The effects of football training on bone health were examined in 55‐ to 70‐year‐old sedentary women and men with prediabetes. Patients (n = 50) with prediabetes (age; 61 ± 9 years, BMI ...29.7 ± 0.6 kg/m2, body fat content; 37 ± 1%, VO2max; 22.7 ± 0.8 mL/min/kg and mean arterial pressure; 104 ± 3 mm Hg) were randomized into a football training group (FTG; n = 27, 14 women) and a control group (CON; n = 23, 11 women). At baseline, 73% and 24% were diagnosed with femur osteopenia and osteoporosis, respectively. FTG performed football training twice weekly 30‐60‐minute sessions in 16 weeks, and both FTG and CON received professional dietary advice. Pre‐ and post‐intervention whole‐body and regional bone mineral content (BMC) and density (BMD) were determined with DXA‐scans, and venous blood samples were drawn and analyzed for plasma bone turnover markers. Change scores were greater (P < 0.05) in FTG compared to CON in leg BMD (0.023 ± 0.005 vs −0.004 ± 0.001 g/cm2) and in leg BMC (32 ± 8 vs −4 ± 6 g). Between‐group changes in favor of FTG (P < 0.05) also occurred in the femur neck BMD (3.2%) and femur shaft BMD (2.5%). Whole‐body BMC and BMD were unchanged in both groups during the intervention. In FTG, resting plasma osteocalcin, P1NP, and CTX‐1 rose (P < 0.05) by 23 ± 8, 52 ± 9 and 38 ± 7%, with greater change scores (P < 0.05) than in CON. Finally, P1NP (formation)/CTX‐1 (resorption) ratio increased (P < 0.05) in FTG (127 ± 15 vs 150 ± 11) from pre‐ to post‐intervention, with no change in CON (124 ± 12 and 123 ± 12). In conclusion, football training provides a powerful osteogenic stimulus and improves bone health in 55‐ to 70‐year‐old women and men diagnosed with prediabetes.
PURPOSEF-sodium fluoride (FNaF) is a well-established bone-seeking agent that has shown promise to assess bone turnover in a variety of disorders, but its distribution in healthy knee joints has not ...been explored. This study aimed to investigate parametric values for FNaF uptake in various bone tissues types of the knee and their spatial distributions.
METHODSTwelve healthy subjects were hand-injected with 92.5 MBq of FNaF and scanned on a 3-T PET/MRI system. Listmode PET data for both knees were acquired for 50 minutes from injection simultaneously with MRI Dixon and angiography data. The image-derived input function was determined from the popliteal artery. Using the Hawkins model, Patlak analysis was performed to obtain Ki (Ki) values and nonlinear regression analysis to obtain Ki, K1, k3/(k2 + k3), and blood volume. Comparisons for the measured kinetic parameters, SUV, and SUVmax were made between tissue types (subchondral, cortical, and trabecular bone) and between regional subsections of subchondral bone.
RESULTSCortical bone had the highest FNaF uptake differing significantly in all measured parameters when compared with trabecular bone and significantly higher SUVmax and K1 than subchondral bone. Subchondral bone also had significantly higher SUV, SUVmax, and Ki than trabecular bone tissue. Regional differences were observed in K1 and k3/(k2 + k3) values.
CONCLUSIONSQuantitative FNaF PET is sensitive to variations in bone vascularization and metabolism in the knee joint.
Pathogenic mutations in the
melanocortin
-
4 receptor (MC4R)
are associated with obesity, increased linear growth, and higher bone mass in children, and rodent studies have indicated an effect of the ...MC4R on bone turnover. Furthermore, GLP-1 receptor agonists (GLP-1 RAs) may influence bone metabolism. However, these associations have not been assessed in adults with pathogenic
MC4R
mutations. Thus, we wished to assess the impact of the MC4R on bone mass and metabolism. Secondly, we wished to investigate the impact of the GLP-1 RA liraglutide on bone mass in adults with pathogenic
MC4R
mutations. 17 patients with obesity-causing
MC4R
mutations (BMI: 35.5 ± 7.6) and 35 matched control participants with common obesity (BMI: 34.3 ± 7.1) underwent a DEXA scan for assessment of bone mineral density (BMD), bone mineral apparent density BMAD = (BMD/√(bone area), and bone turnover markers (BTMs). Individuals with a BMI above 28 (14
MC4R
mutation carriers and 28 matched control participants) underwent 16 weeks treatment with liraglutide 3.0 mg. The
MC4R
group had higher BMD mean difference: 0.065 g/m
2
(− 0.008 to 0.138),
p
= 0.03, but BMAD and BTMS were not different compared to the control group. In response to liraglutide, BMAD increased in the control group, compared to no change in the
MC4R
group mean group difference: 0.0007 (0.0001–0.001),
p
= 0.04. In conclusion, BMD is increased in
MC4R
causal obesity compared to common obesity, but when corrected for body size (BMAD), bone mass was not increased, and no evidence of an influence of the
MC4R
on bone metabolism in adults was found. Liraglutide treatment did not change bone metabolism in
MC4R
causal obesity, but increased bone mass as measured by BMAD in common obesity.
Multiple chemical sensitivity (MCS) is a multisystem syndrome, and limited knowledge of its pathophysiology exists. Based on the population-based Danish cohort
, this study investigated metabolic ...health in people with MCS compared to individuals who did not have MCS. From 9656 cohort participants aged 18-76 years old, 1.95% were categorized as MCS individuals with comorbid functional somatic disorders (MCS
,
= 188), and 1.13% were categorized as MCS without functional somatic disorders (MCS
,
= 109). MCS was characterized based on three criteria: the experience of symptoms upon exposure to common odors and airborne chemicals, symptoms related the central nervous systems and others organ symptoms, and significant impact on every day, social, and occupational life. The remaining study population without MCS or any other functional somatic disorders were regarded as controls. We used adjusted multiple linear regression with link-function to evaluate the associations between lipid and glucose metabolism markers and MCS. We also tested the odds ratio of metabolic syndrome in MCS. Results did not point to statistically significant associations between lipid biomarkers or metabolic syndrome and both MCS groups compared to the controls. We found that MCS individuals may be more insulin resistant and that MCS ÷
may have an impaired glucose metabolism when compared to controls.
The purinergic P2X7 receptor has a major role in the regulation of osteoblast and osteoclast activity and changes in receptor function may therefore affect bone mass in vivo. The aim of this study ...was to determine the association of non-synonymous single-nucleotide polymorphisms in the P2RX7 gene to bone mass and fracture incidence in post-menopausal women. A total of 1694 women (aged 45-58) participating in the Danish Osteoporosis Prevention Study were genotyped for 12 functional P2X7 receptor variants. Bone mineral density was determined at baseline and after 10 years. In addition, vertebral fracture incidence was documented at 10 years. We found that the rate of bone loss was clearly associated with the Arg307Gln amino acid substitution such that individuals heterozygous for this polymorphism had a 40% increased rate of bone loss. Furthermore, individuals carrying the Ile568Asn variant allele had increased bone loss. In contrast, the Gln460Arg polymorphism was associated with protection against bone loss. The Ala348Thr polymorphism was associated with a lower vertebral fracture incidence 10 years after menopause. Finally, we developed a risk model, which integrated P2RX7 genotypes. Using this model, we found a clear association between the low-risk (high-P2X7 function) alleles and low rate of bone loss. Conversely, high-risk (reduced P2X7 function) alleles were associated with a high rate of bone loss. In conclusion, an association was demonstrated between variants that reduce P2X7 receptor function and increased rate of bone loss. These data support that the P2X7 receptor is important in regulation of bone mass.
Abstract
Context
In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected ...changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP’s insulinotropic effect is impaired and effects on bone may be reduced.
Objective
To investigate GIP’s effect on bone biomarkers in patients with T2D.
Design
Randomized, double-blinded, crossover study investigating 6 interventions.
Patients
Twelve male patients with T2D.
Interventions
A primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with “insulin-induced hypoglycemia” (PG lowered to 3 mmol/L), “fasting hyperglycemia” (mean PG ~8 mmol/L), or “aggravated hyperglycemia” (mean PG ~12 mmol/L).
Main Outcome Measures
Bone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH.
Results
On days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion (P < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion (P = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes.
Conclusions
Short-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients.
Précis
Short-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.
OBJECTIVESThe purinergic P2RX7 receptor (P2RX7) has been shown to play a role in the regulation of osteoblast and osteoclast activity. The aim of this study was to determine the presence of ...polymorphisms in exon 13 of the P2X7 gene and the association with osteoclast apoptosis in vitro and bone status in vivo.
METHODSA total of 1764 postmenopausal women were genotyped for three single nucleotide polymorphisms detected after sequencing of exon 13 of P2X7. Bone markers, bone mineral density of the hip and lumbar spine were determined at baseline and after 10 years, and vertebral fracture incidence after 10 years. In-vitro ATP-induced caspase-1 determinations were performed on osteoclasts from the different genotypes.
RESULTSThree polymorphisms were detected (Gln460Arg, Glu496Ala, and Ile568Asn). None of the polymorphisms was related to bone mineral density or changes in bone mineral density over 10 years in hormone replacement therapy naïve women. The Ile568Asn polymorphism was however, associated with effect of hormone replacement therapy. Furthermore, the 10-year fracture incidence was significantly associated with both the Glu496Ala and the Ile568Asn. The Glu496Ala polymorphism was closely related to ATP-induced osteoclast apoptosis in vitro, as osteoclasts from individuals homozygous for the C allele had significantly decreased apoptotic activity.
CONCLUSIONThe P2X7 Glu496Ala and the Ile568Asn single nucleotide polymorphisms are associated with 10-year fracture risk in postmenopausal women and response to hormone replacement therapy treatment. Further, the Glu496Ala polymorphism is strongly influencing osteoclast apoptosis in vitro, which could contribute to increased fracture risk.
Stroke is a leading cause of mortality and morbidity. It is associated with excessive bone loss and risk of fracture in stroke patients is high. The P2Y12R antagonist and platelet inhibitor, ...clopidogrel, is widely used for secondary prevention after a stroke. However, recent studies have shown that clopidogrel has negative effects on bone and that long-term clopidogrel use is associated with increased fracture risk. The purpose of the current study was therefore to investigate the association of clopidogrel treatment with risk of fractures in stroke and TIA patients.
The study was a cohort study including all subjects who were prescribed clopidogrel between 1996 and 2008 in Denmark (
= 77,503). Age- and gender matched controls (
= 232,510) were randomly selected from the background population. The study end-points were occurrence of stroke or TIA and occurrence of fracture. Clopidogrel use was primary exposure.
Ischemic stroke increased risk of fracture by 50% while haemorrhagic stroke and TIA increased the risk by 30%. However, after adjusting for multiple confounders only patients with ischemic stroke and haemorrhagic stroke had increased fracture risk. Clopidogrel use was not associated with increased fracture risk in subjects with ischaemic stroke or TIA. In contrast, after adjusting for multiple confounders clopidogrel treatment was associated with a 10-35% reduced risk of fracture.
Patients with stroke have increased risk of osteoporotic fractures, but clopidogrel treatment does not increase fracture risk. In contrast, patients less adherent to the treatment have lower risk of fractures than non-users and patients with high adherence. However, based on the increased risk in stroke patients, clinicians should consider evaluation of bone status of these patients.
The aim of the study was to examine the acute response of biochemical bone turnover markers (BTM) to high-impact jumping exercise, and to quantify the ground reaction forces (GRF) achieved during ...each jumping exercise, in postmenopausal women. In a randomized controlled cross-over study over three days, 29 postmenopausal women (age (mean±SD): 60.0±5.6 years) were randomly assigned to 6 x 10 repetitions of three different jumps: countermovement jump (CMJ), drop jump (DJ), diagonal drop jump (DDJ). A fourth day without jumping served as a control (CON). Blood samples were collected before (PRE), after (POST), and 2 hours after (2Hr) exercise. Bone turnover was evaluated by bone formation markers (procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin (OC)) and the bone resorption marker C-terminal telopeptide of type-1 collagen (CTX). Peak anteroposterior (Fx), mediolateral (Fy), and vertical (Fz) GRF were measured using a force platform. From PRE to POST, P1NP increased (p<0.01) by 7.7±1.8%, 9.4±1.3%, and 10.6±1.6% for CMJ, DJ, and DDJ, which were higher (p<0.01) than CON. OC increased (p<0.05) by 5.5±1.8% for DJ, which was higher (p<0.05) than CON. CTX was not significantly changed at POST. There were no significant differences in BTM Δ-values between the jumps at any time point. For the CMJ, the combined three-axis peak GRF was positively associated with the PRE to POST Δ-change in P1NP (r=0.71, p<0.05). The acute, jumping-induced increase in P1NP and OC without any rise in CTX may indicate increased bone formation. Moreover, the study shows a dose-response relationship between GRF and the acute P1NP response after countermovement jumps.
Osteocytes are considered the primary mechanosensors of bone, but the signaling pathways they apply in mechanotransduction are still incompletely investigated and characterized. A growing body of ...data strongly indicates that P2 receptor signaling among osteoblasts and osteoclasts has regulatory effects on bone remodeling. Therefore, we hypothesized that ATP signaling is also applied by osteocytes in mechanotransduction. We applied a short fluid pulse on MLO-Y4 osteocyte-like cells during real-time detection of ATP and demonstrated that mechanical stimulation activates the acute release of ATP and that these acute ATP signals are fine-tuned according to the magnitude of loading. ATP release was then challenged by pharmacological inhibitors, which indicated a vesicular release pathway for acute ATP signals. Finally, we showed that osteocytes express functional P2X2 and P2X7 receptors and respond to even low concentrations of nucleotides by increasing intracellular calcium concentration. These results indicate that in osteocytes, vesicular ATP release is an acute mediator of mechanical signals and the magnitude of loading. These and previous results, therefore, implicate purinergic signaling as an early signaling pathway in osteocyte mechanotransduction.
•Mechanisms of mechanically induced ATP signaling among osteocytes are studied.•MLO-Y4 osteocytes release ATP instantly and load-dependently.•The acute mechanically induced ATP response is mediated by vesicular exocytosis.•MLO-Y4 osteocytes express functional P2X2 and P2X7 receptors.
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