Undercarboxylated osteocalcin,muscle strength and indices of bone health in older women

We investigated the association between undercarboxylated osteocalcin (ucOC) and lower-limb muscle strength in women over the age of 70 years. The study also aims to confirm the association between bone turnover markers and heel ultrasound measures. A post-hoc analysis using data collected as part of a randomized placebo-controlled trial of vitamin D supplementation. An immunoassay was used to quantify total OC (tOC), with hydroxyapatite pre-treatment for ucOC. We determined associations of absolute and relative (ucOC/tOC; ucOC%) measures of ucOC with lower-limb muscle strength, heel ultrasound measures of speed of sound (SOS) and broadband ultrasound attenuation (BUA), bone turnover markers (BTMs; P1NP and CTx) and the acute phase protein alpha-1-antichymotrypsin (α-ACT). ucOC%, but not absolute ucOC concentration, was positively associated with hip flexor, hip abductor and quadriceps muscle strength (all p < 0.05). ucOC% was negatively associated with α-ACT (β-coefficient = − 0.24, p = 0.02). tOC was positively associated with both P1NP and CTx (p < 0.001). For each per unit increase in tOC (μg/L) there was a corresponding lower BUA, SOS and SI (β-coefficient = − 0.28; − 0.23 and − 0.23, respectively; all p < 0.04). In conclusion, ucOC% is positively associated with muscle strength and negatively associated with α-ACT. These data support a role for ucOC in musculoskeletal interactions in humans. Whilst tOC is associated with bone health, ucOC% and ucOC may also be linked to falls and fracture risk by influencing muscle function.     

Age-related reference intervals for bone turnover markers from an Australian reference population

BackgroundThis study was performed to establish age-related serum reference intervals for procollagen type I N-propeptide (P1NP) and type I collagen C-telopeptide (CTx) in the Australian population.MethodsFasting sera from 1143 males (mean age 60 years; range 20–97 years) and 1246 females (mean age 53 years; range 20–93 years) who participated in the Geelong Osteoporosis Study were analysed for CTx and P1NP using the automated Roche Modular Analytics E170 analyser.ResultsOptimal age-related reference intervals were based on the central 90% of the distribution. The male CTx reference interval was divided into three age groups. For men aged 25 to 40 years, the interval was 170–600 ng/L; 40 to 60 years, the interval was 130–600 ng/L; and for men aged greater 60 years the interval was 100–600 ng/L.For P1NP the male reference interval was 15–80 μg/L for men aged between 25 to 70 years. In men greater than 70 years of age values were higher possibly due to increased bone turnover.High values are frequently seen for both CTx and P1NP in males aged younger than 25 years. This is probably due to bone growth that is not completely finalised.The female CTx reference interval was divided into four age groups. For women aged less than 30 years, the interval was 150–800 ng/L; 30–39 years, the interval was 100–700 ng/L; 40–49 years, the interval was 100–600 ng/L; and for women aged 50 years or more the interval was 100–700 ng/L.The female P1NP reference interval was divided into four age groups. For women aged less than 30 years, the interval was 25–90 μg/L; 30–39 years, the interval was 15–80 μg/L; 40–49 years, the interval was 15–60 μg/L; and for women aged 50–69 years the interval was 15–75 μg/L. In women greater than 70 years of age values were higher possibly due to increased bone turnover.ConclusionValues obtained from this large study provide sound age-related reference intervals for serum P1NP and CTx values in the Australian population.     

Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: A 12-month randomized controlled trial

ObjectivesTo evaluate the effect of switching from oral bisphosphonates to denosumab on bone mineral density (BMD) in long-term glucocorticoid users.MethodsAdult patients who were receiving long-term prednisolone (≥ 2.5 mg/day for ≥ 1 year) and oral bisphosphonates (≥ 2 years) were recruited. Participants were randomized to either continue oral bisphosphonates or switch to denosumab (60 mg subcutaneously every 6 months) for 12 months. Serial BMD (lumbar spine, hip) and bone turnover markers (serum osteocalcin, P1NP, β-CTX) were measured.Results42 women were recruited (age 54.7 ± 12.9 years; 21 shifted to denosumab and 21 continued on bisphosphonates). The duration of prednisolone therapy was 101 ± 66.3 months and the daily dose was 4.4 ± 2.1 mg. Baseline demographic data, osteoporosis risk factors, and BMD at various sites were similar between the two groups of patients. At month 12, BMD of the spine and hip increased by + 3.4 ± 0.9% (p = 0.002) and + 1.4 ± 0.6% (p = 0.03), respectively, in the denosumab group; whereas the corresponding change was + 1.5 ± 0.4% (p = 0.001) and + 0.80 ± 0.5% (p = 0.12) in the bisphosphonate group. The spinal BMD at month 12 was significantly higher in the denosumab than bisphosphonate group after adjustment for baseline BMD and β-CTX values, and other confounding factors (p = 0.01). Bone turnover markers (β-CTX and P1NP) were more strongly suppressed by denosumab than the bisphosphonates. Minor infections were more common in denosumab-treated patients while other adverse events occurred at similar frequencies between the two groups.ConclusionsIn patients receiving long-term glucocorticoids, switching from oral bisphosphonates to denosumab resulted in greater gain of the spinal BMD and suppression of bone turnover markers after 12 months of therapy. The results have to be confirmed by a larger clinical trial with fracture as endpoint.     

Characterization of bone mineral density in male-to-female transsexuals receiving treatment for reassignment surgery: 15 years of follow-up

BackgroundCross-sex hormone treatment in male-to-female (M2F) transsexuals appears reasonably safe. Little is known about its long-term use. The aim of our study was to evaluate the effect of long-term high dose estrogens, plus the antiandrogen cyproterone acetate, on bone composition and on biochemical/hormonal parameters in M2F transsexuals.MethodsA retrospective analysis was performed on 45 young M2Fs (mean age 39.5 years; body mass index (BMI) = 22) receiving estrogens (previously 100 μg ethinyl estradiol, now 2–4 mg oral estradiol valerate/day or 100 μg transdermal estradiol/day) plus the antiandrogen cyproterone acetate 100 mg/day. Data were retrieved from 20 subjects after reassignment surgery (mean hormonal treatment duration 15.6 years). A complete hormonal and biochemical assessment, as well as bone biochemical markers (parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase and plasma pyridinoline crosslinks), were evaluated. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA).ResultsAll subjects had suppressed serum testosterone levels (mean = 0.57 nmol/l), whereas serum estradiol levels were within the supraphysiological range (mean = 880 pmol/l). A mild osteopenia at both lumbar spine and femoral neck was observed in 15 out of the 20 (75%) M2Fs (BMD = 0.89 ± 0.14 (mean ± standard deviation (SD)) g/cm² versus 1.1 ± 0.09, p < 0.001; lumbar T-score = −1.39 ± 0.84 versus 0.5 ± 1.10, p < 0.0005; femoral T-score = −1.12 ± 0.76 versus 0.08 ± 1.00, p < 0.05, respectively). No differences in plasma crosslink levels or in hormonal and biochemical parameters were found between subjects.ConclusionsOur results indicate that cross-sex hormone treatment of M2Fs, independently of serum testosterone levels, seems acceptably safe over a median treatment period of 15 years in a consistent population of subjects. A protective role for estrogens on bone seems to be present in a minority of subjects.     

Tibial bone responses to 6-month calcium and vitamin D supplementation in young male jockeys: A randomised controlled trial

Young male jockeys compromise bone health by engaging in caloric restriction and high volumes of physical activity during periods of musculoskeletal growth and development. The aim of this randomised, double-blinded, placebo-controlled trial was to establish whether calcium and vitamin D supplementation would improve bone properties of young male jockeys. We conducted a 6-month trial with two groups of weight-, height- and age-matched apprentice male jockeys (age = 20.2 ± 3.2 yrs). Participants were supplemented with 800 mg of calcium and 400 IU of vitamin D (S, n = 8) or a placebo (cellulose) (P, n = 9) daily for 6-months. Baseline calcium intake was (669.7 ± 274.3 (S) vs 790.4 ± 423.9 (P) and vitamin D 64.6 ± 19.5 (S) vs 81.2 ± 24.4 (P) with no statistical differences. Peripheral quantitative computed tomography (pQCT) measured ultra-distal (4%) and proximal (66%) tibial bone properties at baseline and 6 months. Blood-borne markers of bone turnover, P1NP and CTX and vitamin D concentration were assessed. After co-varying for height, weight and baseline bone measurements, the supplemented group displayed greater post-intervention bone properties at the 66% proximal site with cortical content (mg mm) 6.6% greater (p < 0.001), cortical area (mm²) 5.9% larger (p < 0.001), cortical density (mg cm²) 1.3% greater (p = 0.001), and total area (mm²) 4% larger (p = 0.003). No other between group differences in bone variables were observed. Blood analysis indicated higher vitamin D levels (18.1%, p = 0.014) and lower CTx (ng/L) (− 24.8%, p = 0.011) in the supplemented group with no differences observed in P1NP. This is the first randomised controlled trial to examine the efficacy of calcium and vitamin D supplementation in improving bone properties in a highly vulnerable, young athletic, weight-restricted population. Results using pQCT indicate beneficial effects of supplementation on bone properties in as little as six months. Although the study size is small, this intervention appears promising as a strategy for improving bone health in young athletes in weight-restricted sports.     

Circulating concentrations of vitamin E isomers: Association with bone turnover and arterial stiffness in post-menopausal women

The effects of vitamin E on cardiovascular and bone health are conflicting with beneficial and detrimental findings reported. To investigate this further, we carried out a cross-sectional study to determine the relationship between circulating concentrations of the 2 vitamin E isomers, α- and γ-tocopherol (TP) with bone turnover and arterial stiffness.Two hundred and seventy eight post-menopausal women with mean age [SD] 60.9 [6.0] years were studied. Fasting serum α-TP and γ-TP, bone turnover markers; procollagen type 1 amino-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX), parathyroid hormone (PTH), total cholesterol (TC) and triglycerides (TG) were measured. Pulse wave velocity (PWV) and central augmentation index (AI) as markers of arterial stiffness were also determined.A positive correlation was observed between α-TP and γ-TP (r = 0.14, p = 0.022). A significant negative association between α-TP and P1NP only was seen in multiple linear regression analysis following adjustment for serum TC and TG (p = 0.016). In a full multi-linear regression model, following correction for age, years since menopause, smoking habits, alcohol intake, use of calcium supplements, BMI, PTH, serum calcium, and estimated glomerular filtration rate (eGFR), the association between α-TP and P1NP remained significant (p = 0.011). We did not observe any significant association between γ-TP or α-TP/γ-TP ratio with P1NP or CTX. P1NP was significantly lower in subjects with α-TP concentrations of > 30 μmol/L (α-TP > 30 μmol/L; P1NP: 57.5 [20.7], α-TP < 30 μmol/L; P1NP: 65.7 [24.9] μg/L, p = 0.005). PWV was significantly associated with α-TP/γ-TP ratio (p = 0.04) but not with serum α-TP or γ-TP in a full multi-linear regression model adjusting for serum lipids, age, and blood pressure. The data suggest that high serum concentrations of α-TP may have a negative effect on bone formation. The balance of α-TP and γ-TP may be important in maintaining arterial compliance. Longitudinal studies are needed to investigate the impact of the vitamin E isomers on bone and cardiovascular health.     

Optimizing tamoxifen-inducible Cre/loxp system to reduce tamoxifen effect on bone turnover in long bones of young mice

For tamoxifen-dependent Cre recombinase, also known as CreER recombinase, tamoxifen (TAM) is used to activate the Cre to generate time- and tissue-specific mouse mutants. TAM is a potent CreER system inducer; however, TAM is also an active selective estrogen receptor modulator (SERM) that can influence bone homeostasis. The purpose of this study was to optimize the TAM dose for Cre recombinase activation while minimizing the effects of TAM on bone turnover in young growing mice.MethodsTo evaluate the effects of TAM on bone turnover and bone mass, 1-month-old wild-type male and female mice were intraperitoneally injected with TAM at 0, 1, 10 or 100 mg/kg/day for four consecutive days, or 100, 300 mg/kg/day for one day. The distal femurs were analyzed one month after the last TAM injection by microCT, mechanical test, and surface-based bone histomorphometry. Similar doses of TAM were used in Col1 (2.3 kb)-CreERT2; mT/mG reporter male mice to evaluate the dose-dependent efficacy of Cre-ER activation in bone tissue.ResultsA TAM dose of 100 mg/kg × 4 days significantly increased trabecular bone volume/total volume (BV/TV) of the distal femur, femur length, bone strength, and serum bone turnover markers compared to the 0 mg control group. In contrast, TAM doses ≤ 10 mg/kg did not significantly change any of these parameters compared to the 0 mg group, although a higher bone strength was observed in the 10 mg group. Surface-based histomorphometry revealed that the 100 mg/kg dose of TAM dose significantly increased trabecular bone formation and decreased periosteal bone formation at 1-week post-TAM treatment. Using the reporter mouse model Col1-CreERT2; mT/mG, we found that 10 mg/kg TAM induced Col1-CreERT2 activity in bone at a comparable level to the 100 mg/kg dose.ConclusionsTAM treatment at 100 mg/kg/day × 4 days significantly affects bone homeostasis, resulting in an anabolic bone effect on trabecular bone in 1-month-old male mice. However, a lower dose of TAM at 10 mg/kg/day × 4 days can yield similar Col1-CreERT2 induction efficacy with minimum effects on bone turnover in young male mice.     

Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm

BackgroundPreterm infants are at risk of metabolic bone disease due to inadequate mineral intake with unknown consequences for later bone health.ObjectiveTo test the hypotheses that (1) early diet programs peak bone mass and bone turnover; (2) human milk has a beneficial effect on these outcomes; (3) preterm subjects have reduced peak bone mass compared to population reference data.Design20 year follow-up of 202 subjects (43% male; 24% of survivors) who were born preterm and randomized to: (i) preterm formula versus banked breast milk or (ii) preterm versus term formula; as sole diet or supplement to maternal milk. Outcome measures were (i) anthropometry; (ii) hip, lumbar spine (LS) and whole body (WB) bone mineral content (BMC) and bone area (BA) measured using DXA; (iii) bone turnover markers.ResultsInfant dietary randomization group did not influence peak bone mass or turnover. The proportion of human milk in the diet was significantly positively associated with WBBA and BMC. Subjects receiving > 90% human milk had significantly higher WBBA (by 3.5%, p = 0.01) and BMC (by 4.8%, p = 0.03) than those receiving < 10%. Compared to population data, subjects had significantly lower height SDS (? 0.41 (SD 1.05)), higher BMI SDS (0.31 (1.33)) and lower LSBMD SDS (? 0.29 (1.16)); height and bone mass deficits were greatest in those born SGA with birthweight < 1250 g (height SDS ? 0.81 (0.95), LSBMD SDS ? 0.61 (1.3)).ConclusionInfant dietary randomization group did not affect peak bone mass or turnover suggesting the observed reduced final height and LS bone mass, most marked in growth restricted subjects with the lowest birthweight, may not be related to sub-optimal early nutrition. The higher WB bone mass associated with human milk intake, despite its low nutrient content, may reflect non-nutritive factors in breast milk. These findings may have implications for later osteoporosis risk and require further investigation.     

The functional muscle–bone unit in patients with osteogenesis imperfecta type I

ContextOsteogenesis imperfecta (OI) type I is a heritable bone fragility disorder that is caused by mutations affecting collagen type I. We recently showed that patients with OI type I frequently have muscle weakness. As muscle force and bone mass are usually closely related, we hypothesized that muscle weakness in OI type I could contribute to increase bone mass deficit in the lower extremities.ObjectiveTo assess the muscle–bone relationship in the lower extremities of children and adolescents with OI type I.SettingThe study was carried out in the outpatients department of a pediatric orthopedic hospital.Patients and other participantsThirty children and adolescents with OI type I (20 females; mean age [SD]: 11.2 years [3.9]) were compared with 30 healthy age- and sex-matched controls (mean age [SD]: 11.1 years [4.5]).Main outcome measuresTibia bone mineral content (BMC; mg/mm) was measured by peripheral quantitative computed tomography to estimate bone strength at the 4% and 14% sites. Lower extremity peak force (kN) was measured by mechanography using the multiple two-legged hopping test.ResultsCompared with age- and sex-matched controls, patients with OI type I had 17% lower peak force (1.3 kN vs. 1.7 kN; p = 0.002) as well as a 22% lower BMC (128 mg/mm vs. 165 mg/mm; p < 0.001). Stepwise regression analysis showed that muscle force and tibia length were positively related to bone strength (r² = 0.90, p < 0.001) whereas there was no effect of the disease status (OI vs. control).ConclusionsThese results suggest that the muscle–bone relationship is similar between children and adolescents with OI type I and healthy age and sex-matched controls. It also suggests that muscle weakness may contribute to decreased bone strength in individuals with OI type I.     

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

IntroductionOsteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization.We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.MethodsIn this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined.Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis.Results64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p < 0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~ 0; p = 0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p = 0.029). ucOC levels were higher in the fracture group although not significantly (p = 0.058). No differences were found regarding total OC (p = 0.602), apoE (p = 0.467) and Vitamin K (p = 0.371).In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β = 0.607; p = 0.013) and stiffness (β = 0.693; p = 0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β = ? 0.411; p = 0.030) and stiffness (β = ? 0.487; p = 0.009).ConclusionWe demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.     

Low osteocalcin/collagen type I bone gene expression ratio is associated with hip fragility fractures

IntroductionOsteocalcin (OC) is the most abundant non-collagenous bone protein and is determinant for bone mineralization.We aimed to compare OC bone expression and serum factors related to its carboxylation in hip fragility fracture and osteoarthritis patients. We also aimed to identify which of these factors were associated with worse mechanical behavior and with the hip fracture event.MethodsIn this case-control study, fragility fracture patients submitted to hip replacement surgery were evaluated and compared to a group of osteoarthritis patients submitted to the same procedure. Fasting blood samples were collected to assess apolipoproteinE (apoE) levels, total OC and undercarboxylated osteocalcin (ucOC), vitamin K, LDL cholesterol, triglycerides and bone turnover markers. The frequency of the apoε4 isoform was determined.Femoral epiphyses were collected and trabecular bone cylinders drilled in order to perform compression mechanical tests. Gene expression of bone matrix components was assessed by quantitative RT-PCR analysis.Results64 patients, 25 submitted to hip replacement surgery due to fragility fracture and 39 due to osteoarthritis, were evaluated. Bone OC/collagen expression (OC/COL1A1) ratio was significantly lower in hip fracture compared to osteoarthritis patients (p < 0.017) adjusted for age, gender and body mass index. Moreover, OC/COL1A1 expression ratio was associated with the hip fracture event (OR ~ 0; p = 0.003) independently of the group assigned, or the clinical characteristics. Apoε4 isoform was more frequent in the hip fracture group (p = 0.029). ucOC levels were higher in the fracture group although not significantly (p = 0.058). No differences were found regarding total OC (p = 0.602), apoE (p = 0.467) and Vitamin K (p = 0.371).In hip fracture patients, multivariate analysis, adjusted for clinical characteristics, serum factors related to OC metabolism and gene expression of bone matrix proteins showed that low OC/COL1A1 expression ratio was significantly associated with worse trabecular strength (β = 0.607; p = 0.013) and stiffness (β = 0.693; p = 0.003). No association was found between ucOC and bone mechanics. Moreover, in osteoarthritis patients, the multivariate analysis revealed that serum total OC was negatively associated with strength (β = − 0.411; p = 0.030) and stiffness (β = − 0.487; p = 0.009).ConclusionWe demonstrated that low bone OC/COL1A1 expression ratio was an independent predictor of worse trabecular mechanical behavior and of the hip fracture event. These findings suggest that in hip fracture patients the imbalance of bone OC/COL1A1 expression ratio reflects disturbances in osteoblast activity leading to bone fragility.     

Procollagen type 1 amino-terminal propeptide (P1NP) and risk of hip fractures in elderly Norwegian men and women. A NOREPOS study

The current study aimed to assess a possible association between the bone turnover marker procollagen type 1 amino-terminal propeptide (P1NP) and future hip fractures in elderly Norwegian men and women and to elucidate the relation between P1NP, bone mineral density and 25-hydroxyvitamin D (25(OH)D). Men and women aged 71 to 77 from two population based health studies in Norway (1999–2001) were followed for a median period of 7.3 years with respect to hip fractures. The study was designed as a case-cohort study. P1NP and 25(OH)D were analysed in frozen serum samples obtained at baseline in hip fracture patients (n = 340) and in randomly selected sex stratified sub-cohorts. Bone mineral density was measured by dual-energy X-ray absorptiometry (DXA) in a subset of participants. Cox proportional hazards regression with inverse probability weighting and robust variance was performed. No significant correlation between 25(OH)D and P1NP was found. A negative correlation between P1NP and BMD was observed in women (Rho = − 0.36, p = 0.001). A similar trend was observed in men. No association between quartiles of P1NP and rate of subsequent hip fractures was found. Spline analyses suggested a higher rate of hip fracture at P1NP levels above 60 μg/L in both men and women. A higher hip fracture rate, which was independent of BMD, was also indicated in women with very low levels of P1NP.     

Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy

BackgroundPostmenopausal women with osteoporosis/osteopenia are at increased risk of fracture. Aromatase inhibitors further increase bone loss in these patients. This study evaluates whether zoledronic acid prevents the bone loss expected when these patients initiate letrozole.Patients and methodsPostmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a bone mineral density (BMD) T-score <?2.0 were given letrozole 2.5 mg/vitamin D 400 international units daily, calcium 500 mg twice daily, and 4 mg zoledronic acid every 6 months. The BMD was assessed at baseline and 1 year. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year.ResultsForty-six patients completed 1 year of treatment. LS BMD increased by 2.66% (p = 0.01), femoral neck (FN) by 4.81% (p = 0.01), and any measured endpoint by 4.55% (p = 0.0052).ConclusionsZoledronic acid prevents bone loss in postmenopausal women with osteoporosis/osteopenia starting letrozole and is associated with improvements in BMD.     

Twelve months of voluntary heavy alcohol consumption in male rhesus macaques suppresses intracortical bone remodeling

Chronic heavy alcohol consumption is a risk factor for cortical bone fractures in males. The increase in fracture risk may be due, in part, to reduced bone quality. Intracortical (osteonal) bone remodeling is the principle mechanism for maintaining cortical bone quality. However, it is not clear how alcohol abuse impacts intracortical bone remodeling. This study investigated the effects of long-duration heavy alcohol consumption on intracortical bone remodeling in a non-human primate model. Following a 4-month induction period, male rhesus macaques (Macaca mulatta, n = 21) were allowed to voluntarily self-administer water or alcohol (4% ethanol w/v) for 22 h/d, 7 d/wk for 12 months. Control monkeys (n = 13) received water and an isocaloric maltose-dextrin solution. Tetracycline hydrochloride was administered orally 17 and 3 days prior to sacrifice for determination of active mineralization sites. Animals in the alcohol group consumed 2.7 ± 0.2 g alcohol/kg/d (mean ± SE) during the 12 months of self-administration, resulting in a mean daily blood alcohol concentration of 77 ± 9 mg/dl from samples taken at 7 h after the start of a daily session. However, blood alcohol concentration varied widely from day to day, with peak levels exceeding 250 mg/dl, modeling a binge-drinking pattern of alcohol consumption. The skeletal response to alcohol was determined by densitometry, microcomputed tomography and histomorphometry. Significant differences in tibial bone mineral content, bone mineral density, and cortical bone architecture (cross-sectional volume, cortical volume, marrow volume, cortical thickness, and polar moment of inertia) in the tibial diaphysis were not detected with treatment. However, cortical porosity was lower (1.8 ± 0.5 % versus 0.6 ± 0.1 %, p = 0.021) and labeled osteon density was lower (0.41 ± 0.2/mm² versus 0.04 ± 0.01/mm², p < 0.003) in alcohol-consuming monkeys compared to controls, indicating a reduced rate of intracortical bone remodeling. In concordance, plasma CTx was lower (2.5 ± 0.3 ng/ml versus 1.7 ± 0.1 ng/ml, p = 0.028) in the alcohol group. These results suggest that chronic heavy alcohol consumption may negatively impact bone health, in part, by suppressing intracortical bone remodeling.     

Changes in osteopontin and in biomarkers of bone turnover during human endotoxemia

Systemic infection and inflammation in men are associated with bone loss. Rodent studies have elucidated the pathways mediating the effects of bacterial lipopolysaccharide (LPS), activated immune cells and hormones on bone. Here we investigate the changes in biochemical parameters of bone turnover following human endotoxemia, an experimental model of self-limiting systemic infection and inflammation.Ten healthy men received in a randomised, placebo-controlled, cross-over trial once placebo and once 2 ng/kg Escherichia coli endotoxin (LPS). During the following 6 h we monitored parathyoid hormone (PTH) and osteopontin (OPN), a multifunctional protein related to bone pathophysiology, as well as biochemical markers of bone turnover: C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC). In LPS sessions there was a transient fall in PTH at 3 h (p = 0.009) and a nearly two-fold increase in OPN levels after 6 h (LPS: 155 ± 19 pg/ml; placebo: 85 ± 13 pg/ml, p < 0.001). LPS gradually reduced CTX levels (LPS: 0.44 ± 0.4 pg/ml; placebo: 0.59 ± 0.06 pg/ml, p = 0.003), P1NP showed a peak at 4 h (LPS: 89.9 ± 14.7 pg/ml; placebo: 75 ± 9.7 pg/ml, p = 0.028) and circulating OC did not change.The early human response to systemic endotoxemia boosts osteopontin levels and modifies bone biomarkers, indicating a decrease in the lytic activity of osteoclasts, accompanied by an increase in the activity of immature osteoblasts. These changes might present the acute phase response of immune and bone cells to bacterial stimuli in men.     

Peptide YY in adolescent athletes with amenorrhea,eumenorrheic athletes and non-athletic controls

BackgroundBone mineral density (BMD) is lower in amenorrheic athletes (AA) compared with eumenorrheic athletes (EA). Decreased energy availability and altered levels of appetite regulating hormones (ghrelin and leptin) in AA contribute to hypogonadism, an important cause of low BMD. The role of other nutritionally regulated hormones such as peptide YY (PYY) and adiponectin in mediating gonadal status and bone metabolism remains to be determined.ObjectivesOur objective was to determine whether PYY and adiponectin are higher in AA compared with EA and contribute to hypogonadism and impaired bone metabolism in AA.MethodsWe determined PYY and adiponectin in 16 AA, 15 EA and 16 non-athletic controls 12–18 years old, and other nutritionally dependent hormones including ghrelin, leptin and IGF-1. We also measured testosterone, estradiol, PINP and NTX (markers of bone formation and resorption) and BMD.ResultsPYY was higher in AA than EA (111 ± 52 vs. 61 ± 29 pg/ml, p < 0.05), whereas adiponectin did not differ between groups. Although activity scores did not differ, BMI was lower in AA than EA and a larger proportion (62.5% vs. 6.7%) reported disordered eating, indicating lower energy availability. PYY and adiponectin were independent predictors of testosterone in a regression model (p = 0.01 and 0.04), but did not predict estradiol. PYY, but not adiponectin, was an independent and negative predictor of PINP (p = 0.002) and lumbar bone mineral apparent density Z-scores (p = 0.045) in this model.ConclusionHigh PYY levels (but not adiponectin) differentiate AA from EA, and may be an important factor contributing to low bone density in athletes.     

Differences in biochemical bone markers by diabetes type and the impact of glucose

BackgroundDiabetes mellitus is associated with an increased fracture risk, however the fracture risk is 7 fold increased in patients with type 1 diabetes (T1D) and 1.4 fold increased in patients with type 2 diabetes (T2D) with decreased and increased bone mineral density, respectively. Oral ingestion of glucose causes an acute decrease in bone turnover markers, and thus glucose levels may affect bone turnover in diabetes.ObjectiveThe aim was to examine disparities in bone turnover markers between patients with T1D and T2D and evaluate the effect of glucose on bone turnover.MethodsA cross-sectional study was conducted. Patients diagnosed with T1D (n = 98) or T2D (n = 96) were included from the outpatient clinics at two University Hospitals. All individuals had normal renal function. Glucose and bone turnover markers were measured in non-fasting blood samples.ResultsP-procollagen type 1 amino terminal propeptide (P1NP), p-osteocalcin (OC), and s-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL) were lower in patients with T2D compared to T1D, and s-osteoprotegerin (OPG) was higher in T2D. P-C-terminal cross-linked telopeptide of type-I collagen (CTX), p-fibroblast growth factor-23 (FGF-23), p-sclerostin, and p-undercarboxylated osteocalcin (ucOC) were similar in between the two groups of patients. Increasing non-fasting glucose levels were inversely related to p-CTX, p-P1NP, p-OC, and p-ucOC and directly related to s-OPG in simple linear and multiple linear regressions adjusted for factors influencing bone turnover markers including HbA1c.ConclusionBone turnover markers were lower in patients with T2D compared to T1D. Acute blood glucose alterations may change bone turnover mediated by OPG and have detrimental effects on bone health in diabetes.Trial registration number: ClinicalTrials.gov NCT01870557.     

Bone turnover markers and the factors associated with atypical femur fractures among Japanese patients

Many previous reports have indicated that atypical femur fractures (AFFs) are associated with the administration of bisphosphonates (BPs). A number of risk factors and hypotheses regarding the pathogenesis of AFFs have been reported to date. The purpose of the present study was to identify the factors associated with AFFs in Japanese individuals and to elucidate the association between bone metabolism and AFFs by evaluating bone turnover markers (BTMs). We prospectively reviewed all patients with femur fractures and identified the patients with AFFs and typical femur fractures (TFFs). We collected the demographic and clinical data that were relevant to the present study, namely age, gender, affected side, affected site, concomitant medical history, and comorbid conditions, and measured the levels of BTMs within 24 h after trauma. Welch’s test and Fisher’s exact probability test were used for the statistical analyses. A total of 338 patients, including 10 patients with AFFs and 328 patients with TFFs, were analyzed under the inclusion criteria. The use of BPs (p < 0.001) and collagen disease and chronic granulomatous disease (CD/CGD) (p = 0.025) were more frequently observed in patients with AFFs than in patients with TFFs, while the levels of BTMs, including N-terminal propeptides of type 1 procollagen (P1NP), isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b) and undercarboxylated osteocalcin (ucOC) were significantly lower in patients with AFFs than in patients with TFFs. Furthermore, the level of TRACP-5b was found to be significantly lower in patients with atypical subtrochanteric fractures than in atypical diaphyseal fractures (p = 0.025). Moreover, the levels of P1NP (p = 0.016) and TRACP-5b (p = 0.015) were found to be significantly lower in patients with AFFs than in patients with TFFs in a subgroup analysis of BPs users. The use of BPs was considered to be a factor associated with AFFs. Our comparison of the BTMs in patients with AFFs and TFFs indicated that the severe suppression of bone turnover was associated with the pathogenesis of AFFs. The extent of the influence of suppressed turnover on the pathogenesis of AFFs may differ depending on the fracture site.     

Effects of soy isoflavone supplements on bone turnover markers in menopausal women: Systematic review and meta-analysis of randomized controlled trials

IntroductionEffects of soy isoflavone supplements on bone turnover markers remain unclear. This up-to-date systematic review and meta-analysis of randomized controlled trials (RCTs) was performed primarily to more completely and precisely clarify the effects on urinary deoxypyridinoline (DPD) and serum bone alkaline phosphatase (BAP) and secondarily to evaluate the effects on other bone turnover markers, compared with placebo in menopausal women.MethodsPubMed, CENTRAL, ICHUSHI, and CNKI were searched in June 2009 for relevant studies of RCTs. Data on study design, participants, interventions, and outcomes were extracted and methodological quality of each included trial was assessed.ResultsFrom 3740 identified relevant articles, 10 (887 participants), 10 (1210 participants), and 8 (380 participants) RCTs were selected for meta-analysis of effects on DPD, BAP, and serum osteocalcin (OC), respectively, using Review Manager 5.0.22. Daily ingestion of an average 56 mg soy isoflavones (aglycone equivalents) for 10 weeks to 12 months significantly decreased DPD by 14.1% (95% CI: ? 26.8% to ? 1.5%; P = 0.03) compared to baseline (heterogeneity: P < 0.00001; I² = 93%; random effects model). The overall effect of soy isoflavones on DPD compared with placebo was a significant decrease of ? 18.0% (95% CI: ? 28.4% to ? 7.7%, P = 0.0007; heterogeneity: P = 0.0001; I² = 73%; random effects model). Subgroup analyses and meta-regressions revealed that isoflavone dose and intervention duration did not significantly relate to the variable effects on DPD. Daily supplementation of about 84 mg and 73 mg of soy isoflavones for up to 12 months insignificantly increased BAP by 8.0% (95% CI: ? 4.2% to 20.2%, P = 0.20; heterogeneity: P < 0.00001; I² = 98%) and OC by 10.3% (95% CI: ? 3.1% to 23.7%, P = 0.13; heterogeneity: P = 0.002; I² = 69%) compared with placebo (random effects model), respectively.ConclusionsSoy isoflavone supplements moderately decreased the bone resorption marker DPD, but did not affect bone formation markers BAP and OC in menopausal women. The effects varied between studies, and further studies are needed to address factors relating to the observed effects of soy isoflavones on DPD and to verify effects on other bone turnover markers.     

The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons

IntroductionHigh plasma homocysteine levels have been associated with incident osteoporotic fractures, but the mechanisms underlying this association are still unknown. It has been hypothesized that homocysteine might interfere with collagen cross-linking in bone, thereby weakening bone structure. Therefore, we wanted to investigate whether plasma homocysteine levels are associated with bone quality parameters, rather than with bone mineral density.MethodsCross-sectional data of the B-PROOF study (n = 1227) and of two cohorts of the Rotterdam Study (RS-I (n = 2850) and RS-II (n = 2023)) were used. Data on bone mineral density of the femoral neck and lumbar spine were obtained in these participants using dual-energy X-ray assessment (DXA). In addition, participants of B-PROOF and RS-I underwent quantitative ultrasound measurement of the calcaneus, as a marker for bone quality. Multiple linear regression analysis was used to investigate the associations between natural-log transformed plasma levels of homocysteine and bone mineral density or ultrasound parameters.ResultsNatural-log transformed homocysteine levels were inversely associated with femoral neck bone mineral density in the two cohorts of the Rotterdam Study (B = − 0.025, p = 0.004 and B = − 0.024, p = 0.024). In B-PROOF, no association was found. Pooled data analysis showed significant associations between homocysteine and bone mineral density at both femoral neck (B = − 0.032, p = 0.010) and lumbar spine (B = − 0.098, p = 0.021). Higher natural-log transformed homocysteine levels associated significantly with lower bone ultrasound attenuation in B-PROOF (B = − 3.7, p = 0.009) and speed of sound in both B-PROOF (B = − 8.9, p = 0.001) and RS-I (B = − 14.5, p = 0.003), indicating lower bone quality. Pooled analysis confirmed the association between homocysteine and SOS (B = − 13.1, p = 0.016). Results from ANCOVA-analysis indicate that differences in SOS and BUA between participants having a plasma homocysteine level above or below median correspond to 0.14 and 0.09 SD, respectively.DiscussionIn this study, plasma levels of homocysteine were significantly inversely associated with both bone ultrasound parameters and with bone mineral density. However, the size of the associations seems to be of limited clinical relevance and may therefore not explain the previously observed association between plasma homocysteine and osteoporotic fracture incidence.