Spyridon Gerou

Comparative Effect of Zoledronic Acid Versus Denosumab on Serum Sclerostin and Dickkopf-1 Levels of Naive Postmenopausal Women With Low Bone Mass: A Randomized, Head-to-Head Clinical Trial

CONTEXT Decreased bone formation due to a coupling effect limits bone mass increases after antiresorptive treatment. OBJECTIVE The purpose of this study was to compare the effects of 2 potent antiresorptive agents with different mechanism of action on serum levels of Wnt antagonists, sclerostin and dickkopf-1 (Dkk-1). DESIGN This was an interventional, parallel assignment, open-label, randomized clinical trial. SETTING The study was conducted at the outpatient clinics for metabolic bone diseases of 424 General Military Hospital, Thessaloniki, Greece. PATIENTS AND INTERVENTIONS Naive postmenopausal women with low bone mass were assigned to zoledronic acid infusion (n = 46) or denosumab injection (n = 46). One woman in the zoledronic acid group was lost to follow-up. MAIN OUTCOME MEASURES Serum sclerostin and Dkk-1 levels were the main outcomes. Secondary measurements were serum osteoprotegerin, receptor activator of nuclear factor κB ligand, procollagen type 1 N-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen. RESULTS Serum sclerostin levels significantly decreased in the zoledronic acid (P < .001) but increased in the denosumab group (P = .003). Dkk-1 levels significantly decreased in the zoledronic acid group (P = .006) but did not change in the denosumab group (P = .402). Serum osteoprotegerin remained essentially unchanged in either group, whereas receptor activator of nuclear factor κB ligand decreased in the zoledronic acid group (P = .004) but increased in the denosumab group (P = .037). Bone markers (procollagen type 1 N-terminal propeptide, C-terminal cross-linking telopeptide of type 1 collagen, and total serum alkaline phosphatase) decreased in both groups (all P < .001). CONCLUSIONS Although they both decrease bone resorption, zoledronic acid and denosumab exert opposite effects on Wnt signaling: the former decreases serum levels of both sclerostin and Dkk-1, whereas the latter increases sclerostin and does not affect Dkk-1.

The effect of zoledronic acid on serum dickkopf-1, osteoprotegerin, and RANKL in patients with Paget's disease of bone.

Overexpression of dickkopf (DKK)-1 in pagetic osteoblast cultures resulted in stimulation of osteoclast proliferation and inhibition of osteoblast growth. The aim of this study was to evaluate for the first time in Pagets disease of bone (PDB): 1) the serum levels of DKK1; 2) the association of DKK-1 with receptor activator of nuclear factor kappa B (RANKL) and osteoprotegerin (OPG); and 3) the effect of zoledronic acid (ZOL) on serum DKK-1, RANKL, and OPG. The study was conducted as a prospective open-label cohort study. Eleven patients with PDB (median age 60 years) were recruited. Twelve age- gender- and body mass index (BMI)-matched healthy individuals were used as controls at baseline. Blood samples were obtained before treatment (baseline) and after 3, 6, 12, and 18 months following ZOL infusion in patients with PDB. Patients with PDB had significantly higher RANKL (p=0.002), OPG (p=0.001), and bone markers (total alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen) compared with controls at baseline. There was no difference between groups in DKK-1 at baseline. Bone markers were both significantly decreased after therapy. Serum OPG, RANKL, RANKL:OPG ratio, and DKK-1 remained unaffected throughout the study. No correlations were found between OPG, RANKL, RANKL:OPG ratio, and DKK-1 at baseline nor between their changes during the study. Although both OPG and RANKL were increased in patients with PDB, ZOL had no effect on their serum levels. Serum DKK-1 was neither increased in patients with PDB nor related to OPG and RANKL, and was unaffected by ZOL.

Serum vaspin levels in normal pregnancy in comparison with non-pregnant women

OBJECTIVE Pregnancy represents a state of insulin resistance (IR). Vaspin (SERPINA12) is a novel insulin-sensitizing adipokine that might be implicated in endogenous glucose regulation. However, its role in pregnancy and its circulating levels have not been adequately studied. We aimed to evaluate serum vaspin levels in pregnancy and their correlation with known markers of IR. DESIGN A group of 106 women (age 27.9±0.4 years) at the 24-30th week of gestation (pregnancy group) and another 106 age-matched healthy non-pregnant controls (control group) were included in the study. METHODS Serum glucose, insulin, vaspin, adiponectin, and lipid parameters were measured. The quantitative insulin sensitivity check index (QUICKI) was used as an insulin sensitivity index. RESULTS Pregnant women had significantly higher body mass index (BMI), lipids, and serum insulin and lower serum glucose and vaspin levels than controls. Vaspin was positively correlated to adiponectin in both groups (P<0.001 and P<0.004 respectively) but was not correlated to BMI, serum insulin levels, or the QUICKI index in either group. Furthermore, vaspin was negatively correlated to lipid parameters (total cholesterol, triglycerides, and low-density lipoproteins) in the pregnant but not in the non-pregnant women. CONCLUSIONS Vaspin cannot serve as a marker of IR in either pregnant or non-pregnant women, although it is significantly correlated with adiponectin. On the other hand, vaspin might be useful as a surrogate marker of lipid metabolism in pregnancy if confirmed by subsequent studies.

Apelin levels in normal pregnancy

Objective  Apelin is an adipokine secreted from adipose and other tissues with increased expression in obesity, role in glucose metabolism and atherosclerosis, as well as in oxidative stress. Pregnancy is considered a state of hyperlipidemia, oxidative stress and decreased insulin sensitivity. The aim of the present study is to investigate the levels of apelin in human pregnancy and its relation to insulin sensitivity.

Serum osteoprotegerin and RANKL are not specifically altered in women with postmenopausal osteoporosis treated with teriparatide or risedronate: a randomized, controlled trial.

Risedronate and teriparatide have opposite actions on the osteoblast-osteoclast dipole and are expected to influence the RANK/RANKL/osteoprotegerin (OPG) system. We aimed to evaluate changes in serum OPG and RANKL after risedronate or teriparatide administration in postmenopausal osteoporotic women. Seventy-four postmenopausal Caucasian women (age 64.1+/-1.0 years) were studied. Women with osteopenia served as controls (group 1, n=30). Women with osteoporosis were randomly assigned to either risedronate 35 mg once weekly (group 2, n=21) or teriparatide 20 microg once daily (group 3, n=23) for six months. Blood samples for serum RANKL, OPG, N-terminal propeptide of type 1 collagen (P1NP), and C-terminal telopeptide of type 1 collagen (CTx) were obtained before treatment and three and six months after treatment. P1NP and CTx levels remained unchanged in group 1, decreased in group 2 (p<0.001), and increased in group 3 women (p<0.001) throughout the treatment. OPG levels remained unchanged while RANKL decreased gradually in all groups (p<0.001). There was no correlation between OPG or RANKL and P1NP or CTx. Our data suggest that neither antiresorptive nor osteoanabolic therapy causes specific alterations of serum OPG/RANKL levels; therefore, these cytokines cannot substitute for the established markers of bone turnover in the monitoring of response to osteoporosis treatment.

Oxidized low-density lipoprotein and adiponectin levels in pregnancy

Introduction. The aim of the present study was to investigate whether normal pregnancy represents a complex state of oxidative stress, inflammation and insulin resistance. Subjects and methods. One hundred and six pregnant women, between 24th and 28th week of pregnancy (age 27.9 ± 0.4 years) (study group) and one hundred and six age-matched, healthy, non-pregnant women (control group) participated in the study. Serum levels of glucose, insulin, adiponectin, oxidized LDL (oxLDL) and lipid parameters, i.e. total cholesterol (TC), triglycerides (TG), HDL and LDL, were determined. Body mass index (BMI) and QUantitative Insulin sensitivity ChecK Index (QUICKI) were also calculated. Results. Pregnant women presented higher BMI values, insulin and oxLDL serum levels and lower glucose serum levels than controls. Serum levels of lipids (TC, TG, LDL and HDL) were higher in pregnant women. There was a significant positive correlation of oxLDL to adiponectin (p < 0.01) in the study group, but not in the controls, and no other significant correlation with any of the other parameters, in either of groups. Conclusions. Pregnancy is a state of insulin resistance, oxidative stress and pro-atherogenic hyperlipidemia. Adiponectin may, though, have cardioprotective role in pregnant women.

Serum anti-Müllerian hormone levels differentiate control from subfertile men but not men with different causes of subfertility

Aim. To determine stimulated serum anti-Müllerian hormone (AMH) levels in men with different causes of subfertility. Subjects and methods. We prospectively studied 82 subfertile men and 31 controls. The subfertile men underwent a diagnostic procedure to identify the causes of subfertility. Study parameters included testicular volume, levels of follicle-stimulating hormone, luteinizing hormone, total testosterone, prolactin, inhibin B and AMH, and sperm parameters. Results. Clinical diagnoses in subfertile men were idiopathic non-obstructive azoospermia (n = 26, 32%), idiopathic non-obstructive dyspermia (n = 17, 21%), varicocele (n = 16, 20%), cryptorchidism (n = 10, 12%) and other diagnoses (n = 13, 16%). Serum AMH levels in subfertile men were 60% lower than in controls [median (interquartile range) 4.6 (3.6) vs. 11.6 (7.7) ng/ml, p < 0.001], with no significant differences among the different groups of subfertile men. Conclusions. Serum AMH levels differentiate control from subfertile men but not men with different causes of subfertility.

Acute phase response following intravenous zoledronate in postmenopausal women with low bone mass

An acute phase response (APR) is frequently observed in patients treated with intravenous (i.v.) zoledronate (ZOL). We aimed to define clinical and laboratory parameters that may predict ZOL-induced APR in women with low bone mass. Fifty-one postmenopausal women with low bone mass were given a single i.v. infusion of ZOL 5mg. APR was clinically defined by the visual analog pain scale (VAS) for the musculoskeletal symptoms and body temperature. White blood cell count (WBC), leucocyte subpopulations, C-reactive protein (CRP), parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], interleukins (IL)-1b and -6, tumor necrosis factor (TNF)α and interferon (IFN)γ were measured before and 48 h following the infusion. Subsequently, patients were divided into those experiencing APR (APR+) or not (APR-). WBC, granulocytes, CRP, IL-1b and IL-6 were significantly increased, whereas lymphocytes, eosinophils, calcium, phosphate and 25(OH)D decreased 48h after ZOL infusion. Twenty-eight of the 51 patients (54.9%) experienced an APR. APR+ patients were younger and had higher baseline lymphocytes compared to APR- patients. There was no difference (p=0.405) in the development of APR between treatment-naive patients (19/32, 59.4%) and patients previously treated with another oral nitrogen-containing bisphosphonate (9/19, 47.4%). In conclusion, our data suggest that pre-treatment higher lymphocyte number increases the risk of APR while previous treatment with another nitrogen-containing bisphosphonate does not significantly reduce the risk. Serum 25(OH)D concentrations decrease significantly after the infusion, possibly as part of the inflammatory response to ZOL.

Circulating periostin levels in patients with AS: association with clinical and radiographic variables, inflammatory markers and molecules involved in bone formation

OBJECTIVE The aim of this study was to evaluate serum periostin levels in patients with AS in comparison with healthy controls as well as their association with clinical, inflammatory and radiographic parameters and molecules involved in bone formation. METHODS Serum samples for periostin, total Dickkopf-1 (Dkk-1), sclerostin, VEGF and inflammatory markers were obtained from 65 TNF inhibitor-naive patients with AS. The BASDAI, BASFI, modified Stoke AS Spine Score and BASRI for the spine (BASRI-s) were assessed for each patient. Serum periostin levels were also measured in 36 sex-, age- and BMI-matched controls. RESULTS Serum periostin levels were significantly lower in AS patients compared with controls [234.4 pg/ml (s.e.m. 7.5) vs 291.4 (s.e.m. 8.3), respectively; P < 0.001]. Periostin levels were higher in AS patients with elevated CRP (P = 0.005), high BASDAI (P = 0.014) and low BASRI-s (P = 0.033) and were correlated with BMI (r = -0.304, P = 0.014), ESR (r = 0.395, P = 0.001), CRP (r = 0.413, P = 0.001), BASRI-s (r = -0.242, P = 0.047) and sclerostin (r = -0.280, P = 0.024). In multiple regression analysis, periostin levels were an independent variable of CRP (β = 0.160, P = 0.009) and sclerostin levels (β = -0.311, P = 0.012). CONCLUSION Our data suggest that periostin levels are low in patients with AS. Among AS patients, periostin levels are higher in those with higher disease activity, higher systemic inflammation and less extensive radiographic damage. Periostin is independently associated with CRP and sclerostin levels.

The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B

Haemophilia A and B have been associated with increased prevalence of low bone mineral density (BMD). However, the utility of bone turnover markers (BTM) remains unknown. The aim of this study was to evaluate bone metabolism in men with haemophilia and to investigate associations between BTM and bone disease. Serum N‐ (NTX‐I), C‐terminal telopeptide of type I collagen (CTX‐I) and tartrate‐resistant acid phosphatase band‐5b (TRAP‐5b), as bone resorption markers, and osteocalcin (OC) and bone‐specific alkaline phosphatase (b‐ALP), as bone formation markers, were assessed. Seventy men with haemophilia A (n = 59) or B (n = 11) were studied. Patients with low BMD had significantly higher b‐ALP concentrations compared with those with normal BMD (12.8 ± 1.60 vs. 9.72 ± 0.58 μg/L, P = 0.009), without any differences in the other BTM. NTX‐I and CTX‐I concentrations were negatively associated with oestradiol levels and hip BMD and positively with human immunodeficiency virus infection, number of affected joints and arthropathy scores. B‐ALP and OC concentrations were negatively associated with hip BMD, severity of haemophilia and fracture history, and positively with the number of affected joints and testosterone concentrations. After multivariate analysis, NTX‐I levels remained negatively associated with oestradiol levels, whereas b‐ALP concentrations negatively correlated with the level of physical activity and positively with the number of affected joints. Increased bone metabolism exists in men with haemophilia and low BMD. Increased b‐ALP levels may identify patients at high risk for fracture. Increased number of target joints, low physical activity and low oestradiol concentrations are independently associated with increased bone metabolism.