Effects of a 3-month weight-bearing and resistance exercise training on circulating osteogenic cells and bone formation markers in postmenopausal women with low bone mass.

Osteoporosis is a health issue in postmenopausal women. Physical activity is recommended in these subjects, since it has positive effects on bone mass. Cellular mechanisms underlying this effect are still unclear. Osteogenic cells, released after physical exertion, could be a key factor in exercise-induced bone formation. INTRODUCTION: The aim of our research was to explore if a weight-bearing and resistance exercise program could positively affect circulating osteogenic cells (OCs), markers of bone formation and quality of life (QoL) in osteopenic postmenopausal women. METHODS: We recruited 33 postmenopausal women with a T-score at lumbar spine or femoral neck between - 1 and - 2.5 SD. Anthropometric and fitness parameters, bone-remodeling markers, OCs, and QoL were evaluated at the time of enrolment, after 1-month run-in period, and after 3 months of weight-bearing and resistance exercise. RESULTS: After 3 months of training, the pro-collagen type 1 N-terminal peptide (P1NP) and the number of OCs were significantly increased, with no significant increase of the type 1 collagen cross-linked C-telopeptide (sCTX). We also observed a significant increase in body height, one-repetition maximum (1RM) on the pull-down lat machine and leg press, and mean VO2max. The increase of immature circulating OCs was significantly correlated with the improvement of 1RM both of the upper and lower limbs. Moreover, QoL was significantly improved with regard to pain, physical function, mental function, and general QoL. The improvement in QoL, namely in the overall score and in the pain score, was significantly correlated with the increase in height. CONCLUSIONS: The exercise program we trialed is able to increase the markers of bone formation and the commitment of immature OCs with no significant increase in the markers of bone resorption. Our results confirm that combined weight-bearing and resistance physical activity is an effective tool to improve QoL of postmenopausal women with low bone mass. TRIAL REGISTRATION: NCT03195517.

Uric acid and bone mineral density in postmenopausal osteoporotic women: the link lies within the fat.

The association between serum uric acid (SUA) levels and bone mineral density (BMD) is controversial. Fat accumulation is linked to SUA and BMD, thus possibly explaining the mixed results. We found that adiposity drives part of the association between SUA and BMD in women with postmenopausal osteoporosis. INTRODUCTION: Both positive and negative associations between SUA and BMD have been reported. SUA levels and BMD increase with higher body weight and other indices of adiposity; hence, the association between SUA and BMD might be a consequence of the confounding effect of adiposity. We investigated in this cross-sectional study whether the association between SUA and BMD is independent of measures of fat accumulation and other potential confounders. METHODS: SUA levels, femur BMD, markers of bone metabolism, body mass index (BMI), fat mass (FM), waist circumference (WC), and abdominal visceral fat area were measured in 180 treatment-naive postmenopausal osteoporotic women (mean age 66.3 ± 8.5 years, age range 48-81 years). RESULTS: Women with higher SUA levels (third tertile) had significantly higher femur BMD and lower cross-linked C-terminal telopeptide of type I collagen (CTX) and bone alkaline phosphatase (bALP) levels. SUA levels were positively associated with all indices of adiposity. In multivariable analysis with femur BMD as dependent variable, the association between logarithmic (LG)-transformed SUA levels and BMD (beta = 0.42, p < 0.001) was lessened progressively by the different indices of adiposity, like LG-BMI (beta = 0.22, p = 0.007), LG-WC (beta = 0.21, p = 0.01), LG-FM (beta = 0.18, p = 0.01), and LG-abdominal visceral fat area (beta = 0.12, p = 0.05). The association between SUA levels and markers of bone metabolism was dependent on the effect of confounders. CONCLUSION: In postmenopausal osteoporotic women, the strong univariable association between SUA levels and femur BMD is partly explained by the confounding effect of indices of adiposity.

Association between circulating osteoblast progenitor cells and aortic calcifications in women with postmenopausal osteoporosis.

BACKGROUND AND AIMS: Ectopic artery calcification has been documented in women with postmenopausal osteoporosis, in whom an imbalance in the number of circulating osteoprogenitor cells (OPCs) has been identified. Circulating OPCs form calcified nodules in vitro; however, it remains unknown whether an association exists between the number of circulating OPCs and aortic calcifications. We investigated the relationship between OPCs and aortic calcifications in women with postmenopausal osteoporosis. METHODS AND RESULTS: The number of circulating OPCs was quantified by FACS analysis in 50 osteoporotic postmenopausal women. OPCs were defined as CD15-/alkaline-phosphatase(AP)+ cells coexpressing or not CD34. Participants underwent measurement of markers of bone metabolism, bone mineral density and abdominal aortic calcium (AAC) by 64-slice computed tomography. Patients with AAC were older, had lower 25(OH)vitamin D levels and higher circulating CD15-/AP+/CD34- cells than those without AAC. Significant correlates of AAC included age (rho = 0.38 p = 0.006), calcium (rho = 0.35 p = 0.01), 25(OH)vitamin D (rho = -0.31, p = 0.03) and the number of CD15-/AP+/CD34- cells (rho = 0.55 p < 0.001). In regression analyses, the log-transformed number of CD15-/AP+/CD34- cells was associated with the presence (OR = 6.45, 95% CI 1.03-40.1, p = 0.04) and severity (ß = 0.43, p < 0.001) of AAC, independent of age, 25(OH)vitamin D, calcium and other potential confounders. Patients with low 25(OH)vitamin D and high CD15-/AP+/CD34- cells had higher median AAC than other patients (1927/µL, 862-2714/µL vs 147/µL, 0-1665/µL, p = 0.003). CONCLUSION: In women with postmenopausal osteoporosis, the number of circulating CD15-/AP+/CD34- cells is significantly associated with increased aortic calcifications, that appear to be correlated also with reduced 25(OH)vitamin D levels.

Imbalance between endothelial injury and repair in patients with polymyalgia rheumatica: improvement with corticosteroid treatment.

OBJECTIVES: Polymyalgia rheumatica (PMR) is a rheumatic disease that is characterized by intense activation of systemic inflammation. Systemic inflammation has been associated with an imbalance between endothelial injury and repair, defined by an increased number of circulating endothelial microparticles (EMPs) and a reduced number of endothelial progenitor cells (EPCs). We investigated the association between inflammation and endothelial injury and repair in patients with PMR and evaluated the effects of corticosteroid therapy on EMP and EPC levels. DESIGN, SETTING AND SUBJECTS: We conducted a case-control study in 34 patients with never-treated active PMR and 34 healthy age- and sex-matched controls. Patients with PMR participated in a 1-month intervention open-label study with corticosteroid therapy. Circulating EMPs (CD31+/CD42-) and EPCs (CD34+/KDR+) were quantified by fluorescence-activated cell sorting analysis. RESULTS: Patients with PMR had an increased EMP/EPC ratio compared with controls [median (IQR): 6.5 (3.0-11.5) vs. 1.1 (0.7-1.5), P < 0.001], because of both increased EMP and reduced EPC levels. Levels of C-reactive protein (CRP) were associated with an increased EMP/EPC ratio (ß = 0.48, P = 0.001), irrespective of traditional cardiovascular risk factors. Corticosteroid therapy led to a significant CRP reduction [from 3.9 (1.5-6.7) to 0.6 (0.2-1.2) mg dL(-1) , P < 0.05], paralleled by a consistent 81% decline in the EMP/EPC ratio. CRP and EMP/EPC ratio reductions were significantly correlated (rho = 0.37, P = 0.04). CONCLUSIONS: Polymyalgia rheumatica is associated with a significant imbalance between endothelial injury and repair, which is dependent on the degree of systemic inflammation. Attenuation of inflammation by short-term corticosteroid therapy might have a role in limiting endothelial fragmentation and promote endothelial repair.

Circulating immature osteoprogenitor cells and arterial stiffening in postmenopausal osteoporosis.

BACKGROUND AND AIMS: An increased number of circulating osteoprogenitor cells (OPCs) expressing bone-related proteins and the stem cell marker CD34 have been identified in women with postmenopausal osteoporosis, who also have stiffer arteries than nonosteoporotic subjects. We investigated whether an increased number of circulating OPCs underlies the association of osteoporosis with arterial stiffness. METHODS AND RESULTS: The number of circulating OPCs was quantified by FACS analysis in 120 postmenopausal women with or without osteoporosis. OPCs were defined as CD34+/alkaline phosphatase(AP)+ or CD34+/osteocalcin(OCN)+ cells. Participants underwent cardiovascular risk factor assessment, measurement of bone mineral density (BMD), and aortic pulse wave velocity (aPWV) as a measure of arterial stiffness. Osteoporotic women had higher aPWV (9.8 ± 2.8 vs 8.5 ± 1.9 m/s, p = 0.005) and levels of CD34+/AP+ and CD34+/OCN+ cells than nonosteoporotic controls [1045 n/mL (487-2300) vs 510 n/mL (202-940), p < 0.001; 2415 n/mL (1225-8090) vs 1395 n/mL (207-2220), p < 0.001]. aPWV was associated with log-CD34+/AP+ (r = 0.27, p = 0.003), log-CD34+/OCN+ cells (r = 0.38, p < 0.001). In stepwise regression analysis CD34+/OCN+ cells, age, systolic blood pressure and heart rate were significant predictors of aPWV (Model R = 0.62, p < 0.001), independent of cardiovascular risk factors, parathyroid hormone levels and osteoporotic status. CONCLUSION: In women with postmenopausal osteoporosis an increased availability of circulating osteoprogenitor cells has a detrimental influence on arterial compliance, which may in part explain the association between osteoporosis and arterial stiffening.

Association between circulating osteoprogenitor cell numbers and bone mineral density in postmenopausal osteoporosis.

UNLABELLED: The role of circulating osteoprogenitor cells in postmenopausal osteoporosis is unknown. We found that alkaline-phosphatase-positive (AP+) cells are the lacking cells in osteoporosis, whose reduction is related to bone loss. Conversely, the increased number of alkaline phosphatase/CD34-positive cells may reflect the reactive bone marrow contribution to bone formation. INTRODUCTION: Circulating osteoprogenitor cells mineralize in vitro and in vivo. Loss of osteogenic cells may account for bone loss in osteoporosis. We studied whether there is an association between the number of circulating osteoprogenitor cells and bone mineral density (BMD) in postmenopausal women with and without osteoporosis. METHODS: The number of circulating AP+, osteocalcin-positive (OCN+), AP+/CD34+, and OCN+/CD34+ cells was quantified in 54 postmenopausal osteoporotic women and 36 age-matched nonosteoporotic controls. RESULTS: The number of AP+ cells was lower in osteoporotic women than in controls (127 +/- 16 vs 234 +/- 23 per microliter; p < 0.001); higher levels of AP+/CD34+, OCN+, and OCN+/CD34+ cells were found in osteoporotic than controls (p < 0.01 for all). The number of AP+ cells was correlated with lumbar BMD (rho = 0.29; p = 0.008) and proximal femur BMD (rho = 0.31; p = 0.005) whereas inverse correlations were found between AP+/CD34+ cells, OCN+, OCN+/CD34+, and BMD. Reduced AP+ cells and increased AP+/CD34 +, OCN+, and OCN+/CD34+ cells were predictors of low BMD, independent of traditional risk factors for osteoporosis. CONCLUSION: In postmenopausal osteoporotic women, a reduced number of circulating AP+ cells and increased levels of AP+/CD34+, OCN+, and OCN+/CD34+ cells are associated with reduced bone mineral density, the interpretation of such a cellular imbalance needing exploration.

Endothelial progenitor cells are mobilized after major laparotomic surgery in patients with cancer.

The progression of cancer is largely dependent on neoangiogenesis. Circulating endothelial progenitor cells (EPC) have the ability to form complete vascular structures in vitro and play a crucial role in tumor vasculogenesis. Emerging evidence suggests that surgical injury may induce the mobilization of EPC in animal models, and this might have a negative effect on the prognosis of cancer patients. We studied 20 patients (10 men, 65+/-13 years) undergoing laparotomy for surgical treatment of various forms of abdominal cancer, and 20 age- and sex-matched healthy control subjects. The number of circulating EPC, defined as CD34+/KDR+ cells identified among mononuclear cells isolated from peripheral venous blood, was determined preoperatively and at days 1 and 2 after surgery. Surgery induced a significant increase in circulating EPC levels at day 1 (from 278/mL, interquartile range 171-334, to 558/mL, interquartile range 423-841, p<0.001) and day 2 (709/mL, interquartile range 355-834, p<0.001)compared with baseline values. EPC levels did not change in control subjects. Seven subjects who underwent laparotomic surgery for non-neoplastic disease also showed an increase in EPC levels after surgery (p=0.009 and p=0.028 at day 1 and day 2, respectively). We conclude that patients undergoing elective laparotomic surgery for cancer demonstrate an increase in EPC post-operatively. The potential adverse effects of surgical stress-induced EPC mobilization on tumor and metastasis growth in cancer patients need to be addressed in future studies.

Natriuretic peptides levels are related to HDL-cholesterol with no influence on endothelium dependent vasodilatation.

BACKGROUND: The natriuretic peptides, Brain Natriuretic Peptide (BNP), C-type Natriuretic Peptide (CNP), are mediators of cardiovascular homeostasis. The impairment of arterial ability to vasodilate, also known as endothelial dysfunction, represents the first stage of atherosclerotic damage and may be assessed as brachial flow mediated vasodilation (FMV) in human. Generally an altered brachial FMV is documented in association to several cardiovascular risk factors as hypercholesterolemia. Aim of the study was to evaluate the behaviour of BNP and CNP in hyperlipemia and the potential relationship to FMV. PATIENTS AND METHODS: Forty-four hyperlipemic patients (LDL-cholesterol > 130 mg/dl and/or triglycerides > 150, age 35-60 y) of both genders and 20 normolipemic patients, matched for age and sex were investigated. RESULTS: Patients had lower values of brachial FMV in comparison to controls (3.9 +/- 3.5 vs 7.5 +/- 0.5%, p < 0.005), no differences were observed in BNP (4.6 +/- 4.6 vs 5.9 +/- 3.4 ng/mL, p = n.s) and CNP (4.1 +/- 5.8 vs 5.7 +/- 3.3 ng/mL, p = n.s). Univariate analysis showed a positive correlation between BNP and HDL-cholesterol values (r = 0.36, p = 0.001). In the multivariate analysis, LDL-cholesterol (beta = -0.57), HDL-cholesterol (beta = 0.26) and brachial artery diameter (beta = -0.33) were predictors of brachial FMV. The only predictive variable for CNP was HDL-cholesterol (beta = 0.37). CONCLUSIONS: The present study suggested that natriuretic peptides, BNP and CNP, are not altered in patients affected by hypercholesterolemia. Nevertheless, the levels of HDL-cholesterol are strictly related to the values of CNP. This observation, in humans, adds another mechanism to the vascular control exerted by HDL.

Low-grade systemic inflammation impairs arterial stiffness in newly diagnosed hypercholesterolaemia.

BACKGROUND: Excess of cardiovascular risk among patients with chronic inflammatory diseases has been attributed to increased arterial stiffness. Hypercholesterolaemia has been demonstrated to promote a low-grade inflammatory status. The objective of the present study was to define, in hypercholesterolaemia, the influence of plasma lipids, low-grade inflammation, and indices of adiposity on aortic pulse wave velocity, a measure of arterial stiffness and cardiovascular risk. MATERIALS AND METHODS: Anthropometric characteristics, plasma lipids, C-reactive protein and aortic pulse wave velocity were measured in 85 subjects (60 patients with newly diagnosed never-treated hypercholesterolaemia and 25 age- and sex-matched normocholesterolaemic controls). RESULTS: Plasma C-reactive protein and aortic pulse wave velocity were significantly higher among hypercholesterolaemic patients than in controls (P < 0.05 for both). Aortic pulse wave velocity was associated with age (r = 0.24, P = 0.04), body mass index (r = 0.33, P = 0.006), waist (r = 0.42, P < 0.001) and hip (r = 0.32, P = 0.007) circumferences, as well as with systolic (r = 0.34, P = 0.003) and diastolic (r = 0.30, P = 0.01) blood pressures, plasma C-reactive protein (r = 0.51, P < 0.001), total cholesterol (r = 0.45, P < 0.001), and low-density lipoprotein cholesterol (r = 0.46, P < 0.001). In the multivariate analysis, waist circumference and C-reactive protein levels predicted increased aortic stiffness, independently of traditional cardiovascular risk factors. The degree of independent association between cholesterol, systolic blood pressure and aortic stiffness increased when indices of adiposity and inflammation were excluded from the multivariate analysis. Comparable results were obtained when the analyses were restricted to hypercholesterolaemic patients. CONCLUSIONS: Low-grade systemic inflammation and abdominal fat, more than traditional risk factors, are major determinants of reduced arterial distensibility in hypercholesterolaemia.