The relationship between inhibitors of the Wnt signalling pathway (sclerostin and Dickkopf-1) and carotid intima-media thickness in postmenopausal women with type 2 diabetes mellitus.

The aim of the study was to investigate the association of the extracellular inhibitors of Wnt/ß-catenin signalling sclerostin and Dickkopf-1 (Dkk-1) with carotid intima-media thickness (CIMT) in type 2 diabetes mellitus (T2DM). We performed a cross-sectional study including 40 T2DM postmenopausal women and 40 healthy controls. CIMT was measured by B-mode ultrasound. Serum sclerostin and Dkk-1 were measured by solid-phase enzyme-linked immunosorbent assay (ELISA). Serum sclerostin and Dkk-1 concentrations were significantly higher in T2DM group than in controls. There was a significant negative correlation between sclerostin and Dkk-1 and CIMT in T2DM (p = 0.0063 and p = 0.0017, respectively). After adjustment for potential confounders, associations remained significant only for sclerostin. These data suggest that sclerostin, an established modulator of the canonical Wnt signalling, may protect against progression of vascular complications in diabetic patients, possibly by attenuating upregulation of ß-catenin activity in the vascular cells.

Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss.

CONTEXT: Sclerostin, a Wnt signaling antagonist on the osteoblasts produced by osteocytes, is regulated by mechanical strain and is implicated in the pathogenesis of disuse bone loss. There are no data on sclerostin in humans. OBJECTIVE: The aim of the study was to evaluate sclerostin in patients immobilized after stroke, compared with control subjects, and to analyze its relationship with markers of bone formation and resorption. DESIGN: This was a cross-sectional study. SETTING AND PATIENTS: We studied 40 postmenopausal women immobilized after a single episode of stroke 6 months or longer after onset, and 40 postmenopausal women from the general community. Bone status was assessed by quantitative ultrasound measurements at the calcaneus. Bone alkaline phosphatase (b-AP), carboxy-terminal telopeptide of type I collagen (CrossLaps), and sclerostin were evaluated by ELISA. We also used ELISA to measure serum levels of Dickkopf-1, another soluble inhibitor of Wnt/beta-catenin signaling, highly expressed by osteocytes. RESULTS: Immobilized patients had higher sclerostin serum levels (median 0.975 ng/ml; 25th to 75th percentiles 0.662-1.490) than controls (median 0.300 ng/ml; 25th to 75th percentiles 0.165-0.400: P < 0.0001) and an increased bone turnover with a more significant rise in bone resorption (CrossLaps) than formation (b-AP) markers. Sclerostin correlated negatively with b-AP (r = -0.911; P < 0.0001) and positively with CrossLaps (r = 0.391; P = 0.012). Dickkopf-1 did not significantly differ between the groups. Patients also had quantitative ultrasound measurements index lower than controls (P < 0.001). CONCLUSIONS: This study shows for the first time that long-term immobilized patients present hypersclerostinemia associated with reduced bone formation, and suggests that sclerostin could be a link between mechanical unloading and disuse osteoporosis in humans.

Current management of intermittent claudication: the role of pharmacological and nonpharmacological symptom-directed therapies.

Lower extremity peripheral arterial disease (PAD) is a manifestation of atherosclerosis, with a prevalence ranging from 4% to 12% in the adult population and increasing up to 20% in older individuals. Intermittent claudication (IC) may markedly impair walking ability, overall functional status and quality of life. PAD is a marker of systemic atherosclerosis and is associated with increased cardiovascular morbidity and mortality. However, leg disease usually runs a rather benign course in claudicant patients, with only about 1% to 3% of them ever requiring a major amputation over a 5-year period. The goals of treatment for claudication are to relieve exertional symptoms, and improve walking capacity and quality of life. Therapeutic strategies aimed at reducing systemic cardiovascular risk burden and prolonging survival, including intensive risk factor modification and antiplatelet therapy, should be implemented in all patients with PAD. Supervised exercise training has proven the most effective conservative treatment for symptomatic relief of IC. Current evidence for drug therapy of IC supports the use of cilostazol as a first-line drug. Other drugs with more limited evidence of benefit for claudication include pentoxifylline and naftidrofuryl. Endovascular or surgical revascularization is indicated for selected patients with vocation- or lifestyle-limiting claudication who are unresponsive to exercise and pharmacotherapy. New drug candidates for managing claudication symptoms include propionyl-L-carnitine and statins. Preliminary studies suggest that therapeutic angiogenesis holds promise for future treatment of IC.

Therapeutic perspectives.

Osteoporosis and atherosclerosis are linked by biological association. This encourages the search for therapeutic strategies having both cardiovascular and skeletal beneficial effects. Among drugs that may concordantly enhance bone density and reduce the progression of atherosclerosis we can include bisphosphonates (BP), statins, ß -blockers, and possibly anti-RANKL antibodies. Available data come from experimental animals and human studies. All these treatments however lack controlled clinical studies designed to demonstrate dual-action effects.

Pamidronate and osteoporosis prevention in liver transplant recipients.

Osteoporosis is a common complication in patients with end-stage liver disease and after orthotopic liver transplantation (LT), with resulting increasing fracture rate. In this study, we investigated the role of treatment with pamidronate in preventing further bone loss after LT. Eighty-five patients with end-stage liver disease were included in the study. Pamidronate 30 mg was given intravenously every 3 months after LT for the duration of 1 year to 43 patients with osteopenia or osteoporosis prior LT. The remainders served as controls. All patients received a supplementation of calcium and vitamin D. Bone mineral density (BMD) at the lumbar spine and the femoral neck, and markers of bone metabolism were measured before and 12 months after LT. Sixty-two BMD were available at 12 months; only paired BMD were evaluated. A significant increase in lumbar spine BMD was observed in pamidronate treated patients. No change was evident in controls. Femoral neck BMD decreased in both treated and untreated patients. Osteocalcin serum levels and deoxypyridinoline urinary excretion were significantly reduced by treatment. Our study suggests that pamidronate decreases bone turnover and is effective in preventing the course of bone loss after LT, however the efficacy, at the dosage regimen employed and in a follow-up of 12 months, appears to be limited to trabecular bone, with no effect on the cortical structure of the femur.

Association of high alpha2-Heremans-Schmid glycoprotein/fetuin concentration in serum and intima-media thickness in patients with atherosclerotic vascular disease and low bone mass.

OBJECTIVE: Alpha2-Heremans-Schmid glycoprotein (AHSG; fetuin), a member of the cystatin superfamily of cysteine protease inhibitors involved in vascular pathology and bone metabolism, has been reported to be reduced in patients with atherosclerosis and medial calcification related to end stage renal disease or dialysis. No data on fetuin in patients with peripheral artery disease associated with low bone mass and normal renal function are available in the literature. In the present study we evaluated serum fetuin concentrations, bone mass, and markers of bone turnover in patients with atherosclerosis of peripheral vessels and normal kidney function. PATIENTS AND METHODS: Ninety consecutive patients with evidence of atherosclerotic plaques at the common carotid or femoral artery were studied. Severity grade of disease was documented by ultrasound measurement of intima-media thickness (IMT). Fasting serum levels of fetuin were measured by sandwich enzyme immunoassay. MAIN RESULTS: The mean patient serum concentration of fetuin was 57.68+/-13.6 ng/ml, significantly higher than that of control subjects (41.6+/-7.6 ng/ml; p<0.001). The mean serum concentration of bone-specific alkaline phosphatase (BAP) were 8.4+/-2.3 microg/l, significantly lower than controls (13.6+/-1.6 microg/l; p<0.001). Fetuin was correlated with IMT (r=0.8530; p<0.0001) and inversely correlated with BAP (r=-0.5503; p<0.0001). Patients had a vertebral and femoral bone mass significantly lower than controls. CONCLUSION: This study documented for the first time that, in patients with atherosclerosis of peripheral vessels, serum fetuin levels were higher than in healthy subjects, and correlated with the severity of disease; further studies are required to analyse the role of AHSG as an independent predictor of atherosclerotic disease and low bone mass in patients with normal renal function.