Ulrica Bergström

Epidemiology of fractures in children and adolescents

Background and purpose Fractures are most common in youth and in the elderly, with differences in incidence over time and between regions. We present the fracture pattern in a population of youths ≤ 19 years of age, who were seen at Umeå University Hospital, Sweden. Material and methods All injuries seen at the hospital have been recorded in a database since 1993. The data include variables such as age, sex, date, type of injury, mechanism of injury, and treatment. For the period 1993–2007, there were 10,203 injury events that had resulted in at least 1 fracture. Results The incidence for the whole period was 201/104 person years. The incidence increased by 13% during the period 1998–2007, when we were able to control for registration errors. The most common fracture site was the distal forearm. The most common type of injury mechanism was falling. The peak incidence occurred at 11–12 years in girls and at 13–14 years in boys, with a male-to-female incidence ratio of 1.5. We found variations in mechanisms and activities at injury with age, and over time. Interpretation Fractures are caused by a combination of intrinsic and extrinsic factors that vary with age. We believe the increase in incidence is partly explained by changes in childrens activity patterns over time. Further research may help to identify preventive measures to reduce the number of fractures, in particular those involving hospital care, surgical treatment, and—most importantly—long-term impairment.

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk.

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of −0.11 standard deviations [SD] per C allele, P = 6.2×10−9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (−0.14 SD per C allele, P = 2.3×10−12, and −0.16 SD per G allele, P = 1.2×10−15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10−9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10−6 and rs2707466: OR = 1.22, P = 7.2×10−6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16−/− mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%–61% (6.5×10−13<P<5.9×10−4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.

Ventricular Cerebrospinal Fluid Monoamine Transmitter and Metabolite Concentrations Reflect Human Brain Neurochemistry in Autopsy Cases

Concentrations of dopamine (DA), its metabolites 3‐methoxytyramine and homovanillic acid (HVA), noradrenaline (NA), its metabolites normetanephrine (NM) and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), 5‐hydroxytryptamine (5‐HT, serotonin), and its metabolite 5‐hy‐droxyindoleacetic acid (5‐HIAA) were measured in 14 brain regions and in CSF from the third ventricle of 27 human autopsy cases. In addition, in six cases, lumbar CSF was obtained. Monoamine concentrations were determined by reversed‐phase liquid chromatography with electrochemical detection. Ventricular/lumbar CSF ratios indicated persistence of rostrocaudal gradients for HVA and 5‐HIAA post mortem. Ventricular CSF concentrations of DA and HVA correlated positively with striatal DA and HVA. CSF NA correlated positively with NA in hypothalamus, and CSF MHPG with levels of MHPG in hypothalamus, temporal cortex, and pons, whereas CSF NM concentration showed positive correlations with NM in striatum, pons, cingulate cortex, and olfactory tubercle. CSF 5‐HT concentrations correlated positively with 5‐HT in caudate nucleus, whereas the concentration of CSF 5‐HIAA correlated to 5‐HIAA levels in thalamus, hypothalamus, and the cortical areas. These data suggest a specific topographic origin for monoamine neurotransmitters and their metabolites in human ventricular CSF and support the contention that CSF measurements are useful indices of central monoaminergic activity in man.

The hip fracture incidence curve is shifting to the right : a forecast of the age-quake

Background The number of hip fractures has doubled in the last 30–40 years in many countries. Age-adjusted incidence has been reported to be decreasing in Europe and North America, but is there a decreasing trend in all age groups? Patients and methods This population-based study included all hip-fracture patients over 50 years of age (a total of 2,919 individuals, 31% of whom were men) admitted to Umeå University Hospital, Sweden, from 1993 through 2005. Results The incidence of hip fracture declined between the periods 1993–1996 and 2001–2005: from 706 to 625 hip fractures per 105 women and from 390 to 317 hip fractures per 105 men. However, there was a 114% increase in the number of fractures in women aged 90 or older (12 and 25 hip fractures/year, respectively, in the two time periods). For the period 2001–05, women ≥ 90 years of age accounted for almost the same numbers of hip fractures as women aged 75–79 (27 fractures/year). The rate increased during this period, from 2,700 per 105 women to 3,900 per 105 women > 90 years. In men there were declining trends for both relative and absolute numbers. Interpretation Although age-adjusted incidence declined in the population > 50 years of age, absolute fracture rate and incidence increased in the very old. Women over 90 now have the same absolute number of hip fractures every year as women aged 75–79 years. There was a right-shift in hip fracture distribution towards the oldest old, probably due to an increased number of octo/nonagenarians, a new population of particularly frail old people that hardly existed earlier. Better health among septuagenarians may also have delayed the age at which fractures occurred. This changing pattern will strain orthopedic and geriatric resources even more.

Risk of arthropathy after the Bristow-Latarjet repair: a radiologic and clinical thirty-three to thirty-five years of follow-up of thirty-one shoulders.

BACKGROUND Transfer of the coracoid (Bristow-Latarjet [B-L]) is used to stabilize anterior shoulder instability. We report the long-term results of our first 31 operations with this method. MATERIALS AND METHODS Thirty-six patients (mean age, 26.7 years) had a B-L repair from 1977 to 1979. Five patients died, and during 2012 to 2013, the remaining 31 shoulders had a follow-up with questionnaire, physical examination, Western Ontario Shoulder Instability Index, Subjective Shoulder Value, Subjective Assessment of Shoulder Function, subjective assessment of loss of motion, and radiologic imaging. RESULTS One patient required revision surgery because of recurrence and another because of repeat dislocation. Six patients reported subluxations. Eighteen patients (58%) were very satisfied, and 13 (42%) were satisfied. The mean Western Ontario Shoulder Instability Index score (100 possible) was 85, and the median score was 93. According to Samilson-Prieto classification of arthropathy of the shoulder, 39% were classified as normal, 27% as mild, 23% as moderate, and 11% as severe. The classification of arthropathy varied with observers and radiologic views. Age younger than 22 years at the primary dislocation meant less arthropathy at follow-up (P = .045). CONCLUSION The degree of arthropathy 33 to 35 years after the B-L repair seems to follow the natural history of shoulder dislocation with respect to arthropathic joint degeneration. Postoperative restriction of external rotation does not increase later arthropathy.

Injuries in children and adolescents—Analysis of 41,330 injury related visits to an emergency department in northern Sweden

OBJECTIVES We present an overview of the injuries seen at the emergency department of a regional hospital in northern Sweden and the variations in the injury pattern with age, sex and time. METHODS Data consisting of all injuries sustained by those 0-19 years of age seen at the emergency department of Umeå University Hospital between 1998 and 2008 (41,330 injury events) were analysed with respect to injury type, mechanism, activity, age and sex. Rates were calculated using population data from Statistics Sweden. RESULTS The rate of injury related visits to the emergency department was 110/1000 person years. The most common causes of visits to the emergency department were minor injuries such as contusions, abrasions and open wounds. 12% of the injuries resulted in admission to a ward. Variations in type of injury, mechanism and activity at injury were noted, in particular with age, but also with sex. We noted a 31% rate increase of visits to the hospitals emergency department between 1998 and 2008, rate ratio 1.31 (1.27-1.38). There was no significant increase in the rate of injuries resulting in hospitalisation. CONCLUSIONS Our results give an estimate of the rate of all injuries and subsets of injuries resulting in visits to the only hospital emergency department within a well defined catchment area. It was not possible to determine whether the increased rate of visits to the ED was due to an increase in the actual rate of injuries within the catchment area. The variations seen in different age groups reflect the hazards associated with different periods in growth and the ability to cope with these. The results point to areas where improved preventive measures may be implemented or where further research may be of value.

Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm

Background Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. Aim To identify genetic variants associated with forearm BMD and forearm fractures. Methods BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. Results We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10–8) in meta-analysis (lead SNP, rs11951031[T] −0.20 SDs per allele, p=9.01×10–9). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. Conclusions These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.

Monoaminergic dysfunction in Sjögren-Larsson syndrome

The anteroposterior distribution of monoamine and monoamine metabolite concentrations was determined in subcortical brain nuclei of two cases of Sjögren-Larsson syndrome (SLS) and was compared to two control cases. The brains were divided into halves and sectioned coronally. For biochemical analyses, caudate nucleus, putamen, globus pallidus, substantia nigra, nucleus accumbens, amygdala, and hippocampus were dissected macroscopically. Monoamine and its metabolites were determined by reverse-phase liquid chromatography with electrochemical detection. The other hemisphere was studied neuropathologically. The SLS cases revealed cell loss in substantia nigra and putamen and a widespread white-matter destruction. Biochemically, most pronounced alterations were seen in the dopamine system in putamen with severely reduced concentrations of dopamine (DA; 14% of control values) and the catabolic metabolites 3-methoxytyramine (3-MT; 9% of control values) and homovanillic acid (HVA; 20% of control values). In substantia nigra and the other striatal regions studied, a general decrease of 3-MT and HVA concentrations was observed in the SLS subjects compared to the controls, although the decrease was less pronounced than in putamen. Generally, somewhat reduced noradrenaline and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were seen in the SLS cases, whereas serotonin and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were increased compared to the controls in most regions studied. These data suggest a specific monoaminergic dysfunction in patients with SLS. The severe decline in the dopaminergic system in putamen suggests that supplementation of dopamine agonists may ameliorate the symptoms of SLS patients.

Epidemiologic patterns of injuries treated at the emergency department of a Swedish medical center

BackgroundThe injury spectrum published in the literature has mainly been presented for a certain age group, as elderly or for a certain type of injury, as fracture and often restricted to in-hospital care cases. Our objective was to give an overview of the major types of injuries for all age groups and trends in the adult population.MethodsWe analyzed 68,159 adult injury events, which occurred between 1999 and 2008 and was treated at the Emergency Department of Umea University Hospital. All these injuries are registered in a database. The injuries were analyzed depending on frequency, type of injury, and activity at the time of injury. Incidence rates were calculated using population data from Statistics Sweden.ResultsInjury event incidence varied between 614 (2004) and 669 (2007) per 10,000 persons. The most common injury was a fracture, although contusions and wounds were also frequent. Fractures were responsible for almost three quarters of hospital days related to injury. The risk for fractures increased with age, as did contusions and concussions, whereas sprains decreased with age. Fracture incidence increased among the 50- to 59-year age group for both women and men. Fall-related injuries increased significantly for middle-aged adults. Sports-related and work injuries decreased, while injuries occurring during leisure time increased the most.ConclusionA fracture is the most frequent type of injury for adults and accounts for the largest proportion of the trauma care burden. Contusions are also common and responsible for a significant proportion of the in-hospital days. Injuries caused by a fall increased among middle-age adults imply a need for an extension of fall prevention programs.

Wnt16 Is associated with bone mineral density, osteoporotic fracture and bone strength: a Large-Scale Meta-Analysis of Genomewide Association Studies

PC-OC1 A TRANSCRIPTOMIC ANALYSIS OF TYPE II AUTOSOMAL DOMINANT OSTEOPETROSIS OSTEOCLASTS: IDENTIFICATION OF NEW DISEASE MARKERS Amélie E Coudert, Robert Olaso, Corinne Collet, Marie-Christine de Vernejoul INSERM U606, Os et Articulations, Paris, CEA, Gene Expression—Institut de Génomique, Evry, Hopital Lariboisière, Service de Biochimie, Paris, Hopital Lariboisière, Fédération de Rhumatologie, Paris, FranceWNT16 is associated with bone mineral density, osteoporotic fracture and bone strength : a large-scale meta-analysis of genomewide association studies