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There are occasional marked discordances in BMD T-scores at the lumbar spine (LS) and femoral neck (FN). We investigated whether such discordances could contribute independently to fracture prediction using FRAX. We studied 21,158 women, average age 63 years, from 10 prospective cohorts with baseline FRAX variables as well as FN and LS BMD. Incident fractures were collected by self-report and/or radiographic reports. Extended Poisson regression examined the relationship between differences in LS and FN T-scores (ΔLS-FN) and fracture risk, adjusted for age, time since baseline and other factors including FRAX 10-year probability for major osteoporotic fracture calculated using FN BMD. To examine the effect of an adjustment for ΔLS-FN on reclassification, women were separated into risk categories by their FRAX major fracture probability. High risk was classified using two approaches: being above the National Osteoporosis Guideline Group intervention threshold or, separately, being in the highest third of each cohort. The absolute ΔLS-FN was greater than 2 SD for 2.5% of women and between 1 and 2 SD for 21%. ΔLS-FN was associated with a significant risk of fracture adjusted for baseline FRAX (HR per SD change = 1.09; 95% CI = 1.04-1.15). In reclassification analyses, only 2.3-3.2% of the women moved to a higher or lower risk category when using FRAX with ΔLS-FN compared with FN-derived FRAX alone. Adjustment of estimated fracture risk for a large LS/FN discrepancy (>2SD) impacts to a large extent on only a relatively small number of individuals. More moderate (1-2SD) discordances in FN and LS T-scores have a small impact on FRAX probabilities. This might still improve clinical decision-making, particularly in women with probabilities close to an intervention threshold.

Erkki Soini,1 Ossi Riekkinen,2 Heikki Kröger,3,4 Petri Mankinen,1 Taru Hallinen,1 Janne P Karjalainen2 1ESiOR Oy, Kuopio, Finland; 2Bone Index, Kuopio, Finland; 3Kuopio Musculoskeletal Research Unit, University of Eastern Finland, Kuopio, Finland; 4Department of Orthopedics, Traumatology and Hand Surgery, Kuopio University Hospital, Kuopio, Finland Purpose: Osteoporosis is asymptomatic morbidity of the elderly which develops slowly over several years. Osteoporosis diagnosis has typically involved Fracture Risk Assessment (FRAX) followed by dual energy X-ray absorptiometry (DXA) in specialist care. Point-of-care pulse-echo ultrasound (PEUS) was developed to overcome DXA-related access issues and to enable faster fracture prevention treatment (FPT) initiation. The objective of this study was to evaluate the cost-effectiveness of two proposed osteoporosis management (POMs: FRAX→PEUS-if-needed→DXA-if-needed→FPT-if-needed) pathways including PEUS compared with the current osteoporosis management (FRAX→DXA-if-needed→FPT-if-needed).Materials and methods: Event-based probabilistic cost–utility model with 10-year duration for osteoporosis management was developed. The model consists of a decision tree for the screening, testing, and diagnosis phase and is followed by a Markov model for the estimation of incidence of four fracture types and mortality. Five clinically relevant patient cohorts (potential primary FPT in women aged 75 or 85 years, secondary FPT in women aged 65, 75, or 85 years) were modeled in the Finnish setting. Generic alendronate FPT was used for those diagnosed with osteoporosis, including persistence overtime. Discounted (3%/year) incremental cost-effectiveness ratio was the primary outcome. Discounted quality-adjusted life-years (QALYs), payer costs (year 2016 value) at per patient and population level, and cost-effectiveness acceptability frontiers were modeled as secondary outcomes.Results: POMs were cost-effective in all patient subgroups with noteworthy mean per patient cost savings of €121/76 (ranges €107–132/52–96) depending on the scope of PEUS result interpretation (test and diagnose/test only, respectively) and negligible differences in QALYs gained in comparison with current osteoporosis management. In the cost-effectiveness acceptability frontiers, POMs had 95%–100% probability of cost-effectiveness with willingness to pay €24,406/QALY gained. The results were robust in sensitivity analyses. Even when assuming a high cost of PEUS (up to €110/test), POMs were cost-effective in all cohorts.Conclusion: The inclusion of PEUS to osteoporosis management pathway was cost-effective. Keywords: diagnostics, dual-energy X-ray absorptiometry, economic evaluation, Fracture Risk Assessment tool, PICOSTEPS, screening

Background/Objectives: Significance of dietary fatty acids on bone health is not clear, and the evidence is controversial. This study aimed to investigate the relationship between dietary polyunsaturated fatty acids (PUFAs) and bone mineral density (BMD) among elderly women. Subjects/Methods: Subjects (n = 554) were drawn from the Kuopio OSTPRE Fracture Prevention Study. At baseline they filled a 3-day food record and a questionnaire on lifestyle factors, diseases and medications. BMD was measured at lumbar spine (L2-L4), femoral neck and total body by dual energy X-ray absorptiometry at baseline and after 3 years. The associations between dietary fatty acids and BMD were analyzed by a linear mixed model adjusting for potential dietary and non-dietary confounders. Results: Our findings suggested a positive relationship between the dietary PUFAs and BMD at lumbar spine and in total body but not at femoral neck. Further analyses revealed that these results were due to associations among the women without hormone therapy (HT) at baseline. Among them, the intake of total PUFAs as well the intakes of linoleic and linolenic acids and total n-3 and n-6 fatty acids were significantly associated with BMD at lumbar spine; P for trend over the quartiles ranged between 0.013 and 0.001. Similarly, significant associations were demonstrated for total body BMD and fatty acids with an exception of total PUFA. No significant associations were found among women with HT at baseline. Conclusions: Our findings among elderly women without HT support the suggested beneficial effect of dietary PUFAs on bone health. European Journal of Clinical Nutrition (2012) 66, 496-503 doi: 10.1038/ejcn.2011.188; published online 23 November 2011 Keywords: fatty acids; linoleic acid; linolenic acid; bone density; aged; women, Introduction Balanced diet providing especially calcium and vitamin D as well as physical exercise, are the most important non-pharmaceutical factors affecting bone health. Further, other nutrients and foods are suggested [...]

Byline: J. Sirola (1,5), T. Rikkonen (1), M. Tuppurainen (1,2), R. Honkanen (1), J. S. Jurvelin (1,3), H. Kroger (1,4) Keywords: Bone loss; DXA absorptiometry; Grip strength change; Postmenopause; Weight change Abstract: Introduction Weight loss significantly increases postmenopausal bone loss, but the effects of muscle strength change on weight-loss-associated bone loss remain unclear. The study population, 587 peri- and postmenopausal women, was a random sample of the original Osteoporosis Risk Factor and Prevention Study (OSTPRE) study cohort (n=14,220) in Kuopio, Finland. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) was measured with dual x-ray absorptiometry, and grip strength was measured with a pneumatic squeeze dynamometer at baseline in 1989--1991 and at the 10-year follow-up in 1999--2001. Methods Women were divided into three groups according to change in age-grouped grip-strength quartile in both of the measurements: 'decreased' (n=133), 'maintained' (n=300), and 'improved' (n=154). In addition, the study sample was divided into two groups according to weight change during the follow-up: weight losers (n=156) and weight gainers (n=431). Results There were no differences in the change status of grip (muscle) strength between the weight loss and weight gain groups (p&gt 0.500, Pearson chi-square test). Women losing weight during the follow-up and within the improved grip-strength-change group had a significantly lower bone loss rate compared with those in the maintained and decreased grip-strength-change groups (p&lt 0.01 in comparison to the decreased group). This was in contrast to women who gained weight during the follow-up (not significant between any grip-strength-change groups). Furthermore, women who lost body weight and were in the improved grip-strength-change group had a bone loss rate comparable with that of the women who gained body weight (not significant). This was in contrast to the maintained (p&lt 0.05 between weight losers versus gainers in LS) and decreased grip-strength-change groups (p&lt 0.01 weight losers versus gainers in LS and FN). Conclusion The present study suggests that maintaining muscle strength may counteract postmenopausal bone loss related to weight loss. Accordingly, exercise that improves muscle strength may be encouraged for postmenopausal women with weight loss intentions for other health reasons. Author Affiliation: (1) Bone and Cartilage Research Unit (BCRU), University of Kuopio, Mediteknia Building, P.O. Box 1627, 70211, Kuopio, Finland (2) Kuopio University Hospital, Department of Obstetrics and Gynaecology, Kuopio, Finland (3) Kuopio University Hospital, Department of Clinical Physiology &amp Nuclear Medicine, Kuopio, Finland (4) Kuopio University Hospital, Department of Surgery, Kuopio, Finland (5) Mikkeli Central Hospital, Department of Surgery, Mikkeli, Finland Article History: Registration Date: 16/12/2005 Received Date: 25/08/2005 Accepted Date: 05/12/2005 Online Date: 21/02/2006

Byline: J. Huopio (1), H. Kroger (1), R. Honkanen (2), J. Jurvelin (3), S. Saarikoski (4), E. Alhava (1) Keywords: Bone mineral density; Fracture prediction; Perimenopausal; Prospective studies; Quantitative ultrasound Abstract: Low calcaneal ultrasound measurement (quantitative ultrasound, QUS) has been shown to predict fractures in elderly women. However, only a few studies have examined its ability to predict perimenopausal and early postmenopausal fractures. We conducted a prospective population-based cohort study to assess the capability of QUS as compared to axial BMD measurement to predict early postmenopausal fractures at that age. Four hundred and twenty-two women (mean age 59.6, range 53.7--65.3) from the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) were randomly chosen to undergo a calcaneal ultrasound measurement. In all, 9.4% of these women were premenopausal at the time of measurement. Thirty-two follow-up fractures were reported during the mean follow-up of 2.6 years (SD 0.7). These were validated with patient record perusal. Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI) were significantly lower among women with than without fracture (P-values 0.028, 0.001 and 0.001, respectively). Mean T-score adapted from SI was -1.5 (95% CI -1.7 to -1.2) for fracture group and -1.0 (95% CI -1.1 to -0.9) for the non-fracture group. All QUS measurements predicted fractures even after adjusting for age, weight, height, previous fracture history, femoral neck BMD and use of hormone replacement therapy according to Cox regression. The adjusted hazard ratios (HR, 95% confidence interval) of a follow-up fracture for a 1 SD decrease were 1.80 (1.27--2.56), 1.72 (1.21--2.45) and 1.43 (1.01--2.03) for SOS, SI and BUA, respectively. Similarly, the adjusted HR for a 1 SD decrease of spinal BMD was 1.27 (0.85--1.94) and for that of femoral neck BMD 1.14 (0.78--1.70). In receiver operator analyses, the area under the curve (AUC) was greatest for QUS measurements: SOS (AUC=0.68), stiffness (AUC=0.67), BUA (AUC=0.62) and least for lumbar BMD (AUC=0.56), while and femoral neck BMD (AUC=0.59). The difference between AUCs was statistically significant between SI and lumbar BMD (P=0.02, Duncan's P=0.07). We conclude that low calcaneal QUS predicts early postmenopausal fractures as well as or even better than axial BMD. Author Affiliation: (1) Department of Surgery, Kuopio University Hospital, PO Box 1777, 70211, Kuopio, Finland (2) Research Institute of Public Health, University of Kuopio, PO Box 1627, 70211, Kuopio, Finland (3) Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, PO Box 1777, 70211, Kuopio, Finland (4) Department of Obstetrics and Gynaecology, Kuopio University Hospital, PO Box 1777, 70211, Kuopio, Finland Article History: Registration Date: 01/01/2003 Received Date: 03/01/2003 Accepted Date: 26/09/2003 Online Date: 16/01/2004

Byline: J. Sirola (1), H. Kroger (2), R. Honkanen (1), L. Sandini (2), M. Tuppurainen (3), J.S. Jurvelin (4), S. Saarikoski (3) Keywords: KeywordsaHRT; Osteoporosis; Postmenopausal bone loss; Risk factors; Weight change Abstract: aIn the present study we evaluated the risk factors associated with peri- and postmenopausal bone loss and the effect of hormone replacement therapy (HRT) on weight-loss-related bone loss. The study population, 940 peri- and postmenopausal women, was selected from a random sample (n = 2025) of the OSTPRE study cohort (n = 13 100) in Kuopio, Finland. Bone mineral density (BMD g/cm.sup.2) at the lumbar spine and femoral neck, and body weight, were measured at baseline in 1989--91 and at 5-year follow-up in 1994--97 by trained personnel. Five hundred and forty-seven women had never used HRT and 393 women used part-time or continuous HRT during follow-up of 3.8--7.9 years (mean 5.8 years). Similarly, of the 172 weight losers, 97 had never used HRT while 75 used it during follow-up. According to multiple regression analysis on the total study population (n = 940), HRT use, years since menopause and weight increase significantly predicted lower annual bone loss at both the lumbar spine and femoral neck (p &lt 0.005). Low baseline weight and higher age predicted higher bone loss only at the lumbar spine (p &lt 0.001) and high grip strength predicted lower bone loss only at the femoral neck (p = 0.021). In a sub-analysis on weight losers, weight loss predicted greater bone loss in HRT non-users (p &lt 0.05), whereas this was not observed in HRT users. These results remained similar after adjustment for age, weight, height, calcium intake, duration of menopause, baseline BMD and bone-affecting diseases/medication. In conclusion, the transition to menopause, HRT and weight change are the most important determinants of bone loss at both the lumbar spine and femoral neck. Furthermore, HRT seems to be effective in prevention of weight loss related bone loss. Author Affiliation: (1) Research Institute of Public Health, University of Kuopio Finland , FI (2) Department of Surgery, Kuopio University Hospital, Finland, FI (3) Department of Obstetrics and Gynaecology, Kuopio University Hospital, Finland, FI (4) Department of Clinical Physiology &amp Nuclear Medicine, Kuopio University Hospital, Finland, FI (5) Clinical Research Centre, Bone and Cartilage Research Unit, University of Kuopio, Finland, FI (6) OSTPRE study, Teknia Building, University of Kuopio, PO Box 1627, 70211, Kuopio, Finland Tel.: +358 50 3555938. Fax: +358 17 162978 e-mail: jsirola@hytti.uku.fi, FI Article note: Received: 29 March 2002 / Accepted: 26 August 2002

Byline: J. Sirola (1), J. Sirola (2), R. Honkanen (1), H. Kroger (2), J. S. Jurvelin (3), P. Maenpaa (5), S. Saarikoski (4) Keywords: Key words:Bone loss -- Osteoporosis -- Postmenopausal women -- Prospective study -- Statins Abstract: Recent experimental and epidemiologic studies have suggested that the lipid-lowering drugs, statins, may have bone-protective effects. We studied the effects of statin use on the change in bone mineral density (BMD) in a prospective 4.5-year cohort study based on subjects from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study, Finland. Six hundred and twenty women aged 53--64 years were divided into four groups: 55 women reported continuous and 63 women occasional statin use during the follow-up 142 non-users of statins reported hypercholesterolemia whereas 360 non-users did not. Spinal and femoral BMDs were measured by dual-energy X-ray densitometry in 1995--1996 and 1999--2000 and the BMD changes of the four groups were compared. Characteristics of the study population were obtained with postal inquiries. The mean annual spinal and femoral BMD changes of the study groups were 0.29% and -0.50% for the continuous statin users, 0.19% and -0.57% for the occasional statin users, 0.52% and -0.29% for the hypercholesterolemic non-users of statins, and 0.39% and -0.33% for the non-users of statins without hypercholesterolemia, (p= 0.398 and p=0.404) respectively. The corresponding BMD changes adjusted for age, years since menopause, body mass index, BMD at baseline, calcium intake, estrogen and cortisone therapy, duration of follow-up and statin use before the baseline were -0.20% and -0.47%, 0.19% and -0.54%, 0.54% and -0.32%, 0.47% and -0.33% (p= 0.134 and p= 0.628), respectively. Our results suggest that statins do not protect from early postmenopausal bone loss. Randomized trials are needed to confirm these results. Author Affiliation: (1) University of Kuopio, Research Institute of Public Health, FI (2) Department of Surgery, FI (3) Department of Clinical Physiology &amp Nuclear Medicine, FI (5) Obstetrics and Gynaecology, Kuopio University Hospital , FI (4) Department of Biochemistry, University of Kuopio, Kuopio, Finland, FI Article note: Received: 11 October 2001 / Accepted: 3 January 2002

Byline: J. Huuskonen (1), S. B. Vaisanen (2), H. Kroger (1), J. S. Jurvelin (4), E. Alhava (1), R. Rauramaa (2) Keywords: Key words:Alcohol intake -- Bone mineral density -- Bone loss -- Calcium intake -- Men -- Physical training Abstract: The aim of the study was to investigate the effects of regular aerobic exercise training on bone mineral density (BMD) in middle-aged men. A population based sample of 140 men (53--62 years) was randomly assigned into the exercise and reference groups. BMD and apparent volumetric BMD (BMD.sub.vol) of the proximal femur and lumbar spine (dual-energy X-ray absorptiometry, DXA) and anthropomorphic measurements were performed at the randomization and 2 and up to 4 years later. The participation rate was 97% and 94% at the second and third BMD measurements, respectively. As another indication of excellent adherence and compliance, the cardiorespiratory fitness (aerobic threshold) increased by 13% in the exercise group. The 2% decrease in the reference group is regarded as an age-related change in cardiorespiratory fitness. Regardless of the group, there was no association between the increase in aerobic threshold and change in BMD. In the entire group, age-related bone loss was seen in the femoral neck BMD and BMD.sub.vol (p&lt 0.01). BMD and BMD.sub.vol values increased with age in L2--L4 (p&lt 0.004). An increased rate of bone loss at the femoral neck was observed in men with a low energy-adjusted calcium intake (p=0.003). Men who increased their alcohol intake during the intervention showed a decrease in the rate of bone loss at the femoral neck (p=0.040). A decrease in body height associated with decreased total femoral BMD (r= 0.19, p=0.04) and the change in body height was a predictor of bone loss in the femoral neck ([beta]= 0.201). Long-term regular aerobic physical activity in middle-aged men had no effect on the age-related loss of femoral BMD. On the other hand, possible structural alterations, which are also essential for the mechanical strength of bone, can not be detected by the DXA measurements used in this study. The increase seen in lumbar BMD reflects age-related changes in the spine, thus making it an unreliable site for BMD follow-up in men. Author Affiliation: (1) Department of Surgery, Kuopio University Hospital, FI (2) Kuopio Research Institute of Exercise Medicine and Department of Physiology, University of Kuopio, FI (3) Department of Clinical Chemistry, FI (4) Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Finland, FI Article note: Received: August 2000 / Accepted: November 2000

Byline: J. Huuskonen (1), S. B. Vaisanen (2), H. Kroger (1), C. Jurvelin (3), C. Bouchard (4), E. Alhava (1), R. Rauramaa (2) Keywords: Key words: Bone mineral density -- Calcium intake -- Cardiorespiratory fitness -- Men -- Muscle strength Abstract: Osteoporosis is a growing health problem not only in women but also in men. To assess determinants of bone mineral density (BMD) at the spine and proximal femur, a randomly selected sample of 140 Finnish men aged 54--63 years was measured using fan beam dual-energy X-ray absorptiometry. Isometric muscle strength was measured using a computerized measurement system and cardiorespiratory fitness was assessed with maximal oxygen uptake (V[O.sub.2]max) using breath-by-breath respiratory gas analyses during an incremental bicycle ergometer exercise. Intakes of calcium and energy were estimated using 4-day food records. Smoking habits and alcohol consumption were assessed from an interview and a 4 week diary, respectively. Isometric muscle strength of triceps and biceps brachii, extensors and flexors of thigh and rectus abdominis correlated significantly with BMD (r= 0.18--0.35, p= 0.02--0.000). Calcium intake correlated positively with femoral (r= 0.19--0.28, p= 0.03--0.003), but not with lumbar BMD. In addition, calcium intake adjusted for dietary energy content (mg/MJ) correlated with femoral BMD (r= 0.25--0.36, p= 0.03--0.000). Smoking had no effect on BMD, whereas alcohol intake correlated positively with BMD at L2--L4 (r=0.19, p= 0.031). In the multiple linear regression analysis adjusted calcium intake predicted BMD in every site measured, while strength of abdominal muscles predicted BMD at Ward's triangle and femoral neck. Body weight was a predictor of trochanteric BMD. Body height was the best predictor of lumbar and femoral neck area. We conclude that low dietary calcium intake, weak muscle strength and low body weight are risk factors for low BMD in men. Author Affiliation: (1) Department of Surgery, Kuopio University Hospital, Finland, FI (2) Kuopio Research Institute of Exercise Medicine and Department of Physiology, University of Kuopio, Finland, FI (3) Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Finland, FI (4) Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Quebec, Canada, CA Article note: Received: 30 August 1999 / Accepted: 29 December 1999

Byline: R. J. Honkanen (1), K. Honkanen (1), H. Kroger (3), E. Alhava (3), M. Tuppurainen (2), S. Saarikoski (2) Keywords: Key words:Calcium -- Forearm fracture -- HRT -- Osteoporosis -- Risk factor Abstract: This prospective population-based cohort study investigated factors predicting distal forearm fracture (DFF) in perimenopausal women. The study population consisted of 11798 women from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study in Finland. Mean baseline age of these women was 52.3 (SD 2.9) years (range 47--56 years) and 68% were postmenopausal. Three hundred and sixty-eight women (3.1%) had a validated DFF during the 5-year follow-up. Previous wrist fracture, postmenopausal state, age and nulliparity were independent predictors of DFF, while hormone replacement therapy (HRT), dairy calcium and overweight protected against it in multivariate Cox regression analysis: previous wrist fracture increased the DFF risk by 158% (p&lt 0.0001), menopause by 69% (p= 0.002) and age by 6% per year (p= 0.010), whereas the continuous use of HRT decreased the risk by 63% (p= 0.0001), the use of dairy calcium at 1000--1499 mg/day (vs &lt 500 mg/day) by 39% (p= 0.004), overweight (BMI &gt 25 kg/m.sup.2) by 36% (p= 0.0002) and parity by 29% (p= 0.031). Combining dichotomous low weight, low use of calcium, non-use of HRT and previous wrist fracture into a risk score gave a dose--response effect by score level: the presence (vs absence) of all four risk factors resulted in a 12-fold DFF risk. Nevertheless, the sensitivity and specificity of the score for detecting DFF remained low. It was concluded that HRT, high nutritional calcium intake and overweight protect against but a history of wrist fracture predisposes to perimenopausal distal forearm fracture. A simple risk factor inquiry would help to identify perimenopausal women at high risk of distal forearm fracture. Author Affiliation: (1) Research Institute of Public Health, University of Kuopio, Kuopio, Finland, FI (2) Department of Gynecology, Kuopio University Hospital, Finland , FI (3) Department of Surgery, Kuopio University Hospital, Finland, FI Article note: Received: 7 July 1999 / Accepted: 6 September 1999

Byline: J. Huopio (1), H. Kroger (1), R. Honkanen (2), S. Saarikoski (3), E. Alhava (1) Keywords: Key words:Bone density -- Fractures -- Perimenopausal -- Prospective studies -- Risk factors -- Women 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. Author Affiliation: (1) Department of Surgery, Kuopio University Hospital, FI (2) Research Institute of Public Health, University of Kuopio , FI (3) Department of Obstetrics and Gynaecology, Kuopio University Hospital, Kuopio, Finland, FI Article note: Received: 6 April 1999 / Accepted: 18 August 1999

Byline: M. Komulainen (1), H. Kroger (2), M. T. Tuppurainen (1), A.-M. Heikkinen (1), R. Honkanen (4), S. Saarikoski (1) Keywords: Key words:Bone mineral density -- Bone response -- Hormone replacement therapy -- Osteoporosis -- Smoking -- Weight Abstract: Hormone replacement therapy (HRT) prevents postmenopausal bone loss and fractures. However, the occurrence of women with no bone response to HRT has not been widely examined. We identified the densitometric nonresponders to long-term HRT and investigated some characteristics and biochemical variables as possible predictors of densitometric nonresponse in postmenopausal women. The study population was a subsample of the Kuopio Osteoporosis Study (n= 14.220). A total of 464 early postmenopausal women were randomized into four treatment groups: (1) HRT (sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate) (2) vitamin D.sub.3 (3) HRT + Vitamin D.sub.3 combined and (4) placebo. In this study, the data from HRT and placebo groups were analyzed. Lumbar (L2--4) and femoral neck bone mineral density (BMD) were determined by dual-energy X-ray absorptiometry (DXA) at baseline and after 5 years of treatment. A densitometric nonresponder was defined as a woman whose 5-year BMD change was similar to the mean BMD change (+ 95% CI) of the placebo group or worse. Altogether, 74 women in the HRT group and 104 women in the placebo group complied with the treatment. According to spinal BMD analysis, 11% of the women were classified as densitometric nonresponders the corresponding proportion for femoral BMD analysis was 26%. Both smoking (p= 0.003) and low body weight (p= 0.028) were significant risk factors for densitometric nonresponse to HRT. After 6 months of treatment the densitometric nonresponders (hip) had a significantly higher mean serum follicle stimulating hormone (FSH) level (p= 0.038) and lower increases in serum estradiol levels (p= 0.006) than the densitometric responders. The mean changes in serum FSH and alkaline phosphatase levels were significantly lower among the densitometric nonresponders (spine) than responders (p= 0.043 and 0.017, respectively). In conclusion, this prospective study shows that especially current smokers and women with low body weight are at increased risk of poor bone response to HRT. Repeated serum FSH, estradiol and alkaline phosphatase measurements during the first months of long-term HRT may be helpful in identifying the women with no bone response to HRT. Author Affiliation: (1) Department of Obstetrics and Gynecology, Kuopio University Hospital, FI (2) The A.I. Virtanen Institute, University of Kuopio, FI (3) Department of Surgery, Kuopio University Hospital , FI (4) Research Institute of Public Health, University of Kuopio, Kuopio, Finland, FI Article note: Received: 29 January 1999 / Accepted: 2 August 1999

Byline: H. Kroger (1), A. Hauschild (1), M. Ohde (1), K. Bache (2), W. P. Voigt (2), W. Ehrlich (3) Abstract: We could show that both nicotinamide and N-acetylcysteine inhibit collagen induced arthritis in mice. In the present paper, using lower doses of each, we applied combinations of these two substances. We were able to confirm potentiating effects of these combinations. These results may allow new perspectives for the therapy of arthritis to emerge. Author Affiliation: (1) Deutsches Rheumaforschungszentrum Berlin (DRIZ), Hannoversche Strasse 27, 10115, Berlin (2) Bundesinstitut fur gesundheitlichen Verbraucherschutz und Veterinarmedizin Diedersdorfer Weg, 12277, Berlin (3) Warthe-Strasse 71, 12051, Berlin Article History: Registration Date: 30/09/2004

Byline: M.T. Tuppurainen (1), M. Komulainen (1), H. Kroger (2), R. Honkanen (5), J. Jurvelin (3), E. Puntila (4), A.M. Heikkinen (1), E. Alhava (2), S. Saarikoski (1) Keywords: Key words: BMD Estrogen Osteoporosis Prospective study Vitamin D Abstract: The long-term effects on bone of estrogen therapy (HRT) combined with vitamin D.sub.3 supplementation were evaluated and compared with the effects of HRT without vitamin D.sub.3 supplementation in a 4-year prospective, partly randomized study among 60 osteoporotic women (mean age 55.4 years range 49.7--59.4 years). The women studied were a subgroup of the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) (n = 13100). The bone mineral densities (BMD) of the lumbar spine and femoral neck were determined by dual-energy X-ray absorptiometry (DXA) in 3236 perimenopausal women. Those 106 women with baseline BMD more than 2 SDs less than the mean value in this population, either at the lumbar spine (BMD &lt 0.826 g/cm.sup.2) and/or femoral neck (BMD &lt 0.684 g/cm.sup.2), were offered treatment for osteoporosis. After exclusions, 60 women were included in the analyses. Group allocation was: HRT (estradiol valerate (2 mg) plus cyproterone acetate, 1 mg, sequentially: Climen.sup.R) (n = 21) HRT + Vit D: Climen + vitamin D.sub.3 (cholecalciferol, 300 IU/day, no intake during June--August) (n = 23) controls: 16 women who refused all treatment served as a non-randomized control group. In the HRT group, the highly significant increase in lumbar BMD was 5.4%, 5.3%, 4.7% and 4.0% after 1, 2, 3 and 4 years of treatment, respectively, all compared with the baseline values and with the control group. The increase in femoral neck BMD was statistically insignificant (1.4%, 2.2%, 1.9% and 2.1%, respectively p &gt 0.05). In the HRT + Vit D group, the lumbar BMD increased by 3.7%, 4.9%, 4.9% and 4.9% (p &lt 0.001), whereas the 5.8% increase in femoral neck BMD reached significance at 4 years (p &lt 0.01) when compared with the control group as well as with the baseline values. However, there were no statistically significant differences in lumbar or femoral BMD changes between the two HRT groups. In conclusion, estrogen can substantially increase lumbar bone mass in patients with postmenopausal osteoporosis. In addition, the combination of HRT and vitamin D.sub.3 may increase femoral neck BMD in osteoporotic women more than estrogen alone. Author Affiliation: (1) Department of Obstetrics and Gynecology, University Hospital of Kuopio, Kuopio, FI (2) Department of Surgery, University Hospital of Kuopio, Kuopio, FI (3) Department of Clinical Physiology and Nuclear Medicine, University Hospital of Kuopio, Kuopio, FI (4) A.I. Virtanen Institute, University of Kuopio, Kuopio, FI (5) Research Institute of Public Health, University of Kuopio, Kuopio, Finland, FI (6) Institute of Community Medicine, University of Tromso, Norway, NO

Byline: R. Honkanen (1), M. Tuppurainen (3), H. Kroger (4), E. Alhava (4), S. Saarikoski (3) Keywords: Key words: Fracture Menopause Osteoporosis Risk factors Women Abstract: Relationship between selected factors and fractures according to type of fracture were retrospectively examined in 12192 women aged 47--56 years responding to the baseline postal enquiry of the Kuopio Osteoporosis Study, Finland, in 1989. A total of 1358 women reported fractures sustained during the previous 9.4 years, i.e. at ages 38--57 years. The incidence of fractures per 1000 person-years was 17.2 after menopause and 9.5 before (p &lt 0.0001). The adjusted fracture risk was elevated in smokers versus non-smokers (OR: 1.5 (95%CI = 1.3--1.9) and in those with chronic health disorders versus the healthy (OR = 1.3 95% CI 1.1--1.5). Long-term work disability was associated with fractures independently of health disorders (OR = 1.3 95% CI 1.1--1.6). Anthropometric measures were not associated with the overall fracture risk. Menopause was strongly and linearly related to wrist fracture but not to ankle fracture. A 1 SD increase in body mass index decreased the risk of wrist fracture by 21% (p = 0.0001) but increased that of ankle fracture by 24% (p = 0.002). Smoking was related to ankle fracture (OR = 2.2 95% CI 1.6--3.2) but not to wrist fracture (OR = 0.9 95% CI 0.6--1.4). Health disorders were more markedly associated with fractures other than those of the wrist or ankle. Relationships between several risk factors and pre- and perimenopausal fractures vary by type of fracture. This may affect, for example, the comparability of studies with varying fracture profiles. Author Affiliation: (1) Institute of Community Medicine, University of Tromso, Norway, NO (2) Research Institute of Public Health, University of Kuopio, Finland, FI (3) Department of Obstetrics and Gynaecology, Kuopio University Hospital, Finland, FI (4) Department of Surgery, Kuopio University Hospital, Finland, FI (5) A.I. Virtanen Institute, University of Kuopio, Finland, FI

The design of hybrid superconductor-semiconductor random access memories (RAMS) is presented. The RAMs, which provide high-density storage with high-speed data access at very low power dissipation levels, can operate in close proximity to the superconductive processors and can be implemented on the same chip. They utilize the current switches in superconductive electronics to remove important constraints on the design of semiconductor memories. These RAMs can achieve excellent performances unattainable when using individual technologies separately.