P.D. Bezemer

Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial

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 Netherlands 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 Netherlands (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, prospective 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 practices 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 randomly assigned to receive either active treatment with vitamin D3 or placebo. The study was double-blind, and randomization was done in blocks of 10 per general practice, apartment house, or home. Randomization lists were made using a computerized random-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 questionnaire, as described previously [21]. The participants were evaluated annually with a questionnaire 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 questionnaire (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 substudy investigating the effect of vitamin D supplementation on bone mineral density and bone turnover variables. This substudy included a nonrandom sample of participants from several apartment houses and homes for the elderly and is described in detail elsewhere [21]. In the same substudy, 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 random sample of 96 participants drawn from the remaining study population. These participants received a letter giving them an appointment within 10 days; the blood samples 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 randomly 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 resulting total score, ranging from 3 to 9, was entered as a covariate in the model. The level of compliance (weekly intake as reported on the

Smallest real difference, a link between reproducibility and responsiveness.

The aim of this study is to show the relationship between test-retest reproducibility and responsiveness and to introduce the smallest real difference (SRD) approach, using the sickness impact profile (SIP) in chronic stroke patients as an example. Forty chronic stroke patients were interviewed twice by the same examiner, with a 1-week interval. All patients were interviewed during the qualification period preceding a randomized clinical trial. Test-retest reproducibility has been quantified by the intraclass correlation coefficient (ICC), the standard error of measurement (SEM) and the related smallest real difference (SRD). Responsiveness was defined as the ratio of the clinically relevant change to the SD of the within-stable-subject test-retest differences. The ICC for the total SIP was 0.92, whereas the ICCs for the specified SIP categories varied from 0.63 for the category ‘recreation and pastime’ to 0.88 for the category ‘work’. However, both the SEM and the SRD far more capture the essence of the reproducibility of a measurement instrument. For instance, a total SIP score of an individual patient of 28.3% (which is taken as an example, being the mean score in the study population) should decrease by at least 9.26% or approximately 13 items, before any improvement beyond reproducibility noise can be detected. The responsiveness to change of a health status measurement instrument is closely related to its test-retest reproducibility. This relationship becomes more evident when the SEM and the SRD are used to quantify reproducibility, than when ICC or other correlation coefficients are used.

The test of Lasègue: systematic review of the accuracy in diagnosing herniated discs.

STUDY DESIGNnA systematic review of the literature including statistical meta-analysis.nnnOBJECTIVESnTo evaluate published methods of the test of Lasègue or straight leg raising test and the cross straight leg raising test by using a recently developed criteria list and to summarize and explore reasons for variation in diagnostic accuracy.nnnSUMMARY OF BACKGROUND DATAnLittle evidence exists on the diagnostic accuracy of the widely used straight leg raising test and the cross straight leg raising test in diagnosing herniated discs in patients with low back pain.nnnMETHODSnMEDLINE and EMBASE searches up to 1997 showed 17 diagnostic publications evaluating the straight leg raising test with surgery as reference standard. Quality of methods was assessed with a specific checklist. Eleven studies were selected for statistical pooling. Sources of variation and heterogeneity were studied by meta-regression of the diagnostic odds ratio.nnnRESULTSnAll studies were surgical case-series at nonprimary care level. Verification-bias was obvious in one study. Pooled sensitivity for straight leg raising test was 0. 91 (95% CI 0.82-0.94), pooled specificity 0.26 (95% CI 0.16-0.38). Pooled diagnostic odds ratio was 3.74 (95% CI 1.2-11.4). Discriminative power was lower in recent studies, in studies with only inclusion of primary hernias, and with blind assessment of both the index-test (straight leg raising test) and the reference (surgery). For the cross straight leg raising test pooled sensitivity was 0.29 (95% CI 0.24-0.34), pooled specificity was 0.88 (95% CI 0.86-0.90), and the pooled diagnostic odds ratio 4.39 (95% CI 0.74-25.9).nnnCONCLUSIONSnThe diagnostic accuracy of the straight leg raising test is limited by its low specificity. Discriminative power decreased with a more valid design, a more homogenous case-mix, and year of publication. Although the studies may reflect everyday clinical practice, they do not enable a valid evaluation of the diagnostic accuracy of both tests. Diagnostic research should evaluate the validity of the complete diagnostic process and study the evidence of the added value of the different tests used. [Key words: sensitivity, specificity, diagnosis, meta-analysis, test of Lasègue, straight leg raising test]

Incidence and survival of retinoblastoma in the Netherlands: a register-based study 1862-1995

AIM The aim of this study was to determine the (time trends in) incidence and survival of hereditary (familial and sporadic) and non-hereditary retinoblastoma for male and female patients born in the Netherlands between 1862 and 1995. METHOD The national retinoblastoma register was updated and now consists of 955 patients. The missing dates of death were obtained from the municipal registers and the Central Bureau of Genealogy in The Hague. Mortality was compared with the Dutch vital statistics. RESULTS From 1862 to 1995 no significant differences in incidence for retinoblastoma were found in the hereditary subgroups. Further, no significant differences between males and females were found, both overall and in the hereditary subgroups. The average incidence of retinoblastoma increased untill 1944, probably due to incompleteness of the register, and stabilised after 1945 (1 per 17u2009000 live births). From 1900 to 1995 the standardised mortality ratio increased for hereditary retinoblastoma patients from 2.9 to 9.0 and decreased for non-hereditary retinoblastoma patients from 1.9 to 1.0. CONCLUSION Although survival for retinoblastoma was significantly better after 1945 than before, in comparison with the Dutch population the mortality between 1900 and 1990 increased for the hereditary and decreased for the non-hereditary retinoblastoma patients.

Effect of homoeopathic medicines on daily burden of symptoms in children with recurrent upper respiratory tract infections

Abstract Objective: To investigate the intrinsic effects of individually prescribed homoeopathic medicines. Design: Randomised double blind placebo controlled study. Setting: Paediatric outpatient department of university hospital. Patients: 175 children with frequently recurring upper respiratory tract infections. Of the 170 children evaluable, 86 were randomised to homoeopathic medicines (47 boys, 39 girls; median age at start 4.2 years; median number of episodes in past year 4) and 84 to placebo (43 boys, 41 girls; median age at start 3.6 years; median number of episodes in past year 4). Main outcome measures: Mean score for daily symptoms, number of antibiotic courses, and number of adenoidectomies and tonsillectomies over one year of follow up. Results: The mean daily symptom score was 2.61 in the placebo group and 2.21 in the treatment group (difference 0.41; 95% confidence interval -0.02 to 0.83). In both groups the use of antibiotics was greatly reduced compared with that in the year before entering the trial (from 73 to 33 in the treatment group and from 69 to 43 in the placebo group). The proportion of children in the treatment group having adenoidectomies was lower in the treatment group (16%, 8/50) than in the placebo group (21%, 9/42). The proportion having tonsillectomies was the same in both groups (5%). Conclusion: Individually prescribed homoeopathic medicines seem to add little to careful counselling of children with recurrent upper respiratory tract infection in reducing the daily burden of symptoms, use of antibiotics, and need for adenoidectomy and tonsillectomy.

Which source should we use to measure quality of life in children with asthma: the children themselves or their parents.

This study compares the reproducibility, construct validity and responsiveness of self-report and parent-report quality of life questionnaires How Are You (HAY) for 8–12-year-old children with asthma. A total of 228 Dutch children with asthma and their parents completed the HAY and daily recorded the childs asthma symptoms in a diary. Additionally 296 age- and -gender matched healthy children and their parents completed the generic part of the HAY. Reproducibility and responsiveness were examined in a sub-group of 80 children with asthma. In this group, three measurements were carried out, at baseline, after one week and once during the following 6 month when the clinical asthma status had changed. The within-subject standard deviations (SD) of three dimensions (physical activities, social activities, self-management) differed significantly (p < 0.05) in favour of the parent-version, indicating that the reproducibility of the parent version was better than that of the child version. The mean score-differences between children with asthma and healthy children as reported by parents did not significantly differ from those reported by children, except for cognitive activities (e.g. be able to concentrate on school work). The mean differences with regard to children with a different actual asthma status (symptom analysis), as reported by both informants, did not differ. Compared to the child-version, the parent-version showed greater ability to detect changes in childrens quality of life over time for all but one dimension, indicating better responsiveness. The results indicate that in discriminative studies child and parents reports can be substituted on a group-level. In longitudinal studies data have to be obtained from parents. Consequently, caregivers collecting quality of life data for longitudinal purposes in daily practice should collect these data simply from parents.

Evening primrose oil and fish oil for severe chronic mastalgia: A randomized, double-blind, controlled trial

Recently evening primrose oil has been a popular holistic recommendation for the treatment of mastalgia because of its ability to affect prostaglandin metabolism. To investigate the ability of evening primrose oil to alleviate symptoms of mastalgia, the authors conducted a randomized, double-blind clinical trial. Fish oil was included in the study because it also is known to produce changes in prostaglandin metabolism. Control oils were corn oil and wheat germ oil, which were chosen for their common usage and similarity in color to the study oils. Participants for the study were recruited in Holland from 1993 through 1996 through an extensive publicity campaign involving general practitioners, surgeons, patient organizations, Dutch magazines, and posted advertisements. Women who enrolled in the study met these five criteria: cyclic or noncyclic mastalgia for more than 6 months, a minimum of 5 days and a median of at least 7 days of pain per menstrual cycle, age between 18 and 45 years, premenopausal state, and at least one functioning ovary. One hundred twenty women, 94 with cyclic and 26 with noncyclic mastalgia, enrolled in the study. Their mean age was 37.6 years. After the first clinical visit, all patients began keeping a daily pain diary, which included days with pain, severity of pain, and menstrual periods. At 3 months participants returned for a second evaluation. The 120 women recorded a mean number of 70.5 pain days in the 3-month period. On a scale of 1 to 3, the mean severity of pain was 1.64. At this time the patients were randomly assigned to one of four treatment groups that received daily regimens of 3 g of two different treatment oils. The first group received fish oil and control oil (FC); the second, evening primrose oil and control oil (EC); the third, fish oil and evening primrose oil (EF); and the fourth, two control oils (CC). Twelve women dropped out of the trial: eight because of adverse side effects, one for treatment failure, one because she became pregnant, and two because their symptoms had improved. Fifteen patients took fewer than the prescribed numbers of pills, including seven who took less than half of the doses. Eleven women complained of side effects, and four had difficulty taking or remembering pills. Side effects of treatments and placebos included gastric and abdominal symptoms, skin complaints, and weight gain. Women taking fish oil had the most trouble with gastric symptoms (belching, nausea, acidity, pain, fullness, and vomiting); 43% of those in the FC group and 60% of those in the EF group had these problems, compared with 20% and 27% of those in the EC and CC groups, respectively (P <.001). Other side effects were fairly evenly distributed. All patients experienced a decrease in the number of pain days. Fish oil registered a 15.5% decrease in pain days compared with 10.6% for its control oil, and evening primrose oil had a 12.3% decrease, compared with 13.8% for its control oil. The differences were not statistically significant. A slight decrease in severity of pain was reported by the women in all groups (0.06% to 0.08%).

Effects of individually chosen homoeopathic medicines on recurrent URTI in children A clinical trial--I Study methodology

Abstract The effects of homoepathic medicines on children suffering from recurrent upper respiratory tract infection (URTI) were studied in a randomized double-blind placebo-controlled clinical trial conducted at the paediatric outpatients department of the university hospital of the Vrije Universiteit in Amsterdam from 1987 to 1992. The study was designed to meet both the requirements of proper homoeopathic practice and the current standards of a clinical trial. The purpose of a randomized placebo-controlled double-blind trial is to identify the effects of the agents under investigation by equalizing the effects of other factors that may influence outcome. The object of the trial, eligibility criteria, follow-up period, treatments and concurrent interventions, data collection and effect measures are discussed in the light of homoeopathic thinking.