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.N. Enattah and V.-V. Välimäki equally contributed to the study.     

Determinants of Bone Mineral Density in Middle Aged Men: A Population-Based Study

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 (VO₂max) 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. Received: 30 August 1999 / Accepted: 29 December 1999     

Determinants of Bone Loss in Elderly Men and Women: A Prospective Population-Based Study

While several studies have described the rate and pattern of involutional bone loss in women, far less information is available for men. Furthermore, the roles of lifestyle and body build in determining bone loss rate in both sexes have been largely extrapolated from cross-sectional studies. We addressed this issue in a population-based longitudinal study which sought to ascertain rates of bone loss at the femoral neck and lumbar spine in a cohort of men and women aged 60–75 years at baseline, and to relate this loss to anthropometric and lifestyle variables. We additionally investigated the capacity of biochemical markers of bone turnover to predict bone loss rates in these subjects. Women lost bone at all sites; this ranged from 0.20%/year at the lumbar spine to 1.43%/year at the femoral trochanteric region. By contrast, men lost only 0.20%/year at the trochanteric region, and gained at the lumbar spine (0.33%/year) and at Ward’s triangle (0.27%/year) over the 4-year period. Anthropometric measurements were associated with bone loss in both sexes; lower baseline body mass index (BMI) and a greater rate of loss of adiposity over the follow-up period were both associated with greater bone loss at all proximal femoral sites. These attained statistical significance after Bonferroni correction at the total proximal femur among both men (r= 0.29), p<0.01) and women (r= 0.31, p<0.05). Lifestyle factors associated with lower rates of bone loss (after adjustment for BMI) included alcohol consumption at the femoral neck among women (p= 0.007) and physical activity at the lumbar spine among men (p = 0.05). Serum parathyroid hormone, 25-hydroxyvitamin D and biochemical markers of bone turnover did not predict bone loss after adjustment for adiposity. Received: 8 December 1998 / Accepted: 8 April 1999     

Prediction of Osteoporotic Fractures by Bone Densitometry and COLIA1 Genotyping: A Prospective, Population-Based Study in Men and Women

Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mineral density and increased fracture risk. Although the genetic basis of osteoporosis is incompletely understood, previous studies have identified a polymorphism affecting an Sp1 binding site in the COLIA1 gene that predicts bone mineral density and osteoporotic fractures in several populations. Here we investigated the role of COLIA1 genotyping and bone densitometry in the prediction of osteoporotic fractures in a prospective, population-based study of men (n= 156) and women (n= 185) who were followed up for a mean (± SEM) of 4.88 ± 0.03 years. There was no significant difference in bone density, rate of bone loss, body weight, height, or years since menopause between the genotype groups but women with the “ss” genotype were significantly older than the other genotype groups (p= 0.03). Thirty-nine individuals sustained 54 fractures during follow-up and these predominantly occurred in women (45 fractures in 30 individuals). Fractures were significantly more common in females who carried the COLIA1“s” allele (p= 0.001), although there was no significant association between COLIA1 genotype and the occurrence of fractures in men. Logistic regression analysis showed that carriage of the COLIA1“s” allele was an independent predictor of fracture in women with an odds ratio (OR) [95% CI] of 2.59 [1.23–5.45], along with spine bone mineral density (OR = 1.57 [1.04–2.37] per Z-score unit) and body weight (OR = 1.05 [1.01–1.10] per kilogram). Moreover, bone densitometry and COLIA1 genotyping interacted significantly to enhance fracture prediction in women (p= 0.01), such that the incidence of fractures was 45 times higher in those with low BMD who carried the “s” allele (24.3 fractures/100 patient-years) compared with those with high BMD who were “SS” homozygotes (0.54 fracture/100 patient-years). We conclude that in our population, COLIA1 genotyping predicts fractures independently of bone mass and interacts with bone densitometry to help identify women who are at high and low risk of sustaining osteoporotic fractures. Received: 16 November 2000 / Accepted: 9 June 2000     

Vitamin K Status and Bone Mass in Women With and Without Aortic Atherosclerosis: A Population-Based Study

Gammacarboxyglutamate (Gla) is an uncommon amino acid formed by vitamin K action. Increasing evidence indicates that Gla-proteins are involved in the regulation of calcification processes in both bone tissue and atherosclerotic vessel wall. In a population-based study we have previously shown that in a group of 113 postmenopausal women the presence of abdominal aortic calcifications is associated with a reduced vitamin K status. In the present study we investigated whether this reduced vitamin K status was also associated with differences in bone mass or circulating calciotropic hormone levels. Serum immunoreactive osteocalcin with low affinity for hydroxyapatite (irOC_free) was used as a marker for vitamin K status. After correction for age it was found that women with atherosclerotic calcifications had a 7% lower bone mass as measured by metacarpal radiogrammetry (mean difference: 3.2 mm², 95% CI: −0.2–6.5, P= 0.06). No differences between both groups of women were observed for serum intact parathyroid hormone (PTH) and serum 25-hydroxyvitamin D levels. In the atherosclerotic women (n = 34), markers for vitamin K status were inversely associated with bone mass (r =−0.47, P= 0.013), whereas no such association was found in the nonatherosclerotic women (n = 79). It is concluded that the atherosclerotic women in this study may be at higher risk for osteoporotic fractures as evidenced by their lower bone mass and higher serum irOC_free levels. The finding that in atherosclerotic women vitamin K status is associated with bone mass supports our hypothesis that vitamin K status affects the mineralization processes in both bone and in atherosclerotic plaques. Received: 15 January 1996 / Accepted: 3 May 1996     

Bone Microarchitecture in Transgender Adults: A Cross-Sectional Study

Gender-affirming hormone therapy aligns physical characteristics with an individual's gender identity, but sex hormones regulate bone remodeling and influence bone morphology. We hypothesized that trans men receiving testosterone have compromised bone morphology because of suppression of ovarian estradiol production, whereas trans women receiving estradiol, with or without anti-androgen therapy, have preserved bone microarchitecture. We compared distal radial and tibial microarchitecture using high-resolution peripheral quantitative computed tomography images in a cross-sectional study of 41 trans men with 71 cis female controls, and 40 trans women with 51 cis male controls. Between-group differences were expressed as standardized deviations (SD) from the mean in age-matched cisgender controls with 98% confidence intervals adjusted for cross-sectional area (CSA) and multiple comparisons. Relative to cis women, trans men had 0.63 SD higher total volumetric bone mineral density (vBMD; both p = 0.01). Cortical vBMD and cortical porosity did not differ, but cortices were 1.11 SD thicker (p < 0.01). Trabeculae were 0.38 SD thicker (p = 0.05) but otherwise no different. Compared with cis men, trans women had 0.68 SD lower total vBMD (p = 0.01). Cortical vBMD was 0.70 SD lower (p < 0.01), cortical thickness was 0.51 SD lower (p = 0.04), and cortical porosity was 0.70 SD higher (p < 0.01). Trabecular bone volume (BV/TV) was 0.77 SD lower (p < 0.01), with 0.57 SD fewer (p < 0.01) and 0.30 SD thicker trabeculae (p = 0.02). There was 0.56 SD greater trabecular separation (p = 0.01). Findings at the distal radius were similar. Contrary to each hypothesis, bone microarchitecture was not compromised in trans men, perhaps because aromatization of administered testosterone prevented bone loss. Trans women had deteriorated bone microarchitecture either because of deficits in microstructure before treatment or because the estradiol dosage was insufficient to offset reduced aromatizable testosterone. Prospective studies are needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Soft Drink and Milk Consumption,Physical Activity,Bone Mass,and Upper Limb Fractures in Children: A Population-Based Case-Control Study

Carbonated beverages have been reported to increase fracture risk in children but the mechanism is unclear. The aim of this population-based case-control study was to investigate the association between soft drink and milk consumption, physical activity, bone mass, and upper limb fractures in children aged 9–16 years. A total of 206 fracture cases and 206 randomly selected individually matched controls were studied. There were 47 hand fractures; 128 wrist and forearm fractures, and 31 upper arm fractures. An interviewer-administered questionnaire was utilized to retrospectively assess last-year physical activity (including television, computer, and video watching) and to recall the average weekly consumption of milk, colas, and total carbonated drinks. Bone mass at the spine, hip, and total body was assessed by dual-energy X-ray absorptiometry (DXA) and metacarpal morphometry. For total fractures, none of the above drink types was significantly different between cases and controls. For wrist and forearm fractures, there was a positive association between cola drink consumption and fracture risk (OR 1.39/unit, 95% CI: 1.01, 1.91). Cola consumption was significantly correlated with television, computer, and video watching (r = 0.20, P = 0.001) but not bone mineral density or milk drinks. After adjustment for television, computer, and video watching and bone mineral density, the association between cola drinks and fracture risk became nonsignificant (OR 1.31/unit, 95% CI: 0.94, 1.83). No association with other fracture sites was observed. In conclusion, cola, but not total carbonated beverage consumption, is associated with increased wrist and forearm fracture risk in children. However, this association is not independent of other factors and appears to be mediated by television watching and bone mineral density but not by decreased milk intake.     

Peripubertal Moderate Exercise Increases Bone Mass in Boys but Not in Girls: A Population-Based Intervention Study

On the basis of cross-sectional studies in elite athletes and longitudinal studies, physical activity in growing children has been suggested to enhance bone mineral acquisition and prevent osteoporosis later in life. The level of exercise in most of these studies is not applicable in a population on a day-to-day basis. The aim of this study was to determine whether moderate increased exercise within the school curriculum from age 12 to 16 years would have anabolic bone effects. In a population-based setting of 40 boys and 40 girls the school curriculum was enhanced to physical education 4 times per week for 3–4 years. Controls were 82 boys and 66 girls who had had physical education twice a week over a corresponding period. Both cases and controls were measured at age 16 years. Bone mineral content (BMC), areal bone mineral density (aBMD), bone size (femoral neck width) and volumetric BMD (vBMD) were measured in total body, spine and femoral neck (FN) by dual-energy X-ray absorptiometry. Data are presented as mean ± SD. BMC (8 ± 15%, p= 0.04), aBMD (9 ± 13%, p= 0.002) and vBMD (9 ± 15%, p= 0.001) were all higher in FN in the male intervention group compared with controls. FN bone size was no higher in the intervention group than in the controls. In girls, no differences were found when comparing the intervention group with controls. The results remained after adjusting for confounding factors such as weight, height, milk intake and activity after school. In summary, we report that increased bone mass can be achieved in a population-based cohort of boys (but not in girls) by moderate increased physical activity within the school curriculum from age 12 to 16 years. We speculate that the same results can be seen in girls if intervention starts at an earlier age. We conclude that increasing the physical education content of the Swedish school curriculum may improve bone mass in at least peripubertal boys. Received: 20 April 2000 / Accepted: 17 October 2000     

Cross-Sectional Versus Longitudinal Evaluation of Bone Loss in Men and Women

We evaluated age- and sex-specific differences in bone density at a variety of skeletal sites in a population-based sample of 348 men (age 22–90 years) and 351 women (age 21–93 years) by dual-energy X-ray absorptiometry. Several patterns of age-related bone loss were observed, but adjustments for height (or, where possible, calculation of bone mineral apparent density) dampened the apparent rate of bone loss from most skeletal sites as judged from cross-sectional measurements at baseline. Cross-sectional data also overestimated the rate of bone loss observed longitudinally over 4 years at many sites, particularly the hip and spine; conversely, in some forearm regions, cross-sectional rates of loss underestimated the bone loss seen prospectively. Longitudinal rates of bone loss were generally greater among individuals age 70 years or older compared with younger men and women, but some of the latter effect was due to a greater proportion of younger women on hormone replacement therapy, whose rate of bone loss was generally less. These observations highlight the limitations of cross-sectional data for defining the patterns of bone loss over life at different skeletal sites. Received: 6 January 1999 / Accepted: 10 January 2000     

The Assessment of Bone Mass in Men

Bone mineral density (BMD) is widely used in postmenopausal women to identify who should be given therapy for prevention and treatment of osteoporosis and to monitor the efficacy of treatment. There is still uncertainty about how to interpret BMD in men, and few prospective studies exist on the relationship between BMD and fracture risk. Men should be considered for measurement of BMD if they have suffered low trauma fractures, have prevalent vertebral deformities, have radiographic osteopenia, are over age 75, or have conditions that increase their risk for bone loss, such as hypogonadism, glucocorticoid use, or generally poor health. There is insufficient information to recommend a more widespread BMD screening. The World Health Organization has developed criteria for interpreting BMD which are widely used. Patients with BMD at least 2.5 SD below the young adult mean (T-score < -2.5) have osteoporosis, and those with BMD between 1 and -2.5 SD below the young adult mean (-2.5 < T-score < -1.0) have osteopenia. However, the BMD criteria that should be used to identify men in need of therapeutic intervention are still debated. Using male-specific hip BMD cutoffs, approximately 3-6% of U.S. men 50 years and older were estimated to have osteoporosis and 28-47% to have osteopenia. The corresponding figures in women were 13-18% with osteoporosis and 37-50% with osteopenia. Greater accumulation of skeletal mass during growth, slower rate of bone loss, and shorter life expectancy in men contribute to the lower prevalence of osteoporosis relative to women.     

Ethnic, Anthropometric, and Lifestyle Associations with Regional Variations in Peak Bone Mass

The study investigated the ability of ethnicity and anthropometric and lifestyle factors to account for differences within subjects in bone mass at different skeletal sites. The subjects were young, adult, Japanese, Filipino, Hawaiian, and white women ages 25–34. In the preliminary analyses, they were divided into thirds based on their BMD z-scores. Thirty-five percent exhibited high variability in bone mass: they were in the upper third at one or more bone sites and in the lower third at one or more sites. Other women had more generalized low bone mass: 25% were in the lowest third for two or more sites, and there were no sites with low bone mass in the upper third. In subsequent analyses, ethnicity, anthropometry, and lifestyle influences were examined as possible predictors of differences in bone mineral content (BMC) between bone sites in bone-size adjusted models. White women had greater BMC at the proximal radius and calcaneus than at the distal radius compared with other ethnic groups. This may be explained by the fact that they had exceptionally wide bone widths at the distal radius. Of the anthropometric variables, fat mass was associated with higher bone mass at sites with higher proportions of cancellous tissue (calcaneus > spine > radius sites). Muscle mass was associated with greater bone mass at the calcaneus and proximal radius than at the spine. For the lifestyle variables, women with greater milk consumption between the ages of 10–24 years had higher spine bone mass than expected from their measurements at the proximal radius. Women 12–17 years of age who had been more active in sports had higher calcaneous bone mass than expected from their spine measurements. As the study participants were still young women, the results suggest that regional differences in bone mass may partly derive from anthropometric and lifestyle influences during skeletal maturation. Received: 6 March 1998 / Accepted: 15 December 1998     

Increased Trabecular Volumetric Bone Mass Density in Familial Hypocalciuric Hypercalcemia (FHH) Type 1: A Cross-Sectional Study

Familial Hypocalciuric Hypercalcaemia (FHH) Type 1 is caused by an inactivating mutation in the calcium-sensing receptor (CASR) gene resulting in elevated plasma calcium levels. We investigated whether FHH is associated with change in bone density and structure. We compared 50 FHH patients with age- and gender-matched population-based controls (mean age 56 years, 69 % females). We assessed areal BMD (aBMD) by DXA-scans and total, cortical, and trabecular volumetric BMD (vBMD) as well as bone geometry by quantitative computed tomography (QCT) and High-Resolution peripheral-QCT (HR-pQCT). Compared with controls, FHH females had a higher total and trabecular hip vBMD and a lower cortical vBMD and hip bone volume. Areal BMD and HRpQCT indices did not differ except an increased trabecular thickness and an increased vBMD at the transition zone between cancellous and cortical bone in of the tibia in FHH. Finite element analyses showed no differences in bone strength. Multiple regression analyses revealed correlations between vBMD and P-Ca²⁺ levels but not with P-PTH. Overall, bone health does not seem to be impaired in patients with FHH. In FHH females, bone volume is decreased, with a lower trabecular volume but a higher vBMD, whereas cortical vBMD is decreased in the hip. This may be due to either an impaired endosteal resorption or corticalization of trabecular bone. The smaller total bone volume suggests an impaired periosteal accrual, but bone strength is not impaired. The findings of more pronounced changes in females may suggest an interaction between sex hormones and the activity of the CaSR on bone.     

The Relationship of Ghrelin and Adiponectin with Bone Mineral Density and Bone Turnover Markers in Elderly Men

Body weight is commonly considered a significant predictor of bone mineral density (BMD). Adiponectin, an adipocyte-derived hormone, could modulate BMD. Moreover, recent studies have reported that ghrelin is able to stimulate bone formation. In this study, we investigated any associations of adiponectin and ghrelin serum levels with bone turnover markers and BMD in elderly men. In 137 men aged 55 years and older (mean age 67.4 +/- 5.4 years, mean body mass index [BMI] 26.6 +/- 3.4 kg/m(2)), we evaluated serum adiponectin, serum ghrelin, body composition (fat mass and lean mass), BMD, bone alkaline phosphatase (ALP), and the carboxy-terminal telopeptide of type I collagen (betaCTX). Ghrelin showed significant correlations with BMD at the femoral neck (r = 0.25, P < 0.01), total femur (r = 0.22, P < 0.05), and whole body (r = 0.18, P < 0.05). However, after adjusting for age, BMI, and calcium intake, the correlation remained significant only for femoral neck BMD. Ghrelin showed a significant correlation with lean mass but not with fat mass and bone turnover markers. Adiponectin showed a positive association with both bone ALP and betaCTX; the correlation between adiponectin and bone ALP (r = 0.25, P < 0.01) remained significant after adjusting for confounding variables. No significant correlations between adiponectin and BMD at all skeletal sites were observed. In conclusion, our study suggests that in elderly Italian men serum ghrelin was significantly associated with femoral neck BMD and that adiponectin was positively associated with bone ALP. Further studies are needed to elucidate the role of adipocytokines in bone metabolism.     

Choice of Lumbar Spine Bone Density Reference Database for Fracture Prediction in Men and Women: A Population-Based Analysis

The diagnosis of osteoporosis in men is controversial, although most studies demonstrate similar fracture rates for men and women with the same level of hip bone mineral density (BMD). Whether this applies to the lumbar spine is currently uncertain and has important implications with respect to choice of reference population for T-score calculation and osteoporosis diagnosis. This question was specifically addressed in the population-based Canadian Multicentre Osteoporosis Study cohort of 4745 women and 1887 men ages 50+ yr at the time of baseline lumbar spine dual energy x-ray absorptiometry. In up to 10 yr of observation, incident clinical major osteoporotic fractures occurred in 110 men (5.8%) vs 543 women (11.4%) (p < 0.001). Mean lumbar spine BMD in men was greater than in women, both among those with and those without incident major osteoporotic fracture (p < 0.001). Men were at slightly lower risk for incident major osteoporotic fracture than women for an equivalent lumbar spine BMD (age- and BMD-adjusted rate ratio 0.75, 95% confidence interval 0.60–0.93, p = 0.008) with similar findings after adjustment for the World Health Organization fracture risk assessment clinical risk factors or competing mortality. No significant sex difference in the BMD relationship was seen for vertebral fractures (clinical or radiographic) or for all fractures. In summary, this large population-based longitudinal cohort study found similar or lower fracture risk for men vs women after adjustment for absolute lumbar spine BMD and additional covariates. The least complicated model for describing fracture risk is therefore to use the same reference lumbar spine data for generating T-scores in men and women.