Eliisa Löyttyniemi

Genetically defined adult-type hypolactasia and self-reported lactose intolerance as risk factors of osteoporosis in Finnish postmenopausal women.

Objective:To study the relationships of molecularly defined lactose malabsorption (LM) and self-reported lactose intolerance (LI) to bone mineral density (BMD) and fractures among Finnish postmenopausal women.Design:A cross-sectional study of two cohorts.Setting:Helsinki University Central Hospital.Subjects:One cohort was population-based and comprised 453 women, aged 62–78 (mean 69) y. Another comprised 52 women, aged 69–85 (mean 75) y, with osteoporotic fractures and 59 control women, aged 69–83 (mean 74) y, without osteoporosis.Methods:A single nucleotide polymorphism of the lactase (LCT) gene at chromosome 2q21–22 was studied. It shows complete association with intestinal disaccharidase activity, with the genotype CC−13 910 meaning adult-type hypolactasia (primary LM) and the genotypes CT−13 910 and TT−13 910 lactose absorption. BMD of the heel was measured by dual-energy X-ray absorptiometry (DXA).Results:In the population-based cohort, 16.0% of women had self-reported LI but only 15.3% of them had the CC−13 910 genotype. Calcium intake from dairy products (P=0.10) and BMD, adjusted for age, weight, height, exercise, smoking, and estrogen use (P=0.71) were similar for the genotypes. Women with self-reported LI had reduced calcium intake from dairy products (P<0.0001) but they were more frequent users of calcium supplements than lactose-tolerants (P<0.0001). Adjusted BMD was similar for lactose intolerant and tolerant women (P=0.60). Of 104 women with previous fracture in the population-based cohort, 13.5% had the CC−13 910 genotype, which did not differ from the prevalence of 19.3% among 347 women without fractures (P=0.29). The frequency of the CC−13 910 genotype (23.1%) for 52 women with established osteoporosis was similar as for 59 control women (15.3%) (P=0.19).Conclusion:Molecularly defined LM and self-reported LI are not risk factors for osteoporosis, if calcium intake from diet and/or supplements remains sufficient. Our study confirms the poor correlation between self-reported LI and LM established by different techniques.Sponsorhip:Supported by the Research Funding from Helsinki University Central Hospital (Erityisvaltionosuus) and by the Miina Sillanpää Foundation, Helsinki, Finland.

Vitamin D fortification of milk products does not resolve hypovitaminosis D in young Finnish men

Objective:To study if vitamin D fortification of milk products started in February 2003 has improved vitamin D status of young Finnish men, which has been poor before.Design:A longitudinal study of one cohort.Setting:Helsinki University Central Hospital.Subjects:Sixty-five healthy men, studied for the first time in January 2001, were re-examined in January 2004. They were aged 18–21 years in 2001.Methods:Blood was sampled for determination of serum 25-hydroxyvitamin D (25-OHD) and intact parathyroid hormone (iPTH). 25-OHD was measured by both radioimmunoassay (RIA) and high-pressure liquid chromatography (HPLC). Consumption of milk, sour milk and fish and use of vitamin D supplements were assessed using a questionnaire.Results:In January 2004, vitamin D fortification had raised serum 25-OHD level, with the mean of individual percent changes being 20.4% measured with RIA (P=0.0015). The correlation between the RIA and HPLC methods was high (r=0.85). Nineteen men (29.2%) had vitamin D deficiency (25-OHD⩽20 nmol/l) and 48 men (73.8%) had hypovitaminosis D (25-OHD⩽37.5 nmol/l). Serum 25-OHD and iPTH levels correlated inversely (r=−0.30; P=0.017). Serum 25-OHD levels were 52.0% higher for 13 vitamin D supplement users than for 51 non-users (P=0.0001). After exclusion of supplement users, an association between 25-OHD level and consumption of milk products was found (P=0.011), with the median vitamin D level being 6.5 nmol/l higher for those consuming four glasses of milk products or more daily than for those consuming one or less. Likewise, the higher the milk consumption, the higher the difference in 25-OHD between years 2004 and 2001 (P=0.0025).Conclusion:Vitamin D fortification of milk products slightly but insufficiently improved the poor vitamin D status of young Finnish men during winter. Further supplementation is warranted in order to normalize vitamin D levels and to support achievement of maximum peak bone mass.Sponsorship:Supported by Paulo Foundation, Juho Vainio Foundation, Emil Aaltonen Foundation and Research Funding from Helsinki University Central Hospital (Erityisvaltionosuus).

Post-ablative serum thyroglobulin is an independent predictor of recurrence in low-risk differentiated thyroid carcinoma: a 16-year follow-up study

OBJECTIVE To study whether post-surgical and/or post-ablative thyroglobulin (Tg) concentrations may serve as independent predictors of disease recurrence in patients treated for TNM stage I or II well-differentiated thyroid carcinoma (WDTC). DESIGN An observational retrospective study with a median follow-up of 16 years (range 10-24). PATIENTS AND MEASUREMENTS Post-operative and post-ablative Tg concentrations, age, tumour size, local infiltration and nodal metastasis at primary surgery as well as disease recurrences and cancer-specific deaths were evaluated in 495 low-risk (TNM stages I and II) patients, the majority of whom had total thyroidectomy and radioactive iodine remnant ablation as initial treatment. RESULTS Fifty-one patients (10.3%) experienced disease recurrence during follow-up. In multiple logistic regression analysis, post-ablative Tg concentrations (odds ratio (OR) 3.72, confidence interval (CI) 1.71-8.05, P=0.0009) and local infiltration on primary surgery (OR 2.66, CI 1.03-6.90, P=0.04) were the only independent predictors of recurrence. CONCLUSIONS Post-ablative Tg concentration is a strong predictor of disease recurrence in WDTC.

Cdc20 and securin overexpression predict short-term breast cancer survival

Background:Cdc20 is an essential component of cell division and responsible for anaphase initiation regulated by securin degradation. Cdc20 function is strongly regulated by the spindle assembly checkpoint to ensure the timely separation of sister chromatids and integrity of the genome. We present the first results on Cdc20 in a large clinical breast cancer material.Methods:The study was based on 445 breast cancer patients with up to 20 years of follow-up (mean 10.0 years). DNA content was determined by image cytometry on cell imprints, and Cdc20 and securin immunohistochemistry on tissue microarrays of breast cancer tissue.Results:In our results, high Cdc20 and securin expression was associated with aneuploid DNA content. In prognostic analyses, high Cdc20 immunoexpression alone and in combination with high securin immunoexpression indicated aggressive course of disease and up to 6.8-fold (P<0.001) risk of breast cancer death. Particularly, high Cdc20 and securin immunoexpression identified a patient subgroup with extremely short, on average 2.4 years, breast cancer survival and triple-negative breast cancer (TNBC) subtype.Conclusions:We report for the first time the association of high Cdc20 and securin immunoexpression with extremely poor outcome of breast cancer patients. Our experience indicates that Cdc20 and securin are promising candidates for clinical applications in breast cancer prognostication, especially in the challenging prognostic decisions of TNBC.

Molecularly Defined Lactose Malabsorption, Peak Bone Mass and Bone Turnover Rate in Young Finnish Men

Lactose malabsorption (LM; adult-type hypolactasia), an autosomal recessive condition, results from the down-regulation of the activity of lactase enzyme in the intestinal wall. In previous studies the effect of LM on bone mass, bone turnover rate, development of osteoporosis and osteoporotic fractures has remained controversial. We have recently identified a single nucleotide polymorphism (SNP), a C to T change residing 13910 base pairs upstream of the lactase (LCT) gene at chromosome 2q21-22, which shows complete association with lactase persistence, with the C/C–13910 genotype defining LM and the genotypes C/T–13910 and T/T–13910 lactase persistence. The present study was undertaken to examine the relationship of the C/T–13910 polymorphism to peak bone mass, bone turnover rate, and stress fractures among young Finnish men. The study population comprised 234 young men, aged 18.3 to 20.6 years, 184 men were recruits of the Finnish Army, and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content (BMC), density (BMD), and scan area were measured in the lumbar spine and upper femur by dual-energy X-ray absorptiometry (DXA). Blood was sampled for genotyping of the C/T–13910 polymorphism and determination of serum 25-hydroxyvitamin D (25OHD), intact parathyroid hormone (iPTH), type I procollagen aminoterminal propeptide (PINP), and tartrate-resistant acid phosphatase 5b (TRACP5b). Second-void urine samples were collected for the determination of type I collagen aminoterminal telopeptide (NTX). The prevalence of the C/C–13910-genotype of these young adults did not differ significantly from the corresponding population prevalence of C/C–13910 (17.1% vs 18.1%) among Finnish blood donors. Fifteen recruits of the army experienced a stress fracture; 3 of them (20%) had the C/C–13910-genotype. Calcium intake was similar for the three genotypes as were the unadjusted BMCs, scan areas, and BMDs at different measurement sites. The adjustments for age, height, weight, smoking, alcohol consumption, and physical exercise in the multiple regression analysis did not reveal any significant relationships between the lactase genotypes and BMDs at lumbar (P = 0.16), femoral neck (P = 0.99) or total hip (P = 0.96) sites. Serum 25OHD, iPTH, and bone marker levels were similar for the C/C–13910 C/T–13910 and T/T–13910 genotypes. In summary, in young Finnish men, molecularly defined lactose malabsorption does not alter bone turnover rate and impair the acquisition of peak bone mass. Moreover, the C/C–13910 genotype does not seem to be a risk factor for stress fractures in army recruits.

A Prospective Study of Bone Loss and Turnover after Cardiac Transplantation: Effect of Calcium Supplementation With or Without Calcitonin

Abstract: Cardiac transplantation exposes recipients to osteoporosis and increased risk of consequent fractures. The purpose of the present study was to examine the magnitude, timing and mechanism of bone loss following cardiac transplantation, and to establish whether bone loss can be prevented by calcium with or without calcitonin. Thirty patients (29 men, 1 woman), aged 26 – 68 years (mean 48 years), were randomized into three groups of 10 to receive either no additional treatment, oral calcium 1 g twice daily for 12 months or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months. Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward’s triangle) was measured by dual-energy X-ray absorptiometry (DXA) at the time of transplantation and 6 and 12 months later. Markers of bone formation [serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal propeptide (PICP) and aminoterminal propeptide (PINP)] and resorption [serum type I collagen carboxyterminal telopeptide (ICTP)], as well as serum testosterone in men, were assayed before transplantation and at 1 week and 1, 3, 6 and 12 months after transplantation. During the first 6 post-transplant months BMD calculated as a percent change from baseline decreased in the control group by 6.4% (p= 0.014) in the lumbar spine, by 6.0% (p= 0.003) in the femoral neck, by 5.0% (p= 0.003) in the trochanter and by 5.5% (p= 0.130) in Ward’s triangle. Between 6 and 12 months a further decline in BMD occurred only at the three femoral sites, ranging from 2.2% to 9.8% (p= 0.004-0.079). In comparison with the control group, the group receiving calcium alone lost less bone in the trochanter between 0 and 6 months (p= 0.019), and the group receiving calcium together with calcitonin lost less bone in the femoral neck (p= 0.068) and Ward´s triangle (p= 0.076) between 0 and 12 months. Seven (28%) of 25 assessable patients experienced vertebral compression fractures. Calcium with or without calcitonin had no effect on changes in biochemical parameters; consequently, the three study groups were combined. The markers of bone formation increased, the elevations in mean values being 59% for B-ALP at 1 month (p= 0.009), 152% for PICP at 1 week (p < 0.0001) and 27% for PINP at 1 week (p= 0.021). After a temporary decline at 3 months B-ALP (p= 0.0002) and PINP (p < 0.0001) at 1 year were nearly doubled compared with baseline values. Throughout the study the marker of bone resorption, serum ICTP, was above normal, with a peak (mean values 67–69% above baseline) at 1 week (p= 0.0002) to 1 month (p < 0.0001). The mean concentration of total testosterone was decreased by 48% (p < 0.0001) 1 week and by 28% (p= 0.0005) 1 month after transplantation, but this was mainly explained by the concomitant drop in serum albumin. High bone turnover underlies bone loss after cardiac transplantation. Bone loss is most rapid during the first 6 post-transplant months. In the upper femur this bone loss may be reduced by treatment with calcium and calcitonin.

Relation of collagen type I alpha 1 (COLIA 1) and vitamin D receptor genotypes to bone mass, turnover, and fractures in early postmenopausal women and to hip fractures in elderly people

Background: In a previous study, we showed an association between the vitamin D receptor (VDR) gene BsmI restriction fragment polymorphism and peak bone mass in young Finnish adults. Design: The previous finding prompted us to study the relationship of the same polymorphism, as well as of the polymorphism in the Sp1 binding site of the collagen type I alpha 1 (COLIA 1) gene, to bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry and adjusted for age, weight, height, and lifestyle factors. Also studied was the relationship of VDR and COLIA 1 genotypes to markers of bone turnover [serum osteocalcin, type I procollagen carboxy- (PICP), and aminoterminal (PINP) propeptide, and type I collagen carboxyterminal telopeptide (ICTP)] and bone fractures in 513 early postmenopausal women (1-5 years postmenopausal), as well as hip fractures in 172 very old people. Results: The BB, Bb, and bb genotypes of the VDR gene, as well as the SS, Ss, and ss genotypes of the COLIA 1 gene, were distributed similarly among 402 early postmenopausal women with osteopenia in the lumbar spine and among 111 women with normal BMD (P=0.12 for VDR, P=0.53 for COLIA 1). There was no relation between the VDR and COLIA 1 genotypes and lumbar spine BMD among osteopenic women, among normal women, or in the combined study population. Among the women with vertebral osteopenia, the femoral neck BMD did not associate significantly with the VDR or COLIA 1 polymorphisms. The frequencies of the different VDR and COLIA 1 genotypes were similar among women with or without a history of a low-energy fracture. There was a borderline association between the VDR genotype and serum osteocalcin concentrations, with the Bb genotype associated with the highest median level (P=0.037). In a population-based sample of very old individuals (>85 years), the frequencies of the different VDR and COLIA 1 genotypes were similar among those with (n=64) and without (n=108) a history of hip fracture. Conclusion: The present data suggest that, in the Finnish population, the VDR and COLIA 1 genotypes do not determine the bone mass of early postmenopausal women or their bone turnover rate. The polymorphisms are not associated with risk of hip fractures in elderly people or with low-energy fractures in early postmenopausal women.

The same annual dose of 292000 IU of vitamin D3 (cholecalciferol) on either daily or four monthly basis for elderly women: 1‐year comparative study of the effects on serum 25(OH)D3 concentrations and renal function

Objective  Daily dosing of vitamin D supplements may be difficult among older people. Infrequent administration of ‘megadoses’ controlled by health care personnel may overcome adherence problem. We compared the efficacy and safety of two oral dosages (800 IU daily or 97333 IU four monthly) of vitamin D3 resulting in the equal annual dose of 292000 IU.

Muscle-specific glucose and free fatty acid uptake after sprint interval and moderate-intensity training in healthy middle-aged men

We tested the hypothesis that sprint interval training (SIT) causes larger improvements in glucose and free fatty acid uptake (FFAU) in lower and upper body muscles than moderate-intensity training (MIT). Twenty-eight healthy, untrained, middle-aged men were randomized into SIT (n = 14, 4-6 × 30 s of all-out cycling/4 min recovery) and MIT groups [n = 14, 40-60 min cycling at 60% of peak O2 uptake (V̇o2 peak)] and completed six training sessions within 2 wk. Pre- and postmeasurements included V̇o2 peak, whole body (M-value), muscle-specific insulin-stimulated glucose uptake (GU), and fasting FFAU measured with positron emission tomography in thigh [quadriceps femoris (QF) and hamstrings] and upper body (deltoids, biceps, and triceps brachii) muscles. V̇o2 peak and M-value improved significantly by 6 and 12% in SIT, and 3 and 8% in MIT, respectively,. GU increased significantly only in the QF, and there was no statistically significant difference between the training modes. GU increased in all four heads of QF in response to SIT, but only in the vasti muscles in response to MIT, whereas in rectus femoris the response was completely lacking. Training response in FFAU in QF was smaller and nonsignificant, but it also differed between the training modes in the rectus femoris. In conclusion, SIT and MIT increased insulin-stimulated GU only in the main working muscle QF and not in the upper body muscles. In addition, the biarticular rectus femoris did not respond to moderate-intensity training, reflecting most probably poor activation of it during moderate-intensity cycling.

Mortality in acromegaly: a 20-year follow-up study.

OBJECTIVE It is unclear whether mortality still is increased in acromegaly and whether there are gender-related differences. We dynamically assessed outcome during long-term follow-up in our nationwide cohort. PATIENTS AND METHODS We studied standardized mortality ratios (SMRs) relative to the general population and causes of death in acromegaly (n=333) compared with age- and gender-matched controls (n=4995). RESULTS During 20 (0-33) years follow-up, 113 (34%) patients (n=333, 52% women) and 1334 (27%) controls (n=4995) died (P=0.004). SMR (1.9, 95% CI: 1.53-2.34, P<0.001) and all-cause mortality (OR 1.6, 95% CI: 1.2-2.2, P<0.001) were increased in acromegaly. Overall distribution of causes of death (P<0.001) differed between patients and controls but not cardiovascular (34% vs 33%) or cancer deaths (27% vs 27%). In acromegaly, but not in controls, causes of deaths shifted from 44% cardiovascular and 28% cancer deaths during the first decade, to 23% cardiovascular and 35% cancer deaths during the next two decades. In acromegaly, cancer deaths were mostly attributed to pancreatic adenocarcinoma (n=5), breast (n=4), lung (n=3) and colon (n=3) carcinoma. In acromegaly, men were younger than women at diagnosis (median 44.5 vs 50 years, P<0.001) and death (67 vs 76 years, P=0.0015). Compared with controls, women (36% vs 25%, P<0.01), but not men (31% vs 28%, P=0.44), had increased mortality. CONCLUSIONS In acromegaly, men are younger at diagnosis and death than women. Compared with controls, mortality is increased during 20 years of follow-up, especially in women. Causes of deaths shift from predominantly cardiovascular to cancer deaths.