[Newborn screening : the point of view of the paediatrician]. / Dépistage néonatal : le point de vue du pédiatre.

Newborn screening is a public health effort that has changed the prognosis of some congenital diseases. Newborn screening programmes differ between countries in which it is organized. Demographic, epidemiological or economic factors play a role in the choice of the screening panel. In the French Community of Belgium, the programme focuses on 13 metabolic and endocrine diseases, hearing loss and hemoglobinopathies (Brussels and Liege). Newborn screening is a complex process that requires the involvement of all stakeholders : parent information, blood sampling or testing, lab analysis, follow-up of the results, initiate adequate care in case of positive test and genetic counselling. Newborn screening programmes will evolve in the next years. New therapeutic and diagnostic methods will make other genetic diseases candidates for screening. Whole genome sequencing may be the next expansion; it will create new opportunities but will pose new ethical dilemmas. We must all prepare now for future challenges.

Malignant Pleural Mesothelioma : Rationale for a New TNM Classification.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with a poor prognosis. In this regard, a well-defined staging system is of utmost importance in order to correctly diagnose and assign an appropriate treatment to the patient. METHODS: The current TNM-staging system (7th edition) enables to either clinically or pathologically stage the severity of the disease according to extension of the tumor (T), number of nodes (N) and presence of metastases (M). Patients with stage I-III are considered for surgery, while palliative treatment is indicated for stage IV patients according to the current classification. RESULTS: Despite its widespread use, the validity of this staging system is questioned due to the low prevalence, histological variety and retrospective nature of the previous study design. In addition, the role of specific treatment modalities including surgery, has yet to be determined, especially for treatment of early-stage disease. In this regard, the International Association for the Study of Lung Cancer (IASLC) initiated the multi-centre, prospective "Mesothelioma Staging Project" in order to address limitations of the 7th edition and to optimize the staging system in accordance to current needs. CONCLUSIONS: An improved staging system will contribute to the design of prospective multi-institutional clinical trials investigating novel treatment strategies for mesothelioma. In this way comparison of outcome between different medical centres also becomes feasible.

Nutritional status of neurologically impaired children: Impact on comorbidity.

BACKGROUND AND AIMS: Malnutrition is common in neurologically impaired (NI) children. It is, however, ill-defined and under-diagnosed. If not recognized and treated, it increases the burden of comorbidities and affects the quality of life of these children. The aim of this study was to characterize the nutritional status of a cohort of children followed up at a reference center for cerebral palsy (CP) in Brussels, Belgium, and to investigate possible links with the occurrence of comorbidities. MATERIAL AND METHODS: We conducted a single-center retrospective study including all the children followed up at the Inter-university Reference Center for Cerebral Palsy ULB-VUB-ULg. The data were obtained by reviewing medical files. Anthropometric measurements as well as the etiology of neurological impairment, comorbidities, feeding patterns, and laboratory test results were collected. The children were assigned a nutritional diagnosis according to the World Health Organization and Waterlow definitions. RESULTS: A total of 260 children with cerebral palsy were included, 148 males and 112 females. Their mean age was 10.9±4.3 years. The gross motor function classification system (GMFCS) level was I for 79 children, II for 63 children, III for 35 children, IV for 33 children, and V for 50 children. Of the children, 54% had a normal nutritional status, 34% showed malnutrition, and 8% were obese; 38% had oropharyngeal dysphagia. The sensitivity of mean upper arm circumference of

[Alendronate more effective than alfacalcidol in the prevention of osteoporosis in patients with rheumatic disease who are starting glucocorticoid therapy]. / Alendroninezuur effectiever dan alfacalcidol voor preventie van osteoporose bij patiënten met een reumatische ziekte die starten met glucocorticoïdtherapie.

OBJECTIVE: To compare the effects of alendronate and alfacalcidol in the prevention ofglucocorticoid-related osteoporosis in patients with a rheumatic disease. DESIGN: Randomised, double-blind, double-placebo clinical trial (www. clinicaltrials.gov; number: NCT00138983). METHODS: A total of 201 patients with rheumatic disease who were starting glucocorticoid treatment at a daily dose that was equivalent to at least 7.5 mg of prednisone were randomised to alendronate (10 mg) and a placebo capsule ofalfacalcidol daily (n = 100) or alfacalcidol (1 microg) and a placebo tablet ofalendronate daily (n = 101) for 18 months. Primary outcome was change in lumbar spine bone mineral density at 18 months. The main secondary outcome was the incidence of morphometrically confirmed vertebral deformities. RESULTS: Overall, 163 patients completed the study. The bone mineral density of the lumbar spine increased by 2.1% (95% CI: 1.1-3.1) in the alendronate group and decreased by 1.9% (95% CI: -3.I--0.7) in the alfacalcidol group. At 18 months the mean difference in change in bone mineral density between the two groups was 4.0% (95% CI: 2.4-5-5). Three patients in the alendronate group had a new vertebral deformity, compared with 8 patients in the alfacalcidol group, including 5 symptomatic vertebral fractures in 3 patients; the hazard ratio was 0.4 (95% CI: 0.1-1.4). CONCLUSION: Alendronate was more effective than alfacalcidol in preventing glucocorticoid-induced bone loss during this 18-month trial in patients with rheumatic diseases who were starting glucocorticoid treatment.

Detailed molecular characterization of a novel IDS exonic mutation associated with multiple pseudoexon activation.

Mutations affecting splicing underlie the development of many human genetic diseases, but rather rarely through mechanisms of pseudoexon activation. Here, we describe a novel c.1092T>A mutation in the iduronate-2-sulfatase (IDS) gene detected in a patient with significantly decreased IDS activity and a clinical diagnosis of mild mucopolysaccharidosis II form. The mutation created an exonic de novo acceptor splice site and resulted in a complex splicing pattern with multiple pseudoexon activation in the patient's fibroblasts. Using an extensive series of minigene splicing experiments, we showed that the competition itself between the de novo and authentic splice site led to the bypass of the authentic one. This event then resulted in activation of several cryptic acceptor and donor sites in the upstream intron. As this was an unexpected and previously unreported mechanism of aberrant pseudoexon inclusion, we systematically analysed and disproved that the patient's mutation induced any relevant change in surrounding splicing regulatory elements. Interestingly, all pseudoexons included in the mature transcripts overlapped with the IDS alternative terminal exon 7b suggesting that this sequence represents a key element in the IDS pre-mRNA architecture. These findings extend the spectrum of mechanisms enabling pseudoexon activation and underscore the complexity of mutation-induced splicing aberrations. KEY MESSAGE: Novel exonic IDS gene mutation leads to a complex splicing pattern. Mutation activates multiple pseudoexons through a previously unreported mechanism. Multiple cryptic splice site (ss) activation results from a bypass of authentic ss. Authentic ss bypass is due to a competition between de novo and authentic ss.

Dietary practices in isovaleric acidemia: A European survey.

BACKGROUND: In Europe, dietary management of isovaleric acidemia (IVA) may vary widely. There is limited collective information about dietetic management. AIM: To describe European practice regarding the dietary management of IVA, prior to the availability of the E-IMD IVA guidelines (E-IMD 2014). METHODS: A cross-sectional questionnaire was sent to all European dietitians who were either members of the Society for the Study of Inborn Errors of Metabolism Dietitians Group (SSIEM-DG) or whom had responded to previous questionnaires on dietetic practice (n = 53). The questionnaire comprised 27 questions about the dietary management of IVA. RESULTS: Information on 140 patients with IVA from 39 centres was reported. 133 patients (38 centres) were given a protein restricted diet. Leucine-free amino acid supplements (LFAA) were routinely used to supplement protein intake in 58% of centres. The median total protein intake prescribed achieved the WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Centres that prescribed LFAA had lower natural protein intakes in most age groups except 1 to 10 y. In contrast, when centres were not using LFAA, the median natural protein intake met WHO/FAO/UNU [2007] safe levels of protein intake in all age groups. Enteral tube feeding was rarely prescribed. CONCLUSIONS: This survey demonstrates wide differences in dietary practice in the management of IVA across European centres. It provides unique dietary data collectively representing European practices in IVA which can be used as a foundation to compare dietary management changes as a consequence of the first E-IMD IVA guidelines availability.

Dietary practices in propionic acidemia: A European survey.

BACKGROUND: The definitive dietary management of propionic acidaemia (PA) is unknown although natural protein restriction with adequate energy provision is of key importance. AIM: To describe European dietary practices in the management of patients with PA prior to the publication of the European PA guidelines. METHODS: This was a cross-sectional survey consisting of 27 questions about the dietary practices in PA patients circulated to European IMD dietitians and health professionals in 2014. RESULTS: Information on protein restricted diets of 186 PA patients from 47 centres, representing 14 European countries was collected. Total protein intake [PA precursor-free L-amino acid supplements (PFAA) and natural protein] met WHO/FAO/UNU (2007) safe protein requirements for age in 36 centres (77%). PFAA were used to supplement natural protein intake in 81% (n = 38) of centres, providing a median of 44% (14-83%) of total protein requirement. Seventy-four per cent of patients were prescribed natural protein intakes below WHO/FAO/UNU (2007) safe levels in one or more of the following age groups: 0-6 m, 7-12 m, 1-10 y, 11-16 y and > 16 y. Sixty-three per cent (n = 117) of patients were tube fed (74% gastrostomy), but only 22% received nocturnal feeds. CONCLUSIONS: There was high use of PFAA with intakes of natural protein commonly below WHO/FAO/UNU (2007) safe levels. Optimal dietary management can only be determined by longitudinal, multi-centre, prospective case controlled studies. The metabolic instability of PA and small patient cohorts in each centre ensure that this is a challenging undertaking.

[Inborn errors of metabolism: new developments and challenges]. / Les erreurs innées du métabolisme: progrès et défis.

The concept "inborn error of metabolism" (IEM) arose from the observations of Sir A. Garrod at the beginning of the XXth century. The exponential development, during the last decades, of our knowledge in cellular biology and molecular genetics, and the availability of increasingly more precise diagnostic tools, allow the identification of a still growing number of inborn errors of metabolism. Their physiopathology is better understood. Treatments have considerably improved: more specific diets, new medical treatments, enzyme replacement therapy, organ transplantation, hepatocyte or stem cell transplantation... New techniques are under development, including various strategies of gene therapy. Improved therapeutic efficacy combined with earlier diagnosis have dramatically changed the prognosis of many disorders. As a consequence, new challenging questions have to be answered. Today, patients with an IEM, because of the extreme complexity of their management, need to be looked after by a multidisciplinary team of physicians (pediatricians and internists), dieticians, social workers, psychologists... It is essential, in this complex and rapidly expanding field, that experiences should be shared at national and international level, in order to provide the most adequate care for patients.

[Dietetic and nutritional management in a university children's hospital]. / Diététique et nutrition dans un hôpital pédiatrique universitaire.

Dietetics and nutrition are new, expanding disciplines. Feeding man's cub to ensure the best physical, brain and psychic growth to reach the adult age in a "sane" state is the daily challenge of pediatric dieteticians. The role of dieteticians in a pediatric hospital is essential: optimizing sick children's nutrition. A child is highly vulnerable, above all when he is sick. Unappropriate feeding can put his growth and development, as well as his healing at stake. Numerous studies believe that denutrition in pediatric hospitals prevail by 7 to 45%. A survey has been carried out in two care units in the University Children's Hospital Queen Fabiola in Brussels. For one month, the nutritional hazard has been evaluated in every children admitted in these units. One observes that one third of these children shows a high nutritional hazard, and another third a moderate nutritional hazard. The tracking of the nutritional hazard and the appropriate nutritional care must be an integral part of the care given to any child admitted in hospital. A nutrition unit, with all the attending people involved (doctor, dietician, chemist, nurse), is necessary to improve the nutritional care of the patients.

Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system.

BACKGROUND: Multilevel approaches involving environmental strategies are considered to be good practice to help reduce the prevalence of childhood overweight. OBJECTIVES: The objective of this study was to evaluate the effects of VIASANO, a community-based programme using the EPODE methodology, on the prevalence of overweight in two pilot towns in Belgium. METHODS: We analysed data from a national school health monitoring system to compare changes in the prevalence of overweight and obesity over a 3-year period (2007-2010) in children aged 3-4 and 5-6 years in the pilot towns with those of children of the same ages from the whole French-speaking community of Belgium. Heights and weights of all participants were measured by trained school nurses using a standardized method. RESULTS: The prevalence of overweight (-2.1%) and overweight + obesity (-2.4%) decreased in the pilot towns, but remained stable in the comparison population (+0.1% and +0.2%, respectively). After adjustment for lack of homogeneity between the study populations, there was a trend towards a decrease in overweight (P = 0.054) and overweight + obesity (P = 0.058) in the pilot towns compared with the general population. CONCLUSIONS: These results suggest that a community-based programme, such as VIASANO, may be a promising strategy for reducing the prevalence of childhood overweight even over a short period of time.

A simple score for estimating the long-term risk of fracture in patients using oral glucocorticoids.

BACKGROUND: Previous analyses of risk factors for glucocorticoid (GC)-induced osteoporosis have focused on the estimation of relative rather than absolute fracture probability. AIM: To estimate risk scores for the individual probability of fracture in GC users. DESIGN: Retrospective data analysis. METHODS: We evaluated all patients aged 40 years or older with a prescription for oral GCs in the General Practice Research Database (GPRD), which comprises the computerized medical records of around 7 million UK subjects. Individual risk factors for osteoporotic fractures were identified, and combined in a predictive model for 10-year absolute fracture risk. RESULTS: Of 191 752 oral GC users aged > or =40 years, 7412 experienced an osteoporotic fracture. Several characteristics independently contributed to the fracture risk score (GC therapy, age, gender, fall history, fracture history, body mass index, smoking, previous diagnoses, use of medication, recent hospitalization and indication for GC treatment). Scores of 30, 40 and 50 corresponded to absolute 5-year fracture risks of 6.2%, 15.3% and 35.2%, respectively. A woman aged 65 years with RA, low BMI, and a previous history of fracture and falls, who used 15 mg GC daily (total risk score 54) would have a 5-year fracture risk of 47% (a man with similar history, 30.1%). Short-term use of high-dose GC therapy (> or =30 mg) was associated with only a small increased risk of osteoporotic fracture (RR 1.21, 95%CI 1.04-1.42) in patients with a history of GC use. DISCUSSION: This risk score helps to predict an individual's risk of fracture during GC use. Decisions about bone protection treatment could be based on long-term risks of fracture.

Assessment of fracture risk: who should be treated for osteoporosis?

The clinical significance of osteoporosis arises from the fractures that occur. Of these, the hip fracture in particular is associated with high morbidity, mortality and socio-economic costs. The primary goal of osteoporosis treatment is fracture prevention. In this chapter we try to answer the question of how to assess fracture risk and how to identify those above a given risk threshold so that treatment can be given to those in whom fractures can be prevented (cost-) effectively. At first, the two main strategies for fracture prevention--population screening and case finding--are discussed. Then a fracture risk assessment score, based on easily identifiable clinical risk factors, is proposed. This clinical risk factor analysis can guide the decisions whether additional bone assessment is relevant and whether treatment should be started. Finally, we advocate that absolute fracture risk is important for communication with the patient about the decision whether or not to initiate treatment.

Hip fracture prediction in elderly men and women: validation in the Rotterdam study.

The aim of our study was to validate a hip fracture risk function, composed of age and femoral neck bone mineral density (BMD). This estimate of the 1-year cumulative risk was previously developed on the basis of Dutch hip fracture incidence data and BMD in men and women. A cohort of 7046 persons (2778 men) aged 55 years and over was followed for an average of 3.8 years. The 1-year hip fracture risk estimate was calculated for each participant according to the risk function and categorized as low (<0.1%), moderate (0.1 to < 1%), or high (> or =1%). Observed first hip fracture incidence was then analyzed for each of these risk categories by age and gender. Additionally, we calculated the relative risk per standard deviation (SD) decrease in femoral neck BMD in this population. At baseline, 2360 individuals were categorized as low risk, 2567 as moderate risk, and 378 as high risk During follow-up, 110 first hip fractures were observed corresponding to an incidence rate of 4.1/1000 person-years (pyrs) (95% confidence interval 3.4-5.0). The observed incidence rate in the low risk group was 0.2/1000 pyrs (0.1-0.9), 2.7/1000 pyrs (1.8-3.9) in the moderate risk group, and 18.4/1000 pyrs (12.4-27.2) in the high risk group. Below the age of 70 years, incidence was low in all categories, and very few individuals were considered at high risk Above the age of 70 years, the observed incidence was high in the high risk group, while in the low and moderate risk groups, the incidence remained low even over 80 years of age. In women, the age-adjusted relative risk for hip fractures was 2.5 per SD decrease in femoral neck BMD (1.8-3.6), while in men this relative risk was 3.0 per SD (1.7-5.4). In conclusion, we observed a similar relation of hip fracture with femoral neck BMD in men and women and were able to predict accurately hip fracture rates over a period of almost 4 years.

Plasma homocysteine concentration in a Belgian school-age population.

BACKGROUND: Total plasma homocysteine (tHcy) is an independent risk factor for cardiovascular disease in adults. Data for children and adolescents are lacking. OBJECTIVE: The aim of this study was to provide a reference range for tHcy and to explore the relation between tHcy and nutritional indexes in a Belgian pediatric population. DESIGN: tHcy, folate, and vitamin B-12 were measured in 647 healthy children (353 girls and 294 boys) aged 5-19 y. RESULTS: The tHcy distribution was, as in adults, skewed to the right [geometric mean (-1 SD, +1 SD): 7.41 micromol/L (5.51, 9.96)]. Concentrations were lowest in younger children and increased with age. After the tHcy distribution was examined according to age, 3 age ranges were distinguished: 5-9 y [6.21 micromol/L (5.14, 7.50)], 10-14 y [7.09 micromol/L (5.69, 8.84)], and 15-19 y [8.84 micromol/L (6.36, 12.29)]. We observed no significant differences in tHcy values between girls and boys in children aged < 15 y; in postpubertal children, however, concentrations were higher in boys than in girls. In the 3 age groups, folate was inversely correlated with tHcy; the negative relation between tHcy and vitamin B-12 was less strong. Familial cardiovascular disease was more frequent in children who had hyperhomocysteinemia. CONCLUSIONS: These observations suggest that in children, as in adults, genetic, nutritional, and endocrine factors are determinants of the metabolism of homocysteine. The significance of tHcy values in childhood and young adulthood in terms of predicting cardiovascular risk in adulthood should be investigated.

Prediction of fracture from low bone mineral density measurements overestimates risk.

There is a well-established relationship between bone mineral density (BMD) and fracture risk. Estimates of the relative risk of fracture from BMD have been derived mainly from short-term studies in which the correlation between BMD at assessment and BMD in later life ranged from 0.8 to 0.9. Because individuals lose bone mineral at different rates throughout later life, the long-term predictive value of low BMD is likely to decrease progressively with time. This article examines and formalizes the relationship between current BMD, correlation coefficients, and long-term risk. The loss of predictive value has important implications for early assessment and supports the view that measurements should be optimally targeted at the time interventions are contemplated and, when necessary, repeated in later life.

Intervention thresholds for osteoporosis.

The aim of this study was to determine the threshold of fracture probability at which interventions become cost-effective. We modeled the effects of a treatment costing $500/year, given for 5 years, that decreased the risk of all osteoporotic fractures by 35%, followed by a waning of effect for 5 years. Sensitivity analyses included a range of effectiveness (10%-50%) and a range of intervention costs (200-500 dollars/year). Data on costs and risks were from Sweden. Costs included direct costs and costs in added years of life, but excluded indirect costs due to morbidity. A threshold for cost-effectiveness of 60,000 dollars per quality-adjusted life-year (QALY) gained was used. Costs of added years were excluded in a sensitivity analysis for which a threshold value of 30,000 dollars per QALY was used. In the base case, intervention was cost-effective when treatment was targeted to women at average risk at age of >or=65 years. Irrespective of the efficacy modeled (10%-50%) or of cost of intervention (200-500 dollars/year) segments of the population at average risk could be targeted cost-effectively: The lower the intervention cost and the higher the effectiveness, the lower the age at which intervention was cost-effective. With the base case (500 dollars/year; 35% efficacy) treatment in women was cost-effective with a 10 year hip fracture probability that ranged from 1.4% at the age of 50 years to 4.4% at the age of 65 years. The exclusion of osteoporotic fractures other than hip fracture would increase the threshold to a 9%-11% 10 year probability because of the substantial morbidity from fractures other than hip fracture, particularly at younger ages. We conclude that the inclusion of all osteoporotic fractures has a marked effect on intervention thresholds, that these vary with age, and that available treatments can be cost-effectively targeted to individuals at moderately increased risk.

The components of excess mortality after hip fracture.

A high excess mortality is well described after hip fracture. Deaths are in part related to comorbidity and in part due directly or indirectly to the hip fracture event itself (causally related deaths). The aim of this study was to examine the quantum and pattern of mortality following hip fracture. We studied 160,000 hip fractures in men and women aged 50 years or more, in 28.8 million person-years from the patient register of Sweden, using Poisson models applied to hip fracture patients and the general population. At all ages the risk of death was markedly increased compared with population values immediately after the event. Mortality subsequently decreased over a period of 6 months, but thereafter remained higher than that of the general population. The latter function was assumed to account for deaths related to comorbidity and the residuum assumed to be due to the hip fracture. Causally related deaths comprised 17-32% of all deaths associated with hip fracture (depending on age) and accounted for more than 1.5% of all deaths in the population aged 50 years or more. Hip fracture was a more common cause for mortality than pancreatic or stomach cancer. Thus, interventions that decreased hip fracture rate by, say, 50% would avoid 0.75% or more of all deaths.

Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis.

The risk of hip fracture is commonly expressed as a relative risk. The aim of this study was to examine the utility of relative risks of hip fracture in men and women using World Health Organization (WHO) diagnostic criteria for low bone mass and osteoporosis. Reference data for bone mineral density (BMD) at the femoral neck, from the third National Health and Nutrition Examination Survey (NHANES III), were applied to the population of Sweden. Relative risks (RRs) were calculated from the known relationship between BMD at the femoral neck and hip fracture risk. The apparent prevalence of low bone mass and osteoporosis depended on the segment of the young population chosen for reference ranges. Using a reference derived from women aged 20-29 years, the prevalence of osteoporosis was 21.2% in women between the ages of 50 and 84 years and 6.3% in men. The RRs associated with osteoporosis depended markedly on the risk comparison. For example, in men or women aged 50 years, the RR of hip fracture in those with osteoporosis compared to those without osteoporosis was 7.4 and 6.1, respectively. The RR of those at the threshold value for osteoporosis compared to those with an average value for BMD at that age was 6.6 and 4.6 in men and women, respectively. RRs were lower comparing those at the threshold value compared to the risk of the general population at that age (4.2 and 2.9, respectively). When RR was expressed in relation to the population risk rather than to the risk at the average value for BMD, RR decreased at all ages by 37%. Such adjustments are required for risk assessment in individuals and for the combined use of different risk factors. Because the average T score at each age decreased with age, the RR of hip fracture at any age decreased with advancing age in the presence of osteoporosis. The decrease in relative risk with age is, however, associated with an increase in absolute risk. Thus, for clinical use, the expression of absolute risks may be preferred to relative risks.

Added value of bone mineral density in hip fracture risk scores.

Hip fractures constitute a major health problem. For effective prevention, high-risk groups need to be identified. The objective here was to develop hip fracture risk scores while assessing the added value of bone mineral density relative to more conventional risk indicators. We prospectively followed during 4 years a cohort of 5208 persons (2193 men) aged 55 years and over from the Rotterdam Study, a population-based cohort study conducted in the Netherlands. Risk scores for hip fracture were constructed using several conventional risk indicators requiring interview and anthropometry only, and bone mineral density. During follow-up, 50 persons (14 men) suffered hip fracture. Hip fracture risk was independently determined by age, gender, height, the use of a walking aid, cigarette smoking, and either bone mineral density or weight. We developed two risk scores, with and without bone mineral density. The observed 4-year risk ranged from 3/3389 (0.1%) to 17/169 (10.1%) for the lowest and highest category of the score including bone mineral density, respectively. For the score without bone mineral density, these risks were 8/3117 (0.3%) and 16/144 (11.1%), respectively. The area under the receiver operating characteristic curve indicating discriminatory power was 0.88 for the risk score including, and 0.83 for the score excluding, bone mineral density (p for difference = 0.04). In conclusion, risk scores with and without bone mineral density measurement can be used for hip fracture risk assessment in elderly persons. While the score with bone mineral density has a modestly better performance, the score requiring interview and anthropometry only may be especially useful in primary care settings.

Ten-year risk of osteoporotic fracture and the effect of risk factors on screening strategies.

Bone mineral density (BMD) measurements are widely used to estimate the risk of osteoporotic fractures. In addition, many other risk factors have been identified, some of which are known to add to the risk independently of BMD measurements. The combination of BMD with such risk factors increases the gradient of risk/standard deviation (SD) than that achieved by BMD alone. In this paper, we report the fracture probabilities according to age, gender, and relative risk, and have investigated the effects of changes in the gradient of risk for osteoporotic fractures on the sensitivity and specificity of assessments, modeled on the population of Sweden. Ten-year risks of hip, clinical vertebral, forearm, or proximal humeral fracture were computed with increments in gradient of risk that varied from 1.5 to 6.0 per SD change in skeletal risk. The identification of high-risk groups had little effect on the specificity of assessments, but increased the sensitivity over a wide range of assumptions. The inclusion of all four fracture types had little effect on sensitivity, but increased the positive predictive value of the test. Positive predictive value also increased with age, so that values greater than 50% were obtained testing women at the age of 65 years with modest gradient of risk of 2.0-2.5/SD when small segments of the population were targeted (0.5-5%). Screening of women to direct intervention at the age of 65 years and targeting 25% of the population could save up to 23% of all fractures in women over the next 10 years by the use of multiple tests with a moderate gradient of risk (RR = 2.0/SD). Such gradients might be achieved with the use of multiple risk factors to identify patients at risk.