Polymorphisms of the peroxisome proliferator-activated receptor �� (PPAR��) gene are associated with osteoporosis

Summary

Stimulation of PPAR?? turns mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the PPAR?? gene on BMD and fracture risk in two Danish cohorts and found opposing effects of certain SNPs and haplotypes in the two cohorts probably owing to environmental factors.

Introduction

Stimulation of PPAR?? causes development of mesenchymal stem cells to adipocytes instead of osteoblasts leading to decreased osteoblast number and BMD. The aim of this study was to examine the effect of PPARG polymorphisms on BMD and fracture risk in two Danish cohorts: AROS, a case-control population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for 10?years. On the basis of linkage disequilibrium between SNPs throughout the gene and previous studies we chose 10 polymorphisms for investigation.

Methods

In AROS, individuals heterozygous for the polymorphisms rs12497191, rs4135263, and rs1151999 had an increased risk of vertebral fractures (OR?=?1.48?1.76, p?=?0.005?0.04) compared with individuals homozygous for the common allele. In DOPS, individuals heterozygous for rs1151999 had an increased BMD at the hip sites (p????0.02). An interaction between rs1151999 and diet was found on BMD in both cohorts.

Results

For the polymorphism rs1152003 there was an interaction with body weight on BMD at all sites in both cohorts (p????0.07). Stratified analyses revealed that in the high weight group in AROS individuals homozygous for the variant allele had a decreased BMD (p????0.02), whereas the same pattern was found in the low weight group in DOPS (p????0.03). A number of haplotype associations were found as well, the direction of which was opposite in the two cohorts.

Conclusion

Our study suggests an association SNPs in PPARG and haplotypes thereof and BMD and fracture risk. The effect however appears to be modifiable by environmental factors.     

Polymorphisms in the ALOX12 gene and osteoporosis

Summary

ALOX12 produces ligands for PPAR?? thereby turning mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the ALOX12 gene on BMD and fracture risk in two Danish cohorts and found four polymorphisms and a haplotype thereof to be associated with BMD and fracture risk.

Introduction

Stimulation of the PPAR?? with ligands produced by the ALOX enzymes drives mesenchymal stem cells in an adipocyte direction at the expense of osteoblasts leading to decreased osteoblast number and BMD. Previously, polymorphisms in the ALOX12 gene have been associated with osteoporosis.

Methods

We examined the effect of ALOX12 polymorphisms on BMD and the risk of fractures in two Danish cohorts: AROS, a case?Ccontrol population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for up to 10?years. On the basis of linkage disequilibrium (LD) between SNPs throughout the gene and previous genetic association studies we chose ten polymorphisms for investigation. Genotyping was carried out using the Sequenom MassARRAY genotyping system and TaqMan assays.

Results

In AROS, individuals heterozygous for the polymorphisms rs3840880, rs9897850, rs2292350 and rs1126667 had a 3.0?C4.7% decreased lumbar spine BMD (p?=?0.02?C0.06) and an increased risk of vertebral fractures (p?<?0.05) compared with individuals homozygous for either allele. In DOPS, none of the individual SNPs were associated with BMD or incident fractures. In both cohorts, the above-mentioned SNPs comprised an LD-block (pairwise D???=?1.0, r ²?=?0.45?C0.97). A haplotype comprising all the common alleles (frequency 9%) was associated with decreased bone loss at the hip (p?<?0.05) and decreased incidence of osteoporotic fractures (p?<?0.05) in DOPS and increased femoral neck BMD in AROS (p?<?0.05).

Conclusion

Our study suggests that genetic variants in ALOX12 may influence BMD and fracture risk.     

The correlation between calcaneus stiffness index calculated by QUS and total body BMD assessed by DXA in Chinese children and adolescents

Few studies have shown comparison data between calcaneus stiffness index (SI) calculated by quantitative ultrasound (QUS) and bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) in the Chinese population. This study was aimed to examine the correlations between calcaneus SI calculated by QUS and total body BMD and bone mineral content (BMC) measured by DXA in Chinese children and adolescents. We measured the total body BMD and BMC using Lunar Prodigy (GE Healthcare), and speed of sound (SOS), broadband ultrasound attenuation (BUA), and a calculated SI of the left os calcis using Lunar Achilles Express (GE Healthcare) in 392 healthy Chinese schoolchildren and adolescents aged 5–19 years. The short-term precision for DXA was 0.5 % for total body BMD. The precision for QUS was 1.8 % for SI, 2.9 % for BUA, and 0.4 % for SOS. Pearson’s correlation coefficients (r) were calculated to assess the possible correlations between the total body BMC by DXA and SI calculated by QUS. There were significantly positive correlations between SI of the left os calcis and total body BMD (r = 0.693, p < 0.001, n = 392) and BMC (r = 0.690, p < 0.001, n = 392). For all the subjects, significant positive correlations were observed between the calcaneal SI and the age, weight, height, BMI, total body BMD, total body BMC, total body lean mass, and total body fat mass, with r ranging from 0.310 (total body fat mass) to 0.693 (total body BMD) (p < 0.001, n = 392). In conclusion, QUS bone densitometry is a useful measuring method showing the physiological bone development in childhood and adolescence.     

Once-weekly teriparatide reduces the risk of vertebral fracture in patients with various fracture risks: subgroup analysis of the Teriparatide Once-Weekly Efficacy Research (TOWER) trial

Once-weekly teriparatide (human parathyroid hormone [1–34]) (56.5 μg for 72 weeks) injections provided a vertebral fracture risk reduction in Japanese osteoporotic patients evaluated in the Teriparatide Once-Weekly Efficacy Research (TOWER) trial. Using data from the TOWER trial, a subgroup analysis was performed to study the efficacy of once-weekly teriparatide for a variety of baseline clinical risk factors in placebo (n = 281) and teriparatide (n = 261) groups. Significant fracture risk reductions were observed in the subgroups of individuals aged <75 years [relative risk (RR) 0.06, p = 0.007] and ≥75 years (RR 0.32, p = 0.015). A significant risk reduction was observed among patients with prevalent vertebral fracture in the subgroup with 1 (RR 0.08, p = 0.015) or ≥2 (RR 0.29, p = 0.009) prevalent vertebral fractures, and in those with grade 3 deformity (RR 0.26, p = 0.003). Significant risk reduction was observed in the subgroup with lumbar bone mineral density (BMD) < ?2.5 SD (RR 0.25, p = 0.035). In the teriparatide group, no incident fracture was observed in the subgroups with a prevalent vertebral fracture number of 0, with grade 0–2 vertebral deformity, or with lumbar BMD ≥2.5 SD. Significant risk reduction was observed in all of the bone turnover marker and estimated glomerular filtration rate subgroups. In conclusion, once-weekly 56.5 μg teriparatide injection reduced the vertebral fracture risk in patients with varying degrees of fracture risk, age, vertebral fracture number and grade, bone turnover level, and renal function.     

Plasma Level of Homocysteine Associated with Severe Vertebral Fracture in Postmenopausal Women

The aim of this cross-sectional cohort study was to clarify risk factors for severe vertebral fractures in postmenopausal Japanese women. Subjects were ambulatory volunteers age over 50 years who were recruited from a population of outpatients at a primary care institute. At registration, age, body mass index (BMI), bone mineral density (BMD), and present illness were investigated. Biochemical parameters including urinary levels of type I collagen cross-linked N-telopeptides (NTXs), and pentosidine and plasma levels of homocysteine were measured. Values were compared with different fracture grades (grade 0–3). A total of 1,475 postmenopausal women (66.6 ± 9.0 years) were included in the present study. Distributions of vertebral fracture grades were grade 1, 137 cases (9.3 %); grade 2, 124 cases (8.4 %); and grade 3, 162 cases (11.0 %). Age, BMI, BMD, NTX, pentosidine, and homocysteine were significantly associated with vertebral fracture in unadjusted analysis. In addition, a higher prevalence of hypertension was observed in patients with severe fracture. When comparing vertebral fracture grade 0 versus grade 2–3 by multiple regression analysis, pentosidine and homocysteine levels were a significant risk for moderate/severe vertebral fracture (odds ratio [OR] = 1.17, 95 % confidence interval [CI] 1.00–1.38, p = 0.049; OR = 1.22, 95 % CI 1.03–1.46, p = 0.013). Homocysteine levels were also a significant risk when comparing vertebral fracture grade 0 versus grade 3 (OR = 1.27, 95 % CI 1.04–1.58, p = 0.021). Plasma level of homocysteine was an independent risk for severe vertebral fractures.     

Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis

Risedronate decreases osteoporotic fracture incidence; however, its effects remain unclear in elderly osteoporotic patients. Vitamin K mediates carboxylation of osteocalcin (OC), and high undercarboxylated osteocalcin (ucOC) levels indicate vitamin K deficiency and increased osteoporotic fracture risk. We aimed to evaluate the effects of risedronate alone or combined with vitamin K₂ on serum ucOC, OC, and incidence of vertebral fractures in elderly osteoporotic patients. A total of 101 women with postmenopausal osteoporosis aged >60 years were randomly stratified into two groups—R group (n = 51), treated with risedronate alone; and R + K group (n = 50), treated with risedronate and vitamin K₂. Serum ucOC, OC and incidence of vertebral fractures were evaluated before treatment and at 6 and 12 months post-treatment. Decreased ucOC rates at 6 and 12 months were not significant between groups. However, at 6 and 12 months, decreased OC rates in the R group (p < 0.01 and 0.05, respectively) were significantly higher than in the R + K group, and ucOC/OC change rates in the R group (p < 0.05 and 0.001, respectively) were significantly lower than in the R + K group. Vertebral fracture incidence was not significantly different between the groups at 6 and 12 months. ucOC levels in patients with incident vertebral fractures were significantly higher than in patients without incident vertebral fractures in the R group at 6 months (p < 0.05). Although no significant difference was observed for ucOC decrease rate and incidence of vertebral fractures between treatments, ucOC levels in patients with incident vertebral fractures were significantly greater than in patients without when using risedronate alone.     

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     

Cortical and trabecular bone structure analysis at the distal radius—prediction of biomechanical strength by DXA and MRI

The purpose of this study was to investigate whether the combination of dual-energy X-ray absorptiometry (DXA)-based bone mass and magnetic resonance imaging (MRI)-based cortical and trabecular structural measures improves the prediction of radial bone strength. Thirty-eight left forearms were harvested from formalin-fixed human cadavers. Bone mineral content (BMC) and bone mineral density (BMD) of the distal radius were measured using DXA. Cortical and trabecular structural measures of the distal radius were computed in high-resolution 1.5T MR images. Cortical measures included average cortical thickness and cross-sectional area. Trabecular measures included morphometric and texture parameters. The forearms were biomechanically tested in a fall simulation to measure absolute radial bone strength (failure load). Relative radial bone strength was determined by dividing radial failure loads by age, body mass index, radius length, and average radius cross-sectional area, respectively. DXA derived BMC and BMD showed statistically significant (p < 0.05) correlations with absolute and relative radial bone strength (r ≤ 0.78). Correlation coefficients for cortical and trabecular structural measures with absolute and relative radial bone strength amounted up to r = 0.59 and r = 0.74, respectively, (p < 0.05). In combination with DXA-based bone mass, trabecular but not, cortical structural measures, added in multiple regression models significant (p < 0.05) information in predicting absolute and relative radial bone strength (up to R _adj = 0.88). Thus, a combination of DXA-based bone mass and MRI-based trabecular structural measures most accurately predicted absolute and relative radial bone strength, whereas structural measures of the cortex did not provide significant additional information in combination with DXA.     

Influence of education,marital status,occupation, and the place of living on skeletal status,fracture prevalence,and the course and effectiveness of osteoporotic therapy in women in the RAC-OST-POL Study

The RAC-OST-POL population-based, epidemiological study provided data concerning the influence of education, marital status, occupation, and the place of living (residence) on skeletal status, fracture prevalence, and the course and effectiveness of osteoporotic therapy in 625 women older than 55 years, all of them recruited from the District of Raciborz in Poland. Their mean age was 66.4 ± 7.8 years. All the women completed a specially designed questionnaire. The skeletal status was assessed by femoral neck (FN) and total hip (TH) densitometry, using a Lunar DPX system (USA). In univariate analyses, taking into consideration the age differences, bone mineralization was dependent on marital status (Z score for FN and TH was significantly higher in widows than in divorcees; p < 0.05), place of residence (better results in rural areas; p < 0.05), and occupation (better in standing than sitting jobs; p < 0.05 for FN Z score and p < 0.01 for TH Z score). The multivariate model allowed us to verify that only place of living and type of occupation had a significant influence on densitometry results. In direct comparison, fracture prevalence seemed to be borderline significantly more common in widows (33.5 %) and least common among divorcees (11.8 %) (χ ² = 6.9, df = 3, p = 0.07), but reanalysis performed after age adjustment excluded a true impact of marital status on fracture occurrence. Other factors did not affect fracture occurrence. Some factors influenced the use of medications for osteoporosis: higher level of education was associated with a more frequent use of vitamin D (χ ² = 8.49, df = 3, p < 0.05) and of hormone replacement therapy (HRT) (χ ² = 35.7, df = 3, p < 0.00001). HRT was most commonly used by unmarried women (30 %) and least commonly by divorcees (11.8 %) (χ ² = 11.7, df = 3, p = 0.01). Vitamin D was more often used among women from the urban area of Raciborz than by those from surrounding rural areas (χ ² = 9.2, df = 1, p < 0.01). The frequency of use of the three aforementioned medications was associated with the character of occupation. Women with sedentary jobs demonstrated the highest frequency of intake for vitamin D (χ ² = 9.92, df = 3, p < 0.05) and HRT (χ ² = 19.48, df = 3, p < 0.001) as well as for other antiresorptive medications (χ ² = 8.18, df = 3, p < 0.05). We concluded that the results of the epidemiological study demonstrate that both skeletal status and use of antiosteoporotic medications were partially modified by analyzed social factors, whereas fracture prevalence was generally independent from those factors. These data suggest that education, marital status, place of living, and type of occupation may have impacts on implementation of osteoporosis-preventing health programs.     

Haplotypes of Promoter and Intron 1 Polymorphisms in the <Emphasis Type="Italic">COLIA1</Emphasis> Gene Are Associated with Increased Risk of Osteoporosis

Osteoporosis is a common age-related disease with a strong genetic influence. COLIA1 is one of the most extensively studied candidate genes and has consistently been associated with BMD and fracture. We examined the effects of the polymorphisms –1997G>T, –1663indelT, and +1245G>T and their haplotypes on vertebral fractures and bone mineral density (BMD) in a case-control study comprising 462 osteoporotic patients and 336 controls. The ?1663indelT polymorphism was associated with a decreased lumbar spine (ls) BMD, 0.75 ± 0.14 g/cm², in individuals with the del/del genotype versus 0.83 ± 0.18 and 0.85 ± 0.18 g/cm² in individuals with the ins/del and ins/ins genotypes, respectively (p = 0.02). The T-allele of the +1245G>T polymorphism, which was in strong linkage disequilibrium (LD) with –1663indelT, was also associated with a decreased lsBMD (p = 0.02). –1997G>T was not significantly associated with lsBMD. The three most common haplotypes accounted for 98.5% of the alleles. Individuals with one or two copies of haplotype 1 (–1997G/–1663ins/+1245G) had a significantly higher lsBMD, 0.84 ± 0.18 and 0.85 ± 0.15 g/cm², respectively, versus 0.78 ± 0.15 g/cm² in noncarriers (p = 0.01). Individuals with two copies of haplotype 2 (–1997G/–1663del/+1245T) had a significantly lower lsBMD, 0.76 ± 0.14 g/cm², versus 0.85 ± 0.18 and 0.82 ± 0.18 g/cm², respectively, in individuals with zero or one copy (p = 0.03). The odds ratio for vertebral fracture in individuals carrying the variant T-allele of the –1997G>T polymorphism was 1.49 (CI, 1.03–2.16; p = 0.03). Logistic regression revealed that this effect was partly independent of BMD. In conclusion, the ?1663del and +1245T alleles influence BMD negatively, whereas the –1997T-allele has a minor effect on BMD but increases the risk of vertebral fractures. These findings are in agreement with functional studies showing that these polymorphisms influence gene expression.     

Bone mineral loss at the proximal femur in acute spinal cord injury

Summary

This study used quantitative computed tomography to assess changes in bone mineral at the proximal femur after acute spinal cord injury (SCI). Individuals with acute SCI experienced a marked loss of bone mineral from a combination of trabecular and endocortical resorption. Targeted therapeutic interventions are thus warranted in this population.

Introduction

SCI is associated with a rapid loss of bone mineral and an increased rate of fragility fracture. Some 10 to 20 % of these fractures occur at the proximal femur. The purpose of this study was to quantify changes to bone mineral, geometry, and measures of strength at the proximal femur in acute SCI.

Methods

Quantitative computed tomography analysis was performed on 13 subjects with acute SCI at serial time points separated by a mean of 3.5 months (range, 2.6–4.8 months). Changes in bone mineral content (BMC) and volumetric bone mineral density (vBMD) were quantified for integral, trabecular, and cortical bone at the femoral neck, trochanteric, and total proximal femur regions. Changes in bone volumes, cross-sectional areas, and surrogate measures of compressive and bending strength were also determined.

Results

During the acute period of SCI, subjects experienced a 2.7–3.3 %/month reduction in integral BMC (p?<?0.001) and a 2.5–3.1 %/month reduction in integral vBMD (p?<?0.001). Trabecular BMC decreased by 3.1–4.7 %/month (p?<?0.001) and trabecular vBMD by 2.8–4.4 %/month (p?<?0.001). A 3.9–4.0 %/month reduction was observed for cortical BMC (p?<?0.001), while the reduction in cortical vBMD was noticeably lower (0.8–1.0 %/month; p?≤?0.01). Changes in bone volume and cross-sectional area suggested that cortical bone loss occurred primarily through endosteal resorption. Declines in bone mineral were associated with a 4.9–5.9 %/month reduction in surrogate measures of strength.

Conclusions

These data highlight the need for therapeutic interventions in this population that target both trabecular and endocortical bone mineral preservation.     

A Pediatric Bone Mass Scan Has Poor Ability to Predict Adult Bone Mass: A 28-Year Prospective Study in 214 Children

As the correlation of bone mass from childhood to adulthood is unclear, we conducted a long-term prospective observational study to determine if a pediatric bone mass scan could predict adult bone mass. We measured cortical bone mineral content (BMC [g]), bone mineral density (BMD [g/cm²]), and bone width (cm) in the distal forearm by single photon absorptiometry in 120 boys and 94 girls with a mean age of 10 years (range 3–17) and mean 28 years (range 25–29) later. We calculated individual and age-specific bone mass Z scores, using the control cohort included at baseline as reference, and evaluated correlations between the two measurements with Pearson’s correlation coefficient. Individual Z scores were also stratified in quartiles to register movements between quartiles from growth to adulthood. BMD Z scores in childhood and adulthood correlated in both boys (r = 0.35, p < 0.0001) and girls (r = 0.50, p < 0.0001) and in both children ≥10 years at baseline (boys r = 0.43 and girls r = 0.58, both p < 0.0001) and children <10 years at baseline (boys r = 0.26 and girls r = 0.40, both p < 0.05). Of the children in the lowest quartile of BMD, 58 % had left the lowest quartile in adulthood. A pediatric bone scan with a value in the lowest quartile had a sensitivity of 48 % (95 % confidence interval [CI] 27–69 %) and a specificity of 76 % (95 % CI 66–84 %) to identify individuals who would remain in the lowest quartile also in adulthood. Childhood forearm BMD explained 12 % of the variance in adult BMD in men and 25 % in women. A pediatric distal forearm BMD scan has poor ability to predict adult bone mass.     

Adverse Effects of Smoking on Peak Bone Mass May Be Attenuated by Higher Body Mass Index in Young Female Smokers

Smoking is associated with postmenopausal bone loss and fracture, but the effect of smoking on bone in younger women is unclear. Peak bone mass is an important determinant for fracture risk; therefore, our aim was to evaluate the association between smoking and bone mass in 25-year-old women, specifically the influence of daily cigarette consumption and total exposure, duration, age at starting smoking, and time since smoking cessation on bone density and fracture risk. Smoking and bone mineral density (BMD) data were available for 1,054 women from the PEAK-25 cohort. Analyses comparing current smokers with women who never smoked were performed using number of cigarettes per day, pack-years, smoking duration, age smoking started, and, for former smokers, age at quitting. BMD did not differ between never, former, and current smokers; and the relative fracture risk in smokers was not significant (relative risk [RR] = 1.2, 95 % confidence interval 0.8–1.9). Among current smokers, BMD decreased with a dose response as cigarette consumption increased (femoral neck p = 0.037). BMD was not significantly lower in young women who had smoked for long duration or started smoking early (p = 0.07–0.64); long duration and early start were associated with higher body mass index (BMI; p = 0.038). Lower BMD persisted up to 24 months after smoking cessation (p = 0.027–0.050), becoming comparable to never-smokers after 24 months. Hip BMD was negatively associated with smoking and dose-dependent on cigarette consumption. Smoking duration was not associated with BMD, although young women with a long smoking history had higher BMI, which might attenuate the adverse effects from smoking.     

Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of aged rats

Bisphosphonates and low-intensity pulsed ultrasound (LIPUS) are both known to maintain or promote callus formation during diaphyseal fracture healing. However, the effect of these treatments on the repair of metaphyseal fractures has not been elucidated. To evaluate the effects of bisphosphonates and/or LIPUS on cancellous bone healing, an osteotomy was performed on the proximal tibial metaphysis of 9-month-old Sprague–Dawley rats (n = 64). Treatment with alendronate (1 μg/kg/day), LIPUS (20 min/day), or a combination of both was administered for 2 or 4 weeks, after which changes in bone mineral density (BMD), bone histomorphometric parameters, and the rate of cancellous bony bonding were measured. Alendronate suppressed bone resorption parameters at 2 weeks (p = 0.019) and increased bone volume and BMD at 4 weeks (p = 0.034 and p = 0.008, respectively), without affecting bony bonding. LIPUS had no significant effect on any of the histomorphometric parameters at 2 or 4 weeks, but significantly increased in BMD at 4 weeks (p = 0.026) as well as the percentage of bony bonding at both 2 and 4 weeks (p < 0.01). The combined therapy also showed significantly increased BMD compared with the control group at 4 weeks (p = 0.010) and showed a trend toward increased bony bonding. In conclusion, alendronate and LIPUS cause an additive increase in BMD at the affected metaphysis: alendronate increases the bone volume at the osteotomy site without interrupting metaphyseal repair, whereas LIPUS promotes metaphyseal bone repair, without affecting bone histomorphometric parameters.     

Birth weight is more important for peak bone mineral content than for bone density: the PEAK-25 study of 1,061 young adult women

Summary

Lower birth weight has a negative association with adult BMC and body composition in young adult Swedish women.

Introduction

The aim of this study was to evaluate the influence of birth weight on peak bone mass and body composition in a cohort of 25-year-old women.

Methods

One thousand sixty-one women participated in this cross-sectional population-based study using dual energy X-ray absorptiometry (DXA) to assess bone mineral content (BMC), bone mineral density (BMD), and body composition (total body (TB), femoral neck (FN), total hip (TH), lumbar spine L1–L4 (LS), and lean and fat mass). Birth weight data was available for 1,047 women and was categorized into tertiles of low (≤3,180 g), intermediate (3,181–3,620 g), and high (≥3,621 g) birth weight.

Results

Significant correlations were observed between birth weight and TB-BMC (r?=?0.159, p?<?0.001), FN-BMC (r?=?0.096, p?<?0.001), TH-BMC (r?=?0.102, p?=?0.001), LS-BMC (r?=?0.095, p?=?0.002), and lean mass (r?=?0.215, p?<?0.001). No correlation was observed between birth weight and BMD. The estimated magnitude of effect was equivalent to a 0.3–0.5 SD difference in BMC for every 1 kg difference in birth weight (151 g (TB); 0.22 g (FN); 1.5 g (TH), 2.5 kg TB lean mass). The strongest correlations between birth weight and BMC occurred in women with lowest birth weights, although excluding women who weighed <2,500 g at birth, and the correlation remained significant although slightly weaker.

Conclusions

Women with lower birth weight have lower BMC and less lean and fat mass at the age of 25, independent of current body weight. Lower birth weight has a greater negative influence on bone mass than the positive influence of higher birth weight.     

The p.R229Q variant of the NPHS2 (podocin) gene in focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome: a meta-analysis

While many previous studies have reported an association between the p.R229Q variant of the NPHS2 gene and focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS), a conclusive relationship has not been defined. In this study, we performed a meta-analysis of the published data to investigate the impact of the p.R229Q polymorphism on FSGS and SRNS patients. Despite significant heterogeneity within some of the comparisons, the results revealed significantly higher risks of SRNS in individuals homozygous for the variant allele (OR 7.411, 95 % confidence interval 1.876–29.436, p = 0.004) compared to homozygous non-variant individuals. However, the carrier rate of the p.R229Q variant was not significantly different between SRNS patients and steroid-sensitive nephrotic syndrome patients. No statistically significant differences in the p.R229Q carrier rate were observed between FSGS patients and controls or FSGS patients and patients with different pathology classifications. No notable differences in the p.R229Q carrier rate were found between patients and controls in any group with early-onset disease (onset age < 18). In conclusion, our meta-analysis suggests that for adult-onset disease (onset age > 18), the homozygous variant could be a potential predictor of hereditary nephrotic syndrome and that the p.R229Q allele cannot currently be considered a risk factor for predicting FSGS.     

Effect of parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism

The objective of the study was to evaluate the effect of parathyroidectomy (PTX) versus 35 mg once-weekly (ow) risedronate administration on volumetric bone mineral density (vBMD) and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism (PHPT). Our open-label prospective observational study included 32 postmenopausal women with PHPT as the study group: 16 underwent PTX and 16 were treated with 35 mg ow risedronate for 2 years. We assessed areal BMD (aBMD) by DXA, and vBMD and bone mineral content (BMC) (cortical and trabecular area) by peripheral quantitative computed tomography (pQCT) at the tibia at baseline and at 2 years. Risedronate did not result in any significant change on vBMD and structural pQCT indices. PTX resulted in significant increase in trabecular (trab) BMC (6.44 %) and vBMD (4.64 %), with percent increase being significantly higher than risedronate (p < 0.05). At cortical sites, there was no significant change following PTX. However, the percent change in cortical (cort) vBMD was higher following PTX versus risedronate (0.39 % vs. ?0.26 %, p < 0.05). In conclusion, in postmenopausal women with PHPT, PTX is superior to ow risedronate, in terms of improvement of trabecular mineralization and vBMD at the tibia, whereas the effect at cortical sites is less pronounced.     

Association between estrogen receptor-β dinucleotide repeat polymorphism and incidence of femoral fracture

Estrogens are thought to play an important role in bone metabolism through estrogen receptors (ER). Dinucleotide (cytosine–adenine, CA) repeat polymorphism in the human ER-β gene (ESR2) has been reported to be associated with bone mineral density. We aimed to further elucidate the importance of this polymorphism in the pathogenesis of osteoporosis by examining its association with the incidence of femoral fracture. Deoxyribonucleic acids extracted from the renal cortex of 1489 consecutive Japanese autopsies (799 male, mean age 79 years, 690 female, mean age 82 years) with complete clinical/pathological data were enrolled in the study. ESR2 CA repeat polymorphism was determined by polymerase chain reaction using fluorescein-labeled primers. The presence or absence of femoral fracture during each subject’s lifetime was determined by thorough examination of the clinical record. Incidence of femoral fracture in subjects bearing at least one allele of 20 CA repeats (4/132, 3.0 %) was significantly lower than in those without this allele (127/1357, 9.4 %, P = 0.0098). After adjustments for age and sex, logistic regression analysis revealed that having no allele of 20 CA repeats was an independent risk factor of femoral fracture [adjusted odds ratio (OR) 3.875, 95 % confidence interval (CI) 1.392–10.788, P = 0.0095], which was emphasized among women (adjusted OR 6.360, 95 % CI 1.520–26.618, P = 0.0133). Japanese subjects, especially women, bearing at least one allele of 20 CA repeats in the ESR2 may have a lower risk of femoral fracture than those without it, suggesting this polymorphism plays a role in bone metabolism.     

Bone mineral and stiffness loss at the distal femur and proximal tibia in acute spinal cord injury

Summary

Computed tomography and finite element modeling were used to assess bone mineral and stiffness loss at the knee following acute spinal cord injury (SCI). Marked bone mineral loss was observed from a combination of trabecular and endocortical resorption. Reductions in stiffness were 2-fold greater than reductions in integral bone mineral.

Introduction

SCI is associated with a rapid loss of bone mineral and an increased rate of fragility fracture. The large majority of these fractures occur around regions of the knee. Our purpose was to quantify changes to bone mineral, geometry, strength indices, and stiffness at the distal femur and proximal tibia in acute SCI.

Methods

Quantitative computed tomography (QCT) and patient-specific finite element analysis were performed on 13 subjects with acute SCI at serial time points separated by a mean of 3.5 months (range 2.6–4.8 months). Changes in bone mineral content (BMC) and volumetric bone mineral density (vBMD) were quantified for integral, trabecular, and cortical bone at epiphyseal, metaphyseal, and diaphyseal regions of the distal femur and proximal tibia. Changes in bone volumes, cross-sectional areas, strength indices and stiffness were also determined.

Results

Bone mineral loss was similar in magnitude at the distal femur and proximal tibia. Reductions were most pronounced at epiphyseal regions, ranging from 3.0 % to 3.6 % per month for integral BMC (p?<?0.001) and from 2.8 % to 3.4 % per month (p?<?0.001) for integral vBMC. Trabecular BMC decreased by 3.1–4.4 %/month (p?<?0.001) and trabecular vBMD by 2.7–4.7 %/month (p?<?0.001). A 3.8–5.4 %/month reduction was observed for cortical BMC (p?<?0.001); the reduction in cortical vBMD was noticeably lower (0.6–0.8 %/month; p?≤?0.01). The cortical bone loss occurred primarily through endosteal resorption, and reductions in strength indices and stiffness were some 2-fold greater than reductions in integral bone mineral.

Conclusions

These findings highlight the need for therapeutic interventions targeting both trabecular and endocortical bone mineral preservation in acute SCI.     

Bone turnover markers in patients with prostate carcinoma: influence of sex steroids levels

There are limited data about bone turnover markers (BTM) in androgen deprivation therapy (ADT)-treated prostate cancer (PCa) patients, and the relationship between sex steroids, bone mass, and BTM has not been explored. Our objective was to analyze the influence of sex steroids levels on BTM in patients with PCa treated with or without ADT. We performed a cross-sectional study including 83 subjects with PCa (54 % with ADT). BTM, bone mineral density (BMD), and sex steroids were determined. BTM were inversely related to serum level of estrogens. Tartrate-specific acid phosphatase (TRAP-5b) showed a negative correlation with free estradiol (Free E) (r = ?0.274, p = 0.014) and Bio E (r = ?0.256, p = 0.022) that remained after adjustment for age: Free E (β = ?0.241, p = 0.03) and Bio E (β = ?0.213, p = 0.063). Bone-specific alkaline phosphatase (BSAP) concentrations were inversely related to Free E (r = ?0.281, p = 0.011, age-adjusted β = ?0.256, p = 0.024). There was a negative correlation between osteocalcin (OC) levels and Free E (r = ?0.195, p = 0.082; age-adjusted β = ?0.203, p = 0.076) and Bio E (r = ?0.215, p = 0.054; age-adjusted β = ?0.240, p = 0.039). BTM and androgens were inversely related to TRAP-5b: total testosterone (total T) (r = ?0.238, p = 0.033), Free T (r = ?0.309, p = 0.05), and Bio T (r = ?0.310, p = 0.05), but these correlations disappeared after age-adjustment. We did not find any relationship between BMD at different locations and sex steroids. In conclusion, in patients with PCa, estrogen levels influence bone resorption and bone formation whereas androgens may exert actions only in bone resorption. These results suggest that estradiol is the main sex steroid that regulates bone metabolism in males with prostate carcinoma.