Esko Alhava

Bone densitometry of the spine and femur in children by dual-energy x-ray absorptiometry

The bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine (L2-L4) and femoral neck were measured by dual-energy x-ray absorptiometry in 84 healthy Finnish children and adolescents aged 6-19 years. Both BMC (g) and BMD (g/cm2) were closely related to age, height and weight (r values from 0.724 to 0.920). When the BMD values were adjusted for age, height and weight, the mean lumbar BMD was higher in girls than in boys (P = 0.001), whereas in the femoral neck the situation was opposite (P = 0.032). Attempts were also made to normalize the BMD data for the size of bones. When BMD values were corrected for the size of bones, the correlation between age and BMDcorr (g/cm3) at the femoral neck disappeared suggesting that apparent volumetric density (g/cm3) did not change significantly during childhood and adolescence. Statistically higher femoral neck BMD and BMDcorr values were found in the study subjects, who were physically active (P less than 0.005). However, given the influence of nutrition and other environmental factors, one must be careful in interpreting the results concerning the determinants of bone mass.

Development of bone mass and bone density of the spine and femoral neck — a prospective study of 65 children and adolescents

The bone mineral density (BMD, g/cm2) of the lumbar spine (L2-L4) and femoral neck was measured twice with a 1-year interval by dual energy X-ray absorptiometry (DEXA) in 65 healthy children and adolescents aged 7-20 years. In addition, the BMD values were corrected for the size of bones to obtain the bone volumetric density (BMDvol, g/cm3) using a method developed previously. The annual increases of BMD and BMDvol in both spine and femoral neck were most marked in females at the time of menarche (during the age of 11-13 years), and in males between the ages of 13 and 17 years. The males showed significantly higher values in their mean annual increment rates of femoral bone mineral content (BMC) and femoral neck width, whereas no differences in spinal parameters were found. The acquisition of bone mass and bone density stopped or markedly diminished before the age of 20 years, supporting the theory that the major portion of the peak bone mass is attained in late adolescence. We could not find any significant relationship between the increment rate of bone density, and physical activity or calcium intake. This study emphasizes the significant effect of puberty and genetic factors on the development of bone mass and density.

Bone Mineral Density and Risk Factors For Osteoporosis--A Population-Based Study of 1600 Perimenopausal Women

Population-based epidemiological studies on osteoporosis are few. Our study evaluated the effects of menopause and certain putative behavioral risk factors on bone mineral density (BMD). Spinal and femoral neck BMD were measured with dual X-ray absorptiometry (DXA) from 1600 perimenopausal women aged 48–59 years (mean 53.2 years) with no diseases or medications known to affect bone metabolism. These women were a selected sample of the Kuopio Osteoporosis Risk Factor and Prevention Study population (n=14,220). There was a wide variation of BMD among perimenopausal women. Menopause had a major effect on BMD. Postmenopausal women had significantly lower BMD in both spine (-6.2%) and femoral neck (-3.9%) as compared with premenopausal women. Multiple regression analysis showed that weight, menopausal status, age, and grip strength were significant independent predictors of both spinal and femoral BMD. Additionally, physical activity was found to be a significant predictor of femoral BMD, and alcohol consumption was a significant predictor of spinal BMD. However, current anthropometric and lifestyle factors explained only 18.7–25.4% of the variability of BMD. Therefore, the estimation of the risk factor status at menopause is not an adequate substitute for bone densitometry. However, our results may in part help clinicians to identify the risk groups at which to direct bone density measurements.

HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial

OBJECTIVES We investigated the incidence of new non-vertebral fractures during HRT or low-dose vitamin (Vit) D3 supplementation in a 5-year prospective trial. METHODS A total of 464 early postmenopausal women, (a subgroup of the Kuopio Osteoporosis Study, n = 13100) were randomized to four groups: (1) HRT, a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate; (2) Vit D (300 IU/day and 100 IU/day during the fifth year); (3) HRT + Vit D; and (4) placebo. Lumbar (L2-4) and femoral neck bone mineral densities (BMD) were determined by dual X-ray absorptiometry (DXA) at baseline, after 2.5 and 5 years of treatment. All new symptomatic non-vertebral, radiographically defined fractures were recorded. RESULTS Altogether, 368 women (79%) completed the 5 year treatment. In all, 32 women had 39 non-vertebral fractures during a mean of 4.3 year follow-up (HRT 4, Vit D 10, HRT + Vit D 8 and placebo 17). The reduction in the incidence of new non-verterbral fractures was significant in women with HRT alone (P = 0.032) when adjusted by baseline BMD and previous fractures; observed also with the intention-to-treat principle (P = 0.048). When the HRT groups were pooled, HRT showed a significantly lower incidence of new non-vertebral fractures (P = 0.042) than women receiving placebo and also after adjusting as above (P = 0.016); both in valid-case and in the intention-to-treat analysis. In the Vit D group, the fracture incidence was non-significantly decreased (P = 0.229) in comparison with the placebo group. The estimated risk of new non-vertebral fractures among women treated with HRT alone was 0.29 (95% CI, 0.10-0.90) and with Vit D 0.47 (95% CI, 0.20-1.14) and with HRT + Vit D 0.44 (95% CI, 0.17-1.15), in comparison with the placebo group (adjusted by femoral BMD and previous fractures). CONCLUSIONS This study is the first prospective trial confirming the beneficial effect of HRT on prevention of peripheral fractures in non-osteoporotic postmenopausal women. The effect of low-dose Vit D remains to be proved.

Osteoporosis in adult patients with celiac disease

We investigated the bone mineral density (BMD) and prevalence of osteopenia and osteoporosis in adult celiac patients with varying disease states. In this cross-sectional study the data on the severity of celiac disease and BMD were collected from 77 celiac patients (28 newly diagnosed and 49 previously diagnosed celiac patients), and BMD results were compared with those of 157 control subjects matched for age, gender, and menopausal status. The celiac patients had significantly lower BMD than the control subjects at the lumbar spine (-6%) and femoral neck (-5%). The mean BMD did not differ significantly among celiac patients classified by severity of disease. Based on Z scores, 35% of the celiac patients and 17% of the control subjects had low BMDs for age at the lumbar spine (p = 0.005), whereas 31% of celiac patients and 16% of control subjects had Z scores of < or =-1 at the femoral neck (p = 0.01). Altogether, 26% of all celiac patients, but only 5% of control subjects, were classified as having osteoporosis (T score < or =-2.5 SD) at the lumbar spine (p = 0.03), whereas osteoporosis was rare at the femoral neck in both groups (3% vs. 1%, p = 1.00). Prevalence of osteopenia and osteoporosis was highest in newly diagnosed celiac patients and in patients with disease not in remission. A low 25-(OH)D vitamin concentration was a typical biochemical abnormality in our patients (64% of men and 71% of women). The main associated variables of low BMD were age (men), low serum vitamin D level, low body weight, and postmenopausal status (women). The present study suggests that celiac disease constitutes a risk factor for osteoporosis. This finding applies particularly to untreated and poorly treated patients.

Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.

Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate

SummaryHyaluronan (HA), an extracellular high-molecular-mass polysaccharide, is supposed to be involved in the growth and progression of malignant tumours. We studied the cellular expression of HA in 215 operated stage I–IV gastric cancer patients using a specific biotinylated probe. Most (93%) of the tumours showed HA staining in their parenchyma, whereas the stroma inside and around the tumour was stained in every case. When HA expression was compared with the clinical and histological features of the tumours, a strong staining intensity in the tumour parenchyma was found to be associated with deep tumour invasion (pT3 or 4) and with mixed type of Laurén. A high proportion of HA-positive cells of all neoplastic cells was significantly associated with deep tumour invasion, nodal metastasis, positive lymphatic invasion, poor differentiation grade, as well as with inferior prognosis in univariate survival analysis. However, in multivariate analysis, only pT, pN, and vascular and lymphatic invasion emerged as independent predictors of survival in gastric cancer. The results indicate that ectopic HA expression is a frequent feature of gastric adenocarcinoma, and is associated with tumour progression and poor survival rate.

Laparoscopic or Open Cholecystectomy: A Prospective Randomised Trial to Compare Postoperative Pain, Pulmonary Function, and Stress Response

OBJECTIVE Open cholecystectomy (OC) has been superseded by laparoscopic cholecystectomy (LC) for the treatment of cholelithiasis, although this fashion has not been validated by prospective studies. Our aim was to compare the two techniques. DESIGN Prospective, randomised, open study. SETTING University hospital, Finland. PATIENTS 49 patients who required cholecystectomy for cholelithiasis confirmed by ultrasound. INTERVENTIONS 49 patients were randomly allocated to LC (n = 27) or OC (n = 22): 25 and 22, respectively, eventually had the operation. LC was done using a four-trocar technique, and OC through a transverse right subcostal incision, as short as possible. MAIN OUTCOME MEASURES Length of hospital stay and the duration of the sick leave were the primary outcome measures. Secondary outcome measures were: postoperative pain evaluated by visual analogue scale (VAS) and the need for opioids; pulmonary function measured by forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak flow velocity (PEFV), and arterial oxygen tension (PaO2), and endocrine stress measured by plasma catecholamines, cortisol and glucose concentrations. RESULTS The median (range) hospital stay was significantly shorter after LC than OC, being 2.0 (1-15) compared with 4.5 (2-19) days p < 0.01. The duration of sick leave was also significantly shorter after LC than OC, being 14 (7-17) compared with 29 (4-34), p < 0.01. Patients had significantly less postoperative pain after LC than OC as reflected by the need for opioids. Pulmonary function and arterial oxygen tension deteriorated significantly less after LC than OC. The stress response was equal. There were three documented complications, one pneumonia after LC and two wound infections after OC. CONCLUSIONS LC gives significantly better results in terms of less postoperative pain, better pulmonary function, better arterial oxygenation, and shorter hospital stay and duration of sick leave.

Risk factors for perimenopausal fractures: a prospective study

Abstract: This prospective study was aimed at determining the risk factors for the development of fractures in perimenopausal women. The study group (n= 3068) was comprised of a stratified population sample of women aged between 47 and 56 years. During the follow-up period of 3.6 years, 257 (8.4%) of the women sustained a total of 295 fractures. After adjustment for covariates, the relative risk (RR) of sustaining a fracture was found to be 1.4 [95% confidence interval (CI) 1.2–1.6] for a 1 standard deviation (SD) decrease in the spinal and femoral neck bone mineral density (BMD). Women with a previous fracture history were found to have an increased risk of fracture [RR 1.7 (95% CI 1.3–2.2)] and those reporting three or more chronic illnesses exhibited a RR of 1.4 (95% CI 1.0–1.9). Women not using hormone replacement therapy (HRT) had a RR of 1.5 (95% CI 1.1–2.2) for all fracture types. When osteoporotic fractures (vertebral, hip, proximal humerus and wrist fractures; n= 98) were used as an endpoint, the independent risk factors were found to be a low BMD (RR for a 1 SD decrease in both spinal and femoral neck BMD was 1.6, 95% CI 1.3–2.0), a previous fracture history (RR 1.9, 95% CI 1.3–2.9) and nonuse of HRT (RR 2.2, 95% CI 1.3–4.0). The independent risk factors for all other fractures (n = 158) were a low BMD (RR for a 1 SD decrease in the spinal BMD was 1.4, 95% CI 1.2–1.6 and in the femoral neck BMD was 1.3, 95% CI 1.1–1.5), a previous fracture history (RR 1.6, 95% CI 1.1–2.2), smoking (RR 1.8, 95% CI 1.1–2.7) and having had three or more chronic illnesses (RR 1.6, 95% CI 1.1–2.2). Weight, height, age, menopausal status, maternal hip fracture, use of alcohol, coffee consumption or dietary calcium intake were not independently associated with the development of any particular type of fracture. We conclude that the independent risk factors for perimenopausal fractures are a low bone density, previous fracture history, nonuse of HRT, having had three or more chronic illnesses and smoking, the gradient of risk being similar for spinal and femoral neck BMD measurements in the perimenopausal population. The risk factors are slightly different for perimenopausal osteoporotic than for other types of fractures.

The effect of gynecological risk factors on lumbar and femoral bone mineral density in peri- and postmenopausal women

The relationship between gynecological history and bone mineral density (BMD) of the lumbar spine and femoral neck was studied in 3126 perimenopausal women. The study population was a random, stratified sample of participants, selected from the Kuopio Osteoporosis Study, which consisted primarily of all 14,220 women aged 47-56 years in Kuopio Province in 1989. After exclusion of 1521 women reporting past or present hormonal replacement therapy (HRT), 1605 women formed the final study population. Present HRT users had significantly higher lumbar BMD but not femoral BMD, than non-hormone users. Postmenopausal status, late menarche, and bilateral oophorectomy were risk factors for low BMD. Protective factors against low BMD were increased body weight, increased number of pregnancies, as well as hysterectomy without bilateral oophorectomy. The majority (43.8%) of these operations had been performed due to the presence of leiomyomas. No significant correlation was found between nulliparity, breast-feeding or amenorrhea before the age of 30 and BMD. In the multiple regression analysis, gynecological variables could account for only 18.4-26.8% of the variance in BMD, while time since last periods, age, age at menarche, weight and hysterectomy were the most significant variables. We conclude that reproductive history gives rise to some special risk groups, to whom BMD measurements and osteoporosis prevention efforts should be directed. However, it is impossible to predict BMD by gynecological characteristics.