Abstract 2963
Dickkopf-1 (Dkk-1) and sclerostin are inhibitors of the Wingless-type and integrase 1 (Wnt) signaling and they are implicated in the pathogenesis of multiple myeloma (MM) bone disease ...through inhibition of osteoblast function. There is very limited information for the circulating levels of Dkk-1 and sclerostin in different phases of MM and their alterations post therapies with novel agents. Therefore, we studied 284 MM patients (153M/131F, median age 66 years): 167 consecutive patients were newly-diagnosed (20 had asymptomatic MM and 147 symptomatic MM), 29 patients were at the plateau phase of MM and 88 patients had relapsed/refractory MM and received therapy with the combination of lenalidomide plus dexamethasone with or without bortezomib (VRD or RD; Dimopoulos et al, Leukemia 2010). For newly diagnosed patients, serum was stored at the time of diagnosis, while for patients at the plateau phase serum was collected at the time of confirmation of the plateau (at least 6 months with stable M-protein without criteria confirming progression) and for relapsed/refractory patients on day 1 of cycles 1, 4 and 7 of VRD or RD administration. Circulating levels of Dkk-1 and sclerostin were measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA and Biomedica Medizinprodukte, Vienna, Austria, respectively) in all patients and in 20 gender- and age- matched healthy controls. Circulating Dkk-1 and sclerostin concentrations of newly diagnosed symptomatic patients (median: 1383 pg/mL, range:274-32, 862 pg/mL and 415 pg/mL, 0–3,340 pg/mL respectively) were increased compared to controls (1069 pg/mL, 540-2, 709 pg/mL; p<0.001 and 250 pg/mL, 0–720 pg/mL; p=0.03, respectively) and to asymptomatic patients at diagnosis (1044 pg/mL, 480-2, 335 pg/mL; p<0.001 and 140 pg/mL, 0–1,100 pg/mL; p=0.001, respectively). Patients at plateau phase had increased circulating levels of sclerostin (704 pg/mL, 68–2000 pg/mL; p <0.001) compared to controls (p=0.002) as well as to MM patients at diagnosis (p=0.02). In contrast, they had lower serum levels of Dkk-1 (1013 pg/mL, 414–1729 pg/mL) compared to MM patients at diagnosis (p<0.001) and no difference compared to controls. Patients with ISS-3 myeloma at diagnosis had higher values of Dkk-1 and sclerostin than ISS-1 and ISS-2 patients median Dkk-1 values for ISS-1, ISS-2 and ISS-3 were: 1059 pg/mL, 1290 pg/mL and 2649 pg/mL, respectively; p(ANOVA)=0.031; median sclerostin values for ISS-1, ISS-2 and ISS-3 were: 394 pg/mL, 392 pg/mL and 714 pg/mL, respectively; p(ANOVA)=0.001. Patients with lytic disease at diagnosis (n=116) had increased levels of Dkk-1 compared with patients with no lytic disease (n=51): 1475 pg/mL, 327-32, 862 pg/mL vs. 840 pg/mL, 274–1112 pg/mL; p=0.002. There was no difference in sclerostin levels between these patients; however, patients with advanced bone disease (>3 lytic lesions and/or a fracture) had a borderline increase in their circulating sclerostin compared to all others (p=0.072). Dkk-1 circulating levels correlated weakly with sclerostin (r=0.201, p=0.05). Relapsed patients had increased Dkk-1 (1218 pg/mL, 161-19, 325 pg/mL) and sclerostin (886 pg/mL, 90-6, 272 pg/mL) levels compared to controls and to asymptomatic patients at diagnosis (p<0.001 for all comparisons). In patients who received RD, Dkk-1 was increased and sclerostin was decreased after 6 cycles of therapy. Responders to RD had a median increase of 9% in Dkk-1 serum levels after 6 cycles of therapy, while non-responders had a median increase of 91% compared to baseline values (p<0.01). Patients who did not respond to RD showed an increase in bone resorption marker CTX (p=0.021) after 6 cycles of therapy. VRD administration resulted in a significant reduction of sRANKL (p=0.024) and increase of bone formation marker, osteocalcin (p=0.01) after 6 cycles, but showed only minimal reduction of Dkk-1 (p=0.08) and no alterations on sclerostin. In conclusion our study suggests that Dkk-1 is elevated in active myeloma, while sclerostin is elevated even in the plateau phase of the disease. Both correlated with adverse disease features. The increase of Dkk-1 by RD seems to be balanced by a reduction effect of bortezomib on Dkk-1 in VRD. Furthermore, the reduction of sclerostin in RD patients may represent a modulatory effect of lenalidomide on marrow microenvironment. These results further support the rationale for the use of drugs targeting Dkk-1 and sclerostin in MM.
No relevant conflicts of interest to declare.
Thyroid hormone administration is associated with low bone density in some studies. The aim of the present study was to evaluate the influence L-thyroxine, in doses used to treat patients with a ...history of thyroid carcinoma, on serum cathepsin K and other markers of bone metabolism. Cathepsin K is thought to have a role in osteoclast mediated bone resorption.
A group of male patients with differentiated thyroid cancer (DTC) on suppressive L-thyroxine therapy (DTC-group; n = 51; mean age 57 years; TSH < 0.1 mU/L) was selected as a model for hyperthyroidism. The results were compared to a group of healthy euthyroid men (control-group; n = 50; mean age 58 years; TSH 1.5 +/- 0.9 mU/L).
In the DTC-group the median value of cathepsin K was 6.9 pmol/L, in the control group 4.8 pmol/L (p = 0.0052; highly significant h.s.). There was a significant negative correlation of cathepsin K with age (r = -0.279, p = 0.028). The analysis of various bone associated parameters revealed an increase of serum crosslaps in the DTC-group versus euthyroid controls (p = 0.03). A significant correlation could be found for cathepsin K and osteoprotegerin (p = 0.002).
Cathepsin K is increased by a suppressive L-thyroxine therapy and decreases with increasing age. The increased cathepsin K levels seen in DTC-patients on suppressive L-thyroxine therapy are likely to contribute to accelerated bone degradation in these patients.
Comparing patients with primary hyperparathyroidism (PHP) to a normocalcemic control population, those with PHP have a higher incidence of cardiovascular disease and cardiac abnormalities. This study ...aimed at correlating cardiac findings (valvular and myocardial calcification, myocardial hypertrophy) with clinical data (age, sex, clinical manifestation, nephrolithiasis, nephrocalcinosis, hypertension, skeletal abnormalities, hypercalcemic syndrome) and biochemical data (serum calcium, serum phosphate, serum iPTH level, serum creatinine). A group of 132 consecutive patients with surgically verified PHP (94 women, 38 men; ages 15-86, mean age 57 +/- 16 years) were included in this study. Blood chemistry, clinical presentation, radiography, and echocardiography were carried out in all patients for univariate and multivariate analyses of all parameters. There was no statistical correlation between clinical symptoms, biochemical data, and cardiac calcific alterations. Typical skeletal manifestations (osteolysis/subperiostal resorption) and valvular calcifications were significantly correlated to left ventricular hypertrophy (p = 0.005). Cardiac abnormalities such as calcific myocardial deposits or mitral and aortic valvular calcifications do not correlate with laboratory findings and clinical presentation at the time of diagnosis. There was no biochemical or clinical variable that could predict the frequency or severity of valvular sclerosis or calcific deposits in the myocardium. However, PHP-related skeletal abnormalities and valvular calcification were predicting factors for left ventricular hypertrophy, a reversible cardiac manifestation of PHP. Myocardial hypertrophy is more often found with classic symptomatic PHP with osseous abnormalities.
The balance of the 2 cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor
κ B ligand (soluble (s)RANKL), is known to have considerable influence on bone formation and ...degradation.
Plasma concentrations of OPG and (s)RANKL were determined in a total of 31 long-distance runners before and immediately after running distances of either 15 or 42.195 km, respectively.
In both groups of endurance runners, a significant decrease of sRANKL was observed during the run, the extent of which correlated to the running distance. Furthermore, OPG increased only in runners covering the marathon distance of 42.195 km.
We hypothesize that the known positive effect of long-distance running on the skeletal mass may be mediated by the OPG/sRANKL system.
Plasma concentration and urinary excretion of N-terminal proatrial natriuretic peptides in patients with kidney diseases.
Biologically active N-terminal fragments such as proANP(1-30), proANP(31-67), ...and proANP(1-98) derive from the prohormone of α-human atrial natriuretic peptide proANP(99-126) or α-ANP. No systematic data are available for patients with different kidney diseases.
Specific immunoassays were developed to determine plasma and urine concentrations of these fragments in 121 patients with different degrees of kidney function and urinary protein excretion, respectively.
In patients with kidney disease and normal renal function without proteinuria, circulating proANP(1-30) and proANP(31-67) increased 2.8-fold and 6.5-fold, respectively. Urinary excretion of proANP(31-67) increased by a factor of 7.7 in these patients, whereas proANP(1-30) was not affected. Patients with impaired renal function had a dramatic increase of urinary proANP(31-67) excretion even before serum creatinine levels started to rise. The progression of renal failure caused a significant rise of circulating proANP(1-30) (4.3-fold) and proANP(31-67) (3.0-fold) compared with patients with normal renal function. Urinary excretion of proANP peptides significantly increased, particularly when the serum creatinine level was> 5.0 mg/dL proANP(1-30) 26-fold, proANP(31-67) 8.4-fold. Urinary excretion of proANP(1-30) increased up to 4.4-fold and urinary excretion of proANP(31-67) increased up to 2.4-fold in patients with proteinuria in excess of 3 g/24 h.
Plasma concentrations and urinary excretion of proANP(1-30) and proANP(31-67) are affected by kidney disease and function, but not by proteinuria per se. It is proposed that the diseased kidney increases early urinary excretion of proANP fragments to participate in the regulation of renal function as well as sodium and water excretion.
Osteoprotegerin (OPG) and soluble receptor activator of NF-kappa B ligand (sRANKL) together regulate the bone metabolism among other cytokines, whereby cathepsin K has a potent collagen-degrading ...activity. An imbalance of this system may be partly responsible for the skeletal complications of RA. Expanding on a previous study, we investigated the relationship between OPG, sRANKL and cathepsin K levels in the serum of patients with longstanding RA. We measured serum levels of OPG, sRANKL and cathepsin K of 100 patients with active, longstanding RA. We detected elevated serum levels of cathepsin K (median 54.8 pmol/l) and OPG (median 4.8 pmol/l), but normal sRANKL levels (median 0.2 pmol/l). Cathepsin K did not show a correlation with the overexpressed OPG (
P
= 0.64) and sRANKL (
P
= 0.81). The radiological destruction correlates significantly with cathepsin K (
P
= 0.004) and OPG (
P
= 0.007). We speculate that the increased levels of OPG are effective in compensating the action of sRANKL, but do not directly prevent bone degradation, as reflected by the elevated serum levels of cathepsin K.
Objectives. We tested the hypothesis that, in patients with stable heart failure, measuring big endothelin-1 (ET-1) plasma level at rest predicts short-term prognosis better than peak oxygen ...consumption (Vo2max) at exercise.
Background. Cardiopulmonary exercise testing and evaluation of neurohumoral plasma factors are established tools to estimate survival in patients with heart failure. No data, however, exist comparing the prognostic value of both marker categories simultaneously.
Methods. Two hundred twenty-six heart failure patients were studied in regard to a combined end point of death and prioritization for urgent cardiac transplantation within 1 year follow-up.
Results. During the study period 149 patients were without cardiac events (group A), 69 patients died or were urgently transplanted (group B) and 8 patients were alive after a nonurgent heart transplant operation. Norepinephrine (p < 0.0001), atrial natriuretic peptide (p < 0.001), big endothelin plasma levels (p < 0.0001 as well as workload, Vo2max and achieved percentage of predicted peak oxygen consumption (pVo2max) (all p < 0.0001) differed significantly between groups A and B. In multivariate stepwise regression analysis, however, only big ET-1 plasma concentration (×2 = 74.4, p < 0.0001), New York Heart Association function class (×2 = 33.9, p < 0.0001), maximal workload (×2 = 7.2, p < 0.01, and plasma atrial natriuretic peptide (ANP) concentration (×2 = 4.6, p < 0.05) were independently related to outcome. Peak oxygen consumption or pVo2max did not reach statistical significance in this model. Event-free survival rates were significantly lower in patients with a big ET-1 level of 4.3 fmol/ml or more than with lower big ET-1 levels (p < 0.0001).
Conclusion. We conclude that in patients with chronic heart failure who are stable on oral therapy measuring big ET-1 and ANP plasma levels may be a valuable noninvasive adjunct to improve the prognostic accuracy of detecting high risk patients compared with exercise testing alone.
OBJECTIVE: Long-distance running results in considerable stress. Little evidence exists about the role of the atrial and brain natriuretic peptides, ANP and BNP, deriving from the myocardium. The aim ...of our study was to investigate the influence of running 42.195 km on changes in circulating natriuretic propeptides and adrenocortical steroids. DESIGN AND METHODS: We studied 17 male and 2 female runners (age: 28-62 Years) participating in a marathon. Blood samples were obtained before and immediately after the competition. proANP(1-98) and proANP(1-30) as well as Nt-proBNP(8-29) were determined by enzyme immunoassays. RESULTS: Runners finished the competition between 2 h 58 min and 4 h 25 min. We observed a more pronounced increase in proANP(1-98) (+58%) and proANP(1-30) (+99%, both P<0.001) compared with Nt-proBNP(8-29) (+6%; P=0.005). Increases in proANP(1-30) positively correlated with runners' age (r=0.53; P=0.02). We also observed a marked increase in cortisol (+73%) and especially in aldosterone (+431%, both P<0.001). CONCLUSIONS: Cardiac strain during long-distance running may explain the pronounced increase in proANP. Other explanations for the observed rise in plasma levels might be a change in the permeability of myocardial cells and an impaired clearance. A rise in adrenocortical steroids may compensate for the negative influence of ANP on natriuresis and blood pressure. Positive effects of ANP during a marathon could be the regulation of body temperature by influencing sweat glands as well as the stimulation of lipolysis compensating for the enormous energy demand.
N-terminal fragments of the proatrial natriuretic peptide in patients before and after hemodialysis treatment.
Fragments derived from the prohormone of α-human atrial natriuretic peptide (α-ANP) in ...patients with cardiac failure are more closely related to the disease state than intact α-ANP.
Specific immunoassays have been developed to detect proANP 1-30, proANP 31-67, and proANP 1-98. Plasma concentrations of these fragments were determined in 122 hemodialysis patients with and without cardiac dysfunction, with and without hypertension, as well as with and without dialysis-associated hypotensive episodes either before or after a regularly scheduled hemodialysis session. The effects of different dialyzer membranes were also evaluated. The results of these assays along with other markers of volume regulation such as α-ANP and cyclic 3′,5′ guanosine monophosphate (cGMP) were compared with those of healthy controls.
Predialytic and postdialytic plasma concentrations of the proANP fragments were markedly higher in uremic patients than in controls (98-fold for proANP 1-98, 56-fold for proANP 31-67, and 35-fold for proANP 1-30). All proANP fragments, α-ANP, and cGMP decreased during hemodialysis. A strong linear correlation was found between predialytic and postdialytic plasma levels. There was no correlation, however, with the amount of fluid removed during hemodialysis. Patients with altered left ventricular hemodynamics displayed significantly higher plasma concentrations of all proANP fragments and α-ANP, but not cGMP, than patients with normal cardiac function. Hemodialysis patients with moderate or severe hypertension had higher concentrations of proANP fragments, α-ANP, and cGMP than patients with normal blood pressure or patients with only mild hypertension. There was no significant difference in circulating levels of proANP peptides, α-ANP, and cGMP between patients with and without frequent dialysis-associated hypotensive episodes. Cellulose-triacetate dialyzers reduced plasma levels of proANP 1-30, proANP 31-67, and proANP 1-98 significantly more than polysulfone dialyzers, but α-ANP and cGMP levels were not different.
Circulating α-ANP and proANP fragments are influenced by a variety of factors such as end-stage renal disease, hemodialysis treatment, dialyzer membrane material, cardiac dysfunction, and hypertension. Therefore, these are not useful markers to accurately estimate volume status in hemodialysis patients.
OBJECTIVE To evaluate bone mineral density and biochemical parameters of bone metabolism in ambulatory premenopausal female patients with systemic lupus erythematosus (SLE). METHODS 30 women who ...fulfilled the ARA criteria for the classification of SLE were studied. Lumbar and femoral bone mineral density was determined by dual energyx ray absorptiometry. Various laboratory parameters including serum calcium, serum phosphorus, alkaline phosphatase, bone specific isoform of alkaline phophatase, propeptide of type 1 procollagen, deoxypyridinoline excretion, telopeptide of type 1 collagen, serum creatinine, osteocalcin, parathyroid hormone, 25-OH vitamin D, testosterone, progesterone, estradiol, follicle stimulating hormone and luteinotropic hormone were measured. RESULTS According to the WHO criteria 39% of all patients with SLE studied had normal bone mineral density, 46% had osteopenia and 15% had osteoporosis at the lumbar spine; at the femoral neck 38.5% had normal bone mineral density, 38.5% had osteopenia and 23% suffered from osteoporosis. Significantly lower osteocalcin levels were found in SLE patients. All other bone resorption and formation markers measured were not statistically different, but higher serum albumin corrected calcium and lower phosphorus values were found in the SLE group. Of all sex hormones tested lower testosterone and higher follicle stimulating hormone concentrations were seen in patients with SLE. CONCLUSION A high incidence was found of osteopenia and osteoporosis in premenopausal patients with SLE. Bone diminution in SLE seems to be attributable, at least in part, to decreased bone formation in SLE patients.
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