Background Although studies in animals and epidemiologic studieshave indicated that a high vitamin A intake is associated withincreased bone fragility, no biologic marker of vitamin A statushas thus far been used to assess the risk of fractures in humans.
Methods We enrolled 2322 men, 49 to 51 years of age, in a population-based,longitudinal cohort study. Serum retinol and beta carotene wereanalyzed in samples obtained at enrollment. Fractures were documentedin 266 men during 30 years of follow-up. Cox regression analysiswas used to determine the risk of fracture according to theserum retinol level.
Results The risk of fracture was highest among men with thehighest levels of serum retinol. Multivariate analysis of therisk of fracture in the highest quintile for serum retinol (>75.62µg per deciliter [2.64 µmol per liter]) as comparedwith the middle quintile (62.16 to 67.60 µg per deciliter[2.17 to 2.36 µmol per liter]) showed that the rate ratiowas 1.64 (95 percent confidence interval, 1.12 to 2.41) forany fracture and 2.47 (95 percent confidence interval, 1.15to 5.28) for hip fracture. The risk of fracture was furtherincreased within the highest quintile for serum retinol. Menwith retinol levels in the 99th percentile (>103.12 µgper deciliter [3.60 µmol per liter]) had an overall riskof fracture that exceeded the risk among men with lower levelsby a factor of seven (P<0.001). The level of serum beta carotenewas not associated with the risk of fracture.
Conclusions Our findings, which are consistent with the resultsof studies in animals, as well as in vitro and epidemiologicdietary studies, suggest that current levels of vitamin A supplementationand food fortification in many Western countries may need tobe reassessed.
Vitamin A in high doses stimulates bone resorption and inhibitsbone formation. These effects are demonstrated by in vitro dataand by the occurrence of spontaneous fractures in studies inanimals.1 In addition, a high dietary intake of vitamin A increasesthe risk of skeletal deformities in human fetuses.2 There aresubstantial differences among countries in the average dietaryintake of vitamin A. In a study of dietary patterns in Europe,the intake of vitamin A in Scandinavia was up to six times ashigh as the intake in southern Europe.3 The risk of a hip fracturein a Swedish man is approximately twice that in a woman in Englandor the Netherlands4 — an observation that cannot readilybe explained by lifestyle, genetic factors, climate, or longevity.4,5Three reports — one by us6 and two by groups in the UnitedStates7,8 — have indicated an increased risk of hip fracture6,7and low bone density6,8 in women with a high dietary intakeof vitamin A, though one study also reported increased boneloss at low levels of intake.8 However, biologic markers ofretinol status have so far not been evaluated with respect tothe risk of fracture. We used data from a longitudinal, population-basedcohort study to investigate the relation between serum retinollevels and the subsequent risk of fracture among men.
Methods
From 1970 to 1973, we invited all 2841 men born between 1920and 1924 and living in the municipality of Uppsala, Sweden,to participate in a health survey, the Uppsala LongitudinalStudy of Adult Men. A total of 2322 men (82 percent) agreedto participate. The base-line evaluation included a medicaland lifestyle questionnaire and interview, tests of serum samplesobtained after an overnight fast, and anthropometric measurements.9,10At 60 years of age, 1860 men (80 percent of the total cohort)took part in a second evaluation, and at 70 years, 1221 men(53 percent) took part in a third evaluation.
Serum Analyses
In 1986, we measured retinol and beta carotene levels in serumsamples that had been obtained at base line from 2047 subjectsand stored in liquid nitrogen at –196°C. The serumwas protected from light and was not thawed before analysis.Measurements were performed with the use of high-performanceliquid chromatography (with an octadecyl silica column and amethanol mobile phase11). The light absorption of the compoundswas measured with a diode-array detector at a wavelength of305 nm for retinol (coefficient of variation, 3.1 percent) and460 nm for beta carotene (coefficient of variation, 6.5 percent).Retinol remains stable for at least 15 years, especially whenstored at a temperature of –70°C or lower.12 In afive-year study, with annual measurement of serum retinol, theaverage level varied by less than 10 percent throughout thestudy period.13
Serum calcium, albumin, creatinine, cholesterol, and triglycerides,as well as the erythrocyte sedimentation rate, were analyzedby standard methods between 1970 and 1973.10 A blood samplewas obtained for measurement of -glutamyltransferase in a subgroupof 777 participants between 1980 and 1983, and another bloodsample was obtained for aspartate aminotransferase and alanineaminotransferase measurements in 1189 men between 1990 and 1993.
Dietary Assessment
We performed a dietary assessment in a subgroup of 1138 men,using a seven-day dietary record, in conjunction with the thirdevaluation (between 1990 and 1993). The daily intake of calories,vitamin A, and alcohol was calculated with the use of a database from the Swedish National Food Administration. Informationabout vitamin A–containing supplements, including thetype of preparation and the dose but not the duration of use,was also collected.
Matching to National Registers
All hospital admissions in the Uppsala health care region havebeen reported to the Hospital Discharge Register since 1965,and since 1987 this register has covered all public inpatientcare in Sweden. The register is updated yearly and has a highvalidity for identifying cases of fracture.14 The Uppsala LongitudinalStudy of Adult Men cohort has been matched to this registerevery year for all diagnoses, with the use of personal identificationnumbers, which are given to all inhabitants of Sweden. We alsolinked the subjects to national census data bases for 1960,1970, 1980, and 1990, which enabled us to categorize the participantsaccording to socioeconomic status.
Identification of Cases of Fracture
We sought to identify all fractures that occurred in study participantsafter enrollment. We matched the study cohort to the HospitalDischarge Register to identify cases treated on an inpatientbasis. All orthopedic records at the local hospitals in areaswhere the participants in the initial investigation residedwere reviewed to identify fractures according to the type andcircumstances of the injury. Fractures were also confirmed bylinkage, with use of the personal identification number, toradiographic records and county outpatient registries. We excludedseven cases of fracture caused by metastatic cancer.
Statistical Analysis
We used Cox proportional-hazards models to estimate rate ratios,with 95 percent confidence intervals calculated as measuresof association. For each man, the number of years of follow-upwas calculated from the date of enrollment (i.e., the date ofthe first investigation) until the date of a first fracture,the date of death (in the case of 989 participants), the dateof a move from the county of residence (in the case of 130 men),or the end of the follow-up period (December 31, 2001). Datesof deaths and of moves were based on data from the continuouslyupdated Swedish National Population Register.
Serum retinol levels were evaluated both as a continuous variableand as a categorical variable, in quintiles. Separate analyseswere performed for fractures specifically designated as osteoporotic(i.e., fractures of the hip, pelvis, spine, distal forearm,and proximal humerus).15 The results were similar whether ornot we included the seven cases of fracture due to suspectedhigh-impact trauma, and these cases were therefore retainedin the analyses. The nonlinear risk in the highest quintileof the retinol level was determined by inclusion of retinolas a quadratic term in the model together with retinol as acontinuous variable. We then estimated the trend in the riskof fracture by a restricted cubic-spline Cox regression analysis16with eight "knots" (serum retinol percentiles 1, 5, 20, 40,60, 80, 95, and 99), which enabled us to investigate extremeretinol values. The results of this analysis are presented assmoothed plots with 95 percent confidence intervals for boththe overall risk of fracture and the risk of hip fracture.
We considered two separate models: a univariate model and amultivariate model. Age, weight, height, serum beta carotene,serum calcium, and serum albumin at enrollment in the studywere included as continuous variables. For smoking status atbase line, the men were categorized as never having smoked,as former smokers, or as current smokers. Marital status atbase line was categorized as married (or living with a partner)or single. Social class, physical activity at work, and leisurephysical activity were all evaluated in three categories. TheMichigan Alcoholism Screening Test17 was used at the secondevaluation (at 60 years of age) to identify cases of alcoholabuse; the answers were used to categorize alcohol use as none,normal use, or suspected dependence. The estimates remainedsimilar when we also included cholesterol, triglycerides, creatinine,the sedimentation rate, tocopherol (all at the age of 50 years),-glutamyltransferase (at the age of 60 years), and aspartateaminotransferase, alanine aminotransferase, dietary energy intake,and alcohol intake (all at the age of 70 years) in the model.Consequently, these variables were omitted from the reportedanalyses. We further modeled the association between dietaryvitamin A intake in quintiles, estimated according to the reportedintake at the age of 70 years, and the subsequent risk of fracture.
Results
Characteristics of the participants according to the quintilefor serum retinol are shown in Table 1. There was a tendencytoward higher weight and body-mass index as well as higher serumlipid values in higher quintiles for serum retinol. Serum calciumand alcohol consumption as estimated on the basis of the MichiganAlcoholism Screening Test were also positively associated withserum retinol (data not shown). During a total of 56,281 person-yearsof observation, 266 men had one or more fractures (Table 2),and data on serum retinol were available for 241 of them. Theaverage follow-up was 24 years, with a median of 24 years forsubjects with fractures and 29 years for those without fractures.
Table 2. Type and Number of Fractures in the 2322 Study Participants.
The overall risk of fracture increased by 26 percent for everyincrease of 1 SD in serum retinol (multivariate rate ratio,1.26; 95 percent confidence interval, 1.13 to 1.41) (Table 3).The corresponding rate ratio was 1.38 (95 percent confidenceinterval, 1.13 to 1.69) for subjects with two or more fracturesduring follow-up. However, a Wald chi-square test indicateda nonlinear association (P=0.02). The increment was thus mainlyconcentrated in the highest quintile for retinol: multivariaterate ratio for any fracture, as compared with the middle quintile,1.64 (95 percent confidence interval, 1.12 to 2.41) (Table 3),with an estimated population attributable risk of 12 percent.For fractures at sites that are typical of osteoporotic fractures(accounting for 79 percent of all the fractures), the multivariaterate ratio was 1.78 (95 percent confidence interval, 1.17 to2.70). When we restricted the analysis to all fractures in thefirst 20 years of follow-up, the risk was slightly higher inthe highest quintile (multivariate rate ratio, 2.18; 95 percentconfidence interval, 1.14 to 4.16). For hip fractures, the multivariaterate ratio for the highest quintile as compared with the thirdquintile was 2.47 (95 percent confidence interval, 1.15 to 5.28)(Table 3). The serum beta carotene level was not associatedwith the risk of fracture: multivariate rate ratio per 1 SDincrease, 0.95 (95 percent confidence interval, 0.81 to 1.11).
Table 3. Rate Ratio for Any Fracture and for Hip Fracture, According to the Base-Line Serum Retinol Level.
The risk of fracture was further increased in the highest quintilefor serum retinol (P=0.06 for a quadratic term of retinol).With the median value of 64.74 µg per deciliter (2.26µmol per liter) as the reference value, there was an especiallysteep rise in the rate-ratio curve for men with serum levelsabove the 95th percentile (i.e., 88.80 µg per deciliter[3.1 µmol per liter]) (Figure 1). These crude estimateswere not substantially altered after multivariate adjustment.A complementary analytic approach showed that the subjects withretinol levels in the 99th percentile (i.e., >103.12 µgper deciliter [3.60 µmol per liter]) had an overall riskof fracture that was seven times the risk among those with lowerlevels (univariate rate ratio, 6.85 [95 percent confidence interval,3.38 to 13.90]; multivariate rate ratio, 7.14 [95 percent confidenceinterval, 3.43 to 14.86]; P<0.001). Analysis of the riskof hip fractures showed a pattern similar to that for the overallrisk of fracture: a small increase in the risk ratio betweenthe 80th and 95th percentiles for serum retinol and a substantialincrease in the highest percentiles (Figure 2).
Figure 1. Smoothed Plot of Rate Ratios for Any Fracture According to the Serum Retinol Level.
The rate ratios (solid line) and 95 percent confidence intervals (dotted lines) were estimated by restricted cubic-spline Cox regression analysis, with the median serum retinol level, 2.26 µmol per liter, as the reference value. To convert the values for retinol to micrograms per deciliter, divide by 0.03491.
Figure 2. Smoothed Plot of Rate Ratios for Hip Fracture According to the Serum Retinol Level.
The rate ratios (solid line) and 95 percent confidence intervals (dotted lines) were estimated by restricted cubic-spline Cox regression analysis, with the median serum retinol level, 2.26 µmol per liter, as the reference value. To convert the values for retinol to micrograms per deciliter, divide by 0.03491.
Only 111 of the 1221 men for whom dietary data were available(i.e., those who participated in the third evaluation at theage of 70 years) had a subsequent first fracture. Of the 49men (4 percent) who reported the use of vitamin A–containingsupplements, 6 had a subsequent fracture. The highest quintilefor estimated retinol intake (>1.50 mg per day) was associatedwith an energy-adjusted rate ratio of 2.00 (95 percent confidenceinterval, 1.00 to 3.99) for any fracture, as compared with thelowest quintile (<0.53 mg per day). With vitamin A–containingsupplements included in the nutrient calculation, the rate ratiofor the overall risk of fracture was 1.99 (95 percent confidenceinterval, 0.98 to 4.01). We found only a weak association betweenenergy-adjusted dietary intake of vitamin A at the age of 70years and the serum retinol level 20 years earlier (r=0.05,P=0.08). Dietary beta carotene intake was not associated withthe risk of fracture (data not shown).
Discussion
In this prospective, population-based cohort study of men, theoverall risk of fracture was substantially increased among themen with high levels of serum retinol. The risk was concentratedin the highest quintile for serum retinol, with an exponentialincrease within this category. A recent review of the effectsof hypervitaminosis A on bone concluded that the question isnot whether, but rather at what levels, retinol increases bonefragility.1 Our data suggest that serum levels higher than 86µg per deciliter (3 µmol per liter) may increasethe risk of fracture. The normal level of serum retinol appearsto be highly regulated within a range of 20.1 to 80.2 µgper deciliter (0.7 to 2.8 µmol per liter).18 The medianserum retinol value in our study (64.74 µg per deciliter)is similar to the median value (63.02 µg per deciliter[2.20 µmol per liter]) in men of similar age in a recentlarge study in the United States.19
Our findings are consistent with the results of two previousprospective epidemiologic investigations that examined dietaryretinol intake and the risk of hip fracture in women.6,7 Ourstudy, in which retinol was used as a biologic marker togetherwith the overall risk of fracture, corroborates the detrimentaleffect of excess retinol on human bone. Serum retinol has beenpositively associated with both dietary vitamin A intake anduse of supplemental vitamin A in most studies12,20,21,22,23but not all.24 As in the two previous epidemiologic dietarystudies, we compared the risk of fracture among subjects whohad an estimated dietary vitamin A intake of more than 1.5 mgper day with the risk among those whose intake was less than0.5 mg per day. All three studies showed that the risk was increasedby a factor of approximately two among subjects in the highestcategory of vitamin A intake.
The main dietary sources of retinoids are fish, liver, and dairyproducts, together with fortified foods (in Sweden, margarineand low-fat dairy products). A small proportion of carotenoidsfrom vegetables and fruits is also converted to retinol.25 Dietaryvitamin A is absorbed from the intestine and transported tothe liver by chylomicrons. Vitamin A is stored in the liverin the form of retinyl esters but is mobilized from the liveras retinol, normally bound to retinol-binding protein. Retinolis released in target cells and converted to retinoic acid,which exerts its effects by binding to specific nuclear receptors.26Retinoid receptors have been identified in both osteoblasts27and osteoclasts.28,29 Retinoic acid suppresses osteoblast activityand stimulates osteoclast formation in vitro.29,30
Only a small proportion of circulating vitamin A is normallyin the form of retinyl esters.31 In a large cross-sectionalstudy, a linear analysis showed no association between serumretinyl esters in the fasting state and bone density.32 However,serum retinyl esters may simply reflect a temporary excess invitamin A intake rather than long-term vitamin A intake andstorage. Studies of plasma kinetics have shown that the clearanceof serum retinyl esters varies substantially from one personto another,33,34,35 with an average increase in clearance ofmore than 50 percent over a 12-hour period after a moderateintake of vitamin A (1.0 to 1.5 mg).36 Furthermore, in patientswith vitamin A toxicity, serum retinyl esters decrease muchfaster than serum retinol after discontinuation of vitamin Asupplements.31
Serum retinol has been positively associated with age, weight,serum lipids, socioeconomic status, and renal failure and hasbeen negatively associated with smoking, alcohol consumption,infections, and chronic liver diseases.18,19,23,37,38 With theexception of serum lipids and infections, all these factorsalso influence the risk of fracture.39,40,41,42,43 When we controlledfor these possible covariates, only small effects were found.Men with high serum levels of retinol had elevated circulatinglipid levels, a well-known side effect of treatment with vitaminA44 or retinoids,45 as well as high serum calcium levels, whichmay have been attributable to the mobilization of calcium frombone.
Long-term ingestion of large amounts of vitamin A can lead tohypercalcemia.46 Serum calcium might thus be regarded as havinga role in the development of osteoporosis.46,47 However, sinceserum vitamin D was not measured in our study, we cannot ruleout the possibility that a concurrent excessive intake of vitaminD contributed to the increase in serum calcium. Exclusion ofserum calcium from our multivariate analysis resulted in a somewhatstronger association between serum retinol and the risk of fracture.There was no association between a high serum level of betacarotene and an increased risk of fracture. Dietary intake ofbeta carotene influences serum levels of beta carotene but notserum retinol levels.48,49
Our longitudinal, population-based, prospective study involveda cohort of men who were similar in age, and we used hospital-recordverification for complete ascertainment of cases of fracture.We also used a biologic marker of retinol status, rather thandietary assessments alone, as previous studies have done. However,serum retinol was measured only once, and the interval betweenmeasurement and follow-up was long. One would expect that theusefulness of a single serum retinol measurement in predictingthe risk of fracture would be attenuated as the period of observationincreased, which was indicated by our analysis. There was onlya weak association between serum retinol at base line and dietaryvitamin A intake 20 years later, which may be explained in partby the 20-year interval between the evaluations. In addition,a one-week dietary record may not reflect vitamin A intake accurately,50leading to a weakening of the associations identified. Nevertheless,the dietary data, obtained from only half the original studypopulation, appeared to reveal an increased risk of fracturewith a high dietary vitamin A intake, although the small numberof cases and borderline significance of the association limitthe interpretation of this finding.
The results of our study suggest that subclinical hypervitaminosisA may increase the risk of fracture. Johansson et al. have reportedthat subclinical hypervitaminosis A increases the risk of fracturein rats51; our clinical data support this finding.
Supported by grants from the Swedish Research Council, UppsalaUniversity Hospital, and the Söderberg Foundation.
We are indebted to A. Aro, R. Mohsen, H. Heinzl, A. Ahlbom,T. Andersson, L. Berglund, and S. Lucas for expert assistance.
Source Information
From the Department of Surgical Sciences, Section of Orthopedics (K.M.), the Department of Public Health and Caring Sciences, Sections of Geriatrics (H.L.) and Clinical Nutrition Research (B.V.), and the Department of Medical Sciences, Section of Clinical Pharmacology (H.M.), University Hospital, Uppsala, Sweden.
Address reprint requests to Dr. Michaëlsson at the Department of Surgical Sciences, Section of Orthopedics, University Hospital, S-751 85 Uppsala, Sweden, or at karl.michaelsson{at}surgsci.uu.se.
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