n 35) a Mean values SD. * p for the comparison between the study groups. TABLE 4. NUMBER OF FIRST HIP FRACTURE AND NUMBER OF FIRST NONVERTEBRAL FRACTURE a IN THE 1144 STUDY PARTICIPANTS Control group Vitamin D group Hip fracture b All nonvertebral fractures Radius or ulna 7 3 Proximal humerus 7 8 Hip b Other a In addition, 16 persons had two fractures and 4 persons had three fractures. b Two persons in the control group and 3 persons in the vitamin D group had a fracture other than hip fracture first. Approximately 80% of the participant in our study lived in Oslo, Norway, the city with the highest incidence rates of hip fracture ever reported internationally. (16) It has been estimated that the annual incidence of hip fracture in the nursing home population of Oslo exceeds 7 per 100 per year. (13) The incidence in our study population was 5.9 per 100 per year, which is twice as high as in the Dutch study by Lips et al., (11) and also higher than in the French study by Chapuy et al. (9) In this frail population with a very high risk of fracture, we did not find any effect of the intervention with 10 g of vitamin D. On the other hand, 40% of the participants took vitamin D supplements (usually in the form of multivitamin supplements containing 10 g of vitamin D) at baseline. However, there was no indication of a different effect of the intervention in those not taking supplements compared with those taking supplements at baseline. Previous studies in Oslo, Norway have suggested that poor vitamin D status in the elderly is prevalent and that low vitamin D intake is associated with increased risk of hip fracture. (5,18) On the other hand, a recent study performed in three nursing homes in Oslo, of which two participated in our study, reported a median nutritional intake of vitamin D of 4.5 g/day in women and 5.3 g/day in men, and that additional supplementation with vitamin D was frequent. (19) The serum 25-hydroxyvitamin D concentrations at baseline in our subsample also suggest that serious vitamin D deficiency was not very frequent in our study population. However, because we were not able to take blood tests on a random sample of all participants, we cannot exclude the possibility that the blood test subsample, which was somewhat younger and had lower mortality, had better vitamin D status than the rest of the study population. It also should be added that it might be problematic to compare 25- hydroxyvitamin D levels in this study with other studies because of interlaboratory variation. (20) Serum 25-hydroxyvitamin D increased in the vitamin D group compared with the control group. However, we did not find a corresponding decrease in PTH, and the reason for this can only be speculated on. We did not measure renal function or 1,25-dihydroxyvitamin D, the metabolite acting directly on the parathyroid gland. It was of great importance to design a study that was workable and demanded little extra effort from the nursing staff because much of the practical work was carried out by the employees at the large number of participating institutions. Therefore, the practical procedures were as simple as possible. Because milk and cheese constitute two-thirds of the total calcium intake in an average Norwegian diet, (13) calcium intake was estimated based on a few questions on milk and cheese intake. Therefore, the categorization of the participants into high/low intake might be subject to nondifferential misclassification, which could reduce the effect of calcium in the analyses. Because cod liver oil also contains vitamin A, both the control group and the vitamin D group received vitamin A (0.26 mg/ml). For a long time, it has been suggested that high intake of vitamin A is harmful for skeletal health, and, recently, (after the start of this study) it has been questioned whether an adverse effect also might be present at moder-

6 714 MEYER ET AL. FIG. 1. Cumulative percentage with (A) incident hip fracture and (B) nonvertebral fracture in the control group and in the vitamin D group. Intention-to-treat analyses. ately increased intakes. (21,22) On the other hand, in a recent randomized controlled trial, one group received calcium and vitamin D and the other received calcium and vitamin D as a multivitamin formulation including 0.8 mg of retinol. (23) No difference between the two groups, regarding bone mineral density (BMD) of the spine or hip, was found. In our study, the incidence of hip fracture was lower than the estimated incidence in the general nursing home population, which does not support a deleterious skeletal effect of the supplemented vitamin A. Our method of randomization by day of birth may be defined as quasi-randomization. (8) However, because it was double-blinded which group received the vitamin D cod liver oil, it is difficult to see how our procedure of randomization could introduce selection bias. Concerning concealment of allocation, no judgment was made either by the nursing staff or by anyone at the coordinating office on whether a person should participate or not in light of which group he or she belonged to. The only potentially serious problem concerning our allocation procedure, as far as we see it, was that because of the open grouping of participants, nursing staff, etc. could get the impression that one of the groups was doing better than the other and that such anticipation would lead to different treatment and follow-up. However, usually, the number of participants at each ward was small, making comparison less likely. At the coordinating office, data collection from the institutions and evaluation of fractures were done by different persons. In addition, the identification of fractures via the computerized discharge registers at the hospitals enabled us to validate the recording of hip fractures at the institutions independently. Concerning compliance, the nursing staff was instructed to register when and why a participant stopped taking the treatment. This also was asked for when a person from the coordinating office visited each ward several times during the study. In a survey made at the end of the study at 63 of the participating wards, 95% of the wards stated that the participants had received the treatment regularly. (13) The change in 25-hydroxyvitamin D also indicated an effect of the intervention. Originally, the study was planned to include nursing homes only in Oslo, Norway. In spite of hard effort, the recruitment was lower than anticipated, and the study was expanded to include nursing home residents in Bergen, the second largest city in Norway, and in Lier, a neighboring municipality to Oslo. Even so, our primary goal of including 2250 participants was unrealistic. The closing date for treatment was set to June 30, It could be argued that we might have missed a clinical interesting difference because of reduced power. On the other hand, the lack of any suggestion of effect in this study and in the study from Amsterdam strongly suggests that an intervention with 10 g of vitamin D alone does not have a substantial fracturepreventive effect. It should be added that serious vitamin D deficiency was uncommon in these two study populations, and the results do not rule out the possibility of a fracturepreventing effect of an intervention with vitamin D alone in elderly individuals with poor vitamin D status. In conclusion, in this randomized controlled trial we did not find that an intervention with 10 g of vitamin D over 2 years could prevent hip fracture and other osteoporotic fractures in institutionalized elderly people. ACKNOWLEDGMENTS We thank Thale Briseid and Anne-Marie Aas for their contribution in the preparation of the study, Hilde and Roger Antonsen for contribution in the data collection, Egil Haug who was responsible for the blood analyses, Cathrine Lofthus who checked the computerized discharge registers for hip fracture, and the nursing staff and nursing home residents who participated in the study. The trial was economically supported by Peter Møller, avd. av Orkla ASA, Norwegian Dairies, the City Council of Oslo, and Odd Fellow. Cod liver oil was donated by Peter Møller, avd. av Orkla ASA, Oslo, Norway. REFERENCES 1. Johnell O, Sernbo I 1986 Health and social status in patients with hip fractures and controls. Age Ageing 15:

7 CAN VITAMIN D SUPPLEMENTATION PREVENT FRACTURE Cumming RG 1996 Nursing home residence and risk of hip fracture. Am J Epidemiol 143: Feldman D, Malloy PJ, Gross C 1996 Vitamin D: Metabolism and action. In: Marcus R, Feldman D, Kelsey J (eds.) Osteoporosis. Academic Press, San Diego, CA, USA, pp Falch JA, Mowe M, Bøhmer T, Haug E 1992 Serum levels of intact parathyroid hormone in elderly patients with hip fracture living at home. Acta Endocrinol (Copenh) 126: Meyer HE, Henriksen C, Falch JA, Pedersen JI, Tverdal A 1995 Risk factors for hip fracture in a high incidence area: A case-control study from Oslo, Norway. Osteoporos Int 5: Ooms ME, Roos JC, Bezemer PD, van der Vijgh WJ, Bouter LM, Lips P 1995 Prevention of bone loss by vitamin D supplementation in elderly women: A randomized doubleblind trial. J Clin Endocrinol Metab 80: Dawson-Hughes B, Harris SS, Krall EA, Dallal GE, Falconer G, Green CL 1995 Rates of bone loss in postmenopausal women randomly assigned to one of two dosages of vitamin D. Am J Clin Nutr 61: Gillespie WJ, Henry DA, O Connell DL, Robertson J 1997 Vitamin D and vitamin D analogues in the prevention of fractures in involutional and post-menopausal osteoporosis. In: Gillespie WJ, Madhok R, Swiontkowski M, Robinson CM, Murray GD (eds.) Musculoskeletal Injuries Module of The Cochrane Database of Systematic Reviews. The Cochrane Collaboration, Issue 2. Oxford University Press, London, UK. 9. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, Delmas PD, Meunier PJ 1992 Vitamin D 3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 327: Dawson-Hughes B, Harris SS, Krall EA, Dallal GE 1997 Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 337: Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM 1996 Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 124: Pocock SJ 1991 Clinical Trials. A Practical Approach. John Wiley & Sons, Chichester, UK. 13. Kvaavik E, Meyer HE, Smedshaug GB, Falch JA, Tverdal A, Pedersen JI 2000 The intervention study Prevention of Hip Fractures. Method and implementation. Nor J Epidemiol 10: Holick MF 1998 Vitamin D: Intestinal absorption. In: Shils ME, Olson JA, Shike M (eds.) Modern Nutrition in Health and Disease. Lea & Febiger, Philadelphia, PA, USA, pp Falch JA, Steihaug S 2000 Vitamin D deficiency in Pakistani premenopausal women living in Norway is not associated with evidence of reduced skeletal strength. Scand J Clin Lab Invest 60: Falch JA, Kaastad TS, Bohler G, Espeland J, Sundsvold OJ 1993 Secular increase and geographical differences in hip fracture incidence in Norway. Bone 14: Lips P, Wiersinga A, van Ginkel FC, Jongen MJ, Netelenbos JC, Hackeng WH, Delmas PD, van der Vijgh WJ 1988 The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J Clin Endocrinol Metab 67: Mowe M, Bohmer T, Haug E 1998 Vitamin D deficiency among hospitalized and home-bound elderly. Tidsskr Nor Laegeforen 118: Kvaavik E 1997 En forundrsøkelse til prosjektet Forebyggelse av lårhalsbrudd. Inntak av kalsium og vitamin D på sykehjem i Oslo. Institute for Nutrition Research, University of Oslo, Oslo, Norway. 20. Lips P, Chapuy MC, Dawson-Hughes B, Pols HA, Holick MF 1999 An international comparison of serum 25- hydroxyvitamin D measurements. Osteoporos Int 9: Melhus H, Michaelsson K, Kindmark A, Bergstrom R, Holmberg L, Mallmin H, Wolk A, Ljunghall S 1998 Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 129: Binkley N, Krueger D 2000 Hypervitaminosis A and bone. Nutr Rev 58: Bæksgaard L, Andersen KP, Hyldstrup L 1998 Calcium and vitamin D supplementation increases spinal BMD in healthy, postmenopausal women. Osteoporos Int 8: Address reprint requests to: Haakon Eduard Meyer, M.D., Ph.D. Norwegian Institute of Public Health P.O. Box 4404 Nydalen 0403 Oslo, Norway Received in original form January 2, 2001; in revised form April 9, 2001; accepted June 21, 2001.