Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium cross-links as specific urinary markers

Urinary excretion of the bone collagen derived pyridinium cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) was measured in 19 patients (4 M:15 F) with untreated thyrotoxicosis, and 20 pre-, and 20 postmenopausal women taking T4 100-200 micrograms daily for autoimmune hypothyroidism. Both PYD and DPD excretion (nanomoles per mmol creatinine) was elevated in the thyrotoxic patients compared to 287 controls; median 131 vs. 26 and 37.5 vs. 7.2, respectively, P less than 0.0001. In premenopausal women mean urinary pyridinium cross-link excretion and serum osteocalcin levels were similar in both T4-treated and matched control groups, despite suppression of serum TSH concentrations to below 0.1 mU/L in 14 of the 20 taking T4. In postmenopausal women mean (+/- 1 SE) urinary PYD excretion (nanomoles per mmol creatinine) was raised in those taking T4, relative to euthyroid controls; 40.0 +/- 2.7 vs. 32.1 +/- 2.3, P less than 0.05. DPD excretion and serum osteocalcin levels were also higher, but not significantly. When only the T4-treated women with a subnormal serum TSH were considered the difference in PYD excretion was more marked, and mean DPD excretion was also significantly elevated; 13.7 +/- 1.3 vs. 10.1 +/- 0.8, P less than 0.05. Conclusion: bone collagen breakdown is increased in thyrotoxicosis, and in postmenopausal women taking sufficient T4 to suppress serum TSH. Similarly treated premenopausal women appear to be at lower risk.     

Oral prednisolone supplement abolishes the acute adverse effects following initiation of depot bromocriptine therapy

OBJECTIVE We measured pyridinium cross-links, markers of bone resorption, by an enzyme-linked immunosorbent assay (ELISA) in hypothyroid patients to see whether bone resorption was reduced in hypothyroidism and whether it increased with T4 treatment. DESIGN AND PATIENTS Eight hypothyroid patients, whose initial TSH levels were 268.1 ± 87.7 mU/l (mean ± SE), were treated with T4 (100μg/day). Urinary excretion of pyridinium cross-links was assayed before and after T4 treatment. MEASUREMENTS Pyrilinks and Pyrilinks-D kits were used. The Pyrilinks assay measures free forms of pyridinoline and deoxypyridinoline together (PYD), while the Pyrilinks-D assay measures deoxypyridinoline (DPD) alone. The Pyrilinks reference ranges for normal subjects are 8–24nmol/mmol creatinine in males and 10–28nmol/mmol creatinine in normal premenopausal females. The DPD reference ranges obtained from normal men and women aged 40–50 years were 3.20 ± 0.75 (mean ± SD) nmol/mmol creatinine and 4.55 ± 1.22 nmol/mmol creatinine, respectively. RESULTS The sensitivity of the assay was enhanced by simply using less diluted urine samples. Concentrations of both compounds of the urinary pyridinium cross-links were low in untreated hypothyroid patients and increased gradually as thyroid hormone status improved from hypothyroidism to euthyroidism. One month after treatment when the TSH levels in the patients were still as high as 74.4 ± 44.5 mU/l, urinary PYD excretion has increased to 2.6 times the pretreatment level. When the TSH levels of the patients decreased below 10 mU/l, both PYD and DPD increased significantly to 3.8 and 3.3 times pretreatment values, respectively. CONCLUSIONS Although hyperthyroidism or excess treatment with thyroid hormone has been known to induce bone resorption, this is the first report that urinary excretion of pyridinium cross-links is reduced in hypothyroidism and is normalized by physiological thyroid hormone replacement.     

Urinary markers of bone resorption, pyridinoline and deoxypyridinoline, are increased in sickle cell patients with further increments during painful crisis

The painful crisis is the hallmark of sickle-cell disease (SCD). Bone resorption, as part of physiological bone turnover, results in release into the circulation with subsequent urinary excretion of the collagen cross-links pyridinoline (PYD) and deoxypyridinoline (DPD). Urinary PYD and DPD concentrations could reflect the extent of bone infarction during painful sickle-cell crisis. Urinary concentrations of PYD and DPD, adjusted for urine creatinine, were measured in sickle-cell patients (38 clinically asymptomatics and 27 during painful crisis) and healthy controls (n 5 25) using high-performance liquid chromatography(HPLC). PYD and DPD concentrations were higher in asymptomatic HbSS/HbSb0-thalassemia patients compared to controls (P <0.05) with further increments during painful crisis in both HbSS/HbSb0-thalassemia and HbSC/HbSb1-thalassemia patients (P < 0.05). In the asymptomatic HbSS/HbSb0-thalassemia patients, there was a statistically significant positive correlation between DPD and hemolytic rate.Based on urinary PYD and DPD concentrations, bone degradation is increased in asymptomatic sickle-cell patients, with further increments during painful crisis. Urinary PYD and DPD concentrations are potentially diagnostic and prognostic tools in SCD.     

Increased urinary endothelin-1 excretion in newly diagnosed type 2 diabetic patients

To investigate whether urinary and plasma endothelin (ET)-1 concentrations are responsive to the alteration of intravascular blood volume in uncontrolled diabetic patients, we determined urinary ET-1 excretion and plasma ET-1 concentration in 42 newly diagnosed type 2 diabetic patients and 38 normal subjects. Mean fasting plasma glucose value (12.8 +/- 0.72 mmol l-1) and plasma renin activity (PRA, 2.80 +/- 0.44 ng ml-1 hr-1) in diabetic patients were significantly higher as compared to normal controls (mean plasma glucose value: 5.2 +/- 0.83 mmol l-1; mean PRA value: 1.34 +/- 0.17 ng ml-1 hr-1), whereas plasma ET-1 value (1.33 +/- 0.07 pmol l-1) was not significantly different from that (1.29 +/- 0.06 pmol l-1) of normal controls. Mean urinary ET-1 excretion level (7.53 +/- 0.74 nmol mol-1 creatinine) was significantly higher than that (5.36 +/- 0.37 nmol mol-1 creatinine) of normal controls. Urinary ET-1 excretion was correlated with plasma glucose value (r = 0.360, p < 0.05) and PRA value (r = 0.381, p < 0.05). Urinary ET-1 excretion rate (5.17 +/- 0.37 nmol mol-1 creatinine) and PRA value (1.42 +/- 0.18 ng ml-1 hr-1) declined to normal levels when mean plasma glucose value decreased to the level of 7.1 +/- 0.39 mmol l-1 in diabetic patients after 4 months of glycemic control. Our results indicated that renal-derived ET-1 was responsive to the alteration of intravascular blood volume in untreated newly diagnosed type 2 diabetic patients.     

Urinary hydroxy-pyridinium crosslinks provide indices of cartilage and bone involvement in arthritic diseases

The urinary concentrations relative to creatinine of the collagen crosslinks, pyridinoline (PYD) and an analogue derived specifically from bone collagen, deoxy-pyridinoline (DPD), were measured using a high performance liquid chromatography (HPLC) technique in 41 patients with rheumatoid arthritis (RA) and 45 patients with osteoarthritis (OA), and were compared with values of 118 healthy control individuals. The levels of DPD were increased significantly in both RA and OA suggesting accelerated bone degradation in both disease groups. PYD concentrations were also significantly increased in both diseases, but larger increases were detected in patients with RA, for which this index correlated with clinical measures of joint involvement and biochemical variables of inflammatory activity. Cross-sectional studies showed that treatment with disease modifying drugs (gold and D-penicillamine) led to decreased crosslink levels but longterm corticosteroids resulted in increased urinary crosslinks, probably due to the induction of bone resorption. Measurement of both pyridinium crosslinks in urine may therefore provide information on the stage, activity, level of bone involvement and efficacy of drug therapy in arthritic diseases.     

Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism

Estrogen replacement therapy (ERT) decreases total serum calcium by about 0.5 mg/dl in postmenopausal women with primary hyperparathyroidism (PHPT). We investigated the ability of raloxifene, which has skeletal antiresorptive properties similar to those of ERT, to decrease serum calcium concentrations and markers of bone turnover in PHPT. Eighteen postmenopausal women with asymptomatic PHPT were randomized to 8 wk of raloxifene (60 mg/d) or placebo, followed by a 4-wk washout. At baseline, the groups were well matched. The calcium concentration decreased significantly by 8 wk of raloxifene administration (10.8 +/- 0.2 to 10.4 +/- 0.2 mg/dl; P < 0.05), as did markers of bone resorption and formation [osteocalcin, 11.4 +/- 1.6 to 9.9 +/- 1.6 nmol/liter (P < 0.05); serum N-telopeptide, 21.2 +/- 3.4 to 17.3 +/- 2.8 nmol bone collagen equivalents/liter (P < 0.05)]. Four weeks after raloxifene was discontinued, indices were indistinguishable from baseline. Raloxifene administration did not affect serum PTH, 1,25-dihydroxyvitamin D, total alkaline phosphatase, or urinary calcium excretion. Calcium and bone marker changes were therefore similar to those observed with ERT in PHPT. This short-term study suggests that raloxifene may be a useful approach to the treatment of postmenopausal women with mild PHPT.     

Reduction of urinary levels of pyridinoline and deoxypyridinoline and serum levels of soluble receptor activator of NF-kappaB ligand by etanercept in patients with rheumatoid arthritis

The effects of soluble TNF-α receptor, etanercept, on bone metabolism were investigated in patients with rheumatoid arthritis (RA). Thirty RA patients were administered etanercept once or twice a week for more than 6 months. We evaluated clinical and laboratory parameters and measured urinary excretion levels of pyridinoline (PYD), deoxypyridinoline (DPD), cross-linked N-telopeptides of type I collagen (NTX), and serum levels of bone alkaline phosphatase (BAP), osteoprotegerin (OPG), and soluble receptor activator of NFκB ligand (sRANKL) at the baseline and at 3 and 6 months after initial treatment with etanercept. Etanercept treatment resulted in an improvement of symptoms due to RA and in a reduction of urinary excretion levels of PYD and DPD as well as serum sRANKL levels, with a significant difference at 6 months, and an increase of serum BAP levels at 3 and 6 months after the initial treatment with etanercept. Urinary NTX and serum OPG levels did not show a significant change at 3 and 6 months after the initial treatment, but serum OPG levels did show a reverse correlation with serum CRP levels, suggesting that the regulation of inflammation in RA may result in an induction of OPG production. Etanercept may have the ability to reduce the levels of bone resorption markers and to increase the levels of a bone formation marker while reducing sRANKL formation in RA patients.     

First-line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma

BACKGROUND: Bone involvement is frequently observed in multiple myeloma (MM) patients both at diagnosis and during the course of the disease. The evaluation of biochemical markers of bone turnover could allow a dynamic evaluation of the effects of a given therapy on bone metabolism. METHODS: In the present study, markers of bone resorption [urinary free pyridinoline (PYD), deoxypyridinoline (DPYD), N-terminal telopeptide of collagen I (NTX) and C-terminal telopeptide (serum crosslaps)] and of bone formation [bone alkaline phosphatase (BAP) and osteocalcin] were evaluated at diagnosis and after induction therapy in 40 patients (23M, 17F, median age = 53.5 yr) enrolled in the 'Bologna 2002' clinical trial. By study design, all patients received 4 months of combined thalidomide (100 mg/d for 2 wk then 200 mg/d), dexamethasone (40 mg/d on days 1-4, 9-12, 17-20/28 on odd cycles and on days 1-4 on even cycles) and zoledronic acid (4 mg/28 d). RESULTS: At diagnosis, although bone resorption markers were increased in more than 40% of the patients, only NTX (P = 0.029) and crosslaps (P = 0.000) were significantly related to the extent of skeletal lesions, as assessed by X-ray. After 4 months of therapy, a significant decrease in mean (+/-SE) urinary NTX (52.7 +/-6.9 nmol/mmol creatinine +/-6.9 vs. 14 +/- 1.42 nmol/mmol creatinine, P = 0.000) and serum crosslaps (6242.4 +/-945 pmol/L vs. 1414.9 +/- 173.8 pmol/L, P = 0.000) was observed in patients obtaining > or =partial response, at variance to what has been detected in patients showing 相似文献   

Serum concentrations of interleukin 6, osteocalcin, intact parathyroid hormone, and markers of bone resorption in patients with rheumatoid arthritis.

OBJECTIVE: To analyze serum concentrations of interleukin 6 (IL-6), osteocalcin, intact parathyroid hormone (PTH), and type 1 collagen carboxyterminal telopeptide (ICTP) as well as the urinary concentrations of crosslinked N-telopeptides of type 1 collagen (NTx) and deoxypyridinoline (Dpd) in patients with rheumatoid arthritis (RA) to investigate their role in the etiology of the osteopenia in this disease. METHODS: Using ELISA and radioimmunoassay methods, we estimated serum concentrations of IL-6, osteocalcin, ICTP, intact PTH, and spot urine concentrations of NTx and Dpd in 25 female patients with active RA, 25 female patients with suppressed disease, and 25 age matched healthy female controls. RESULTS: Patients with active RA had significantly higher (p < 0.001) concentrations of IL-6 (94.0+/-12.1 pg/ml) compared to patients with suppressed disease (13.2+/-0.8 pg/ml) and healthy controls (12.3+/-0.8 pg/ml). Serum osteocalcin was significantly lower (p < 0.001) in patients with active RA (1.9+/-0.2 ng/ml) compared to patients with suppressed disease (2.7+/-0.2 ng/ml) and the controls (2.9+/-0.2 ng/ml). Similarly, serum intact PTH was significantly lower (p < 0.001) in patients with active disease (29.9+/-1.5 ng/ml) compared to patients with suppressed RA (38.0+/-1.6 ng/ml) and controls (49.8+/-2.4 ng/ml). Serum ICTP was also significantly higher (p < 0.01) in patients with active RA (9.5+/-0.3 microg/l) versus patients with suppressed disease (4.1+/-0.2 microg/l) and controls (3.4+/-0.2 microg/l). In patients with active disease, spot urine concentrations of NTx (123.1+/-5.1 nmol bone collagen equivalent/mmol creatinine) and Dpd (15.1+/-0.7 nmol/mmol creatinine) were significantly higher (p < 0.001) than in patients with suppressed disease (58.4+/-2.5 nmol bone collagen equivalent/mmol creatinine and 10.1+/-0.5 nmol/mmol creatinine, respectively) and healthy controls (53.4+/-2.1 nmol bone collagen equivalent/mmol creatinine and 9.7+/-0.5 nmol/mmol creatinine, respectively). There were no significant correlations between serum IL-6 and serum ICTP (r = 0.2357, p = 0.257) or urinary NTx (r = 0.1436, p = 0.494) or between serum intact PTH and ICTP (r = 0.0206, p = 0.922) in patients with active RA. CONCLUSION: There are no significant correlations between bone resorption markers and serum IL-6 and intact PTH in patients with RA.     

Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia.

Osteoclastic activity is increased in tumor-associated hypercalcemia, which, thus, constitutes an excellent opportunity to assess new markers of the bone resorption rate. We have measured the fasting urinary excretion of the pyridinium cross-links pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) in 36 hypercalcemic cancer patients (mean +/- SD, 3.2 +/- 0.4 mmol/L for total serum Ca and 1.66 +/- 0.24 mmol/L for Ca2+). Thirty-two of them were reevaluated after treatment with iv bisphosphonates. Urinary Pyr and D-Pyr levels were higher than those in healthy controls (130 +/- 62 vs. 40 +/- 19 nmol/mmol creatinine for Pyr and 20 +/- 15 vs. 6 +/- 3 nmol/mmol creatinine for D-Pyr; P less than 0.001 for both). This represented a mean 3.3-fold increase over the normal mean compared to 5.8- and 3.4-fold increases for fasting urinary Ca and hydroxyproline, respectively. Individual values were elevated in 83% and 75% of the cases for Pyr and D-Pyr compared to 97% and 83% for urinary Ca and hydroxyproline, respectively. The levels of Pyr and D-Pyr tended to be higher in patients with head and neck tumors than in patients with breast cancer. Urinary Pyr and D-Pyr correlated with each other (r = 0.72; P less than 0.001) and were highly correlated with hydroxyproline (r = 0.68 and 0.83, respectively; P less than 0.001 for both), but poorly correlated with urinary Ca (r = 0.21; P = NS and r = 0.42; P = 0.01, respectively), suggesting that these markers reflect different events of bone resorption. Similarly, after bisphosphonate therapy, urinary Pyr and D-Pyr levels fell by 31% and 50%, respectively, compared to 38% for hydroxyproline and 76% for urinary Ca. There was a significant correlation between posttreatment D-Pyr and serum Ca levels (r = 0.43; P less than 0.05). In summary, we found that the urinary excretion of Pyr and D-Pyr was markedly increased in hypercalcemic cancer patients and was adequately lowered by bisphosphonate therapy. The urinary excretion of the pyridinium cross-links, especially D-Pyr, should be helpful to specifically quantitate bone matrix resorption and monitor the inhibition of bone resorption in cancer patients receiving antiosteolytic drugs.     

Vitamin D repletion in patients with primary hyperparathyroidism and coexistent vitamin D insufficiency

Vitamin D insufficiency is common in patients with primary hyperparathyroidism (PHPT) and may be associated with more severe and progressive disease. Uncertainty exists, however, as to whether repletion of vitamin D should be undertaken in patients with PHPT. Here we report the effects of vitamin D repletion on biochemical outcomes over 1 yr in a group of 21 patients with mild PHPT [serum calcium <12 mg/dl (3 mmol/liter)] and coexistent vitamin D insufficiency [serum 25 hydroxyvitamin D [25(OH)D] <20 microg/liter (50 nmol/liter)]. In response to vitamin D repletion to a serum 25(OH)D level greater than 20 microg/liter (50 nmol/liter), mean levels of serum calcium and phosphate did not change, and serum calcium did not exceed 12 mg/dl (3 mmol/liter) in any patient. Levels of intact PTH fell by 24% at 6 months (P < 0.01) and 26% at 12 months (P < 0.01). There was an inverse relationship between the change in serum 25(OH)D and that in intact PTH (r = -0.43, P = 0.056). At 12 months, total serum alkaline phosphatase was significantly lower, and urine N-telopeptides tended to be lower than baseline values (P = 0.02 and 0.13, respectively). In two patients, 24-h urinary calcium excretion rose to exceed 400 mg/d, but the group mean 24-h urinary calcium excretion did not change. These preliminary data suggest that vitamin D repletion in patients with PHPT does not exacerbate hypercalcemia and may decrease levels of PTH and bone turnover. Some patients with PHPT may experience an increase in urinary calcium excretion after vitamin D repletion.     

Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links

Pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) are two cross-links of collagen molecules that are present in the extracellular matrix and released during its degradation. In contrast to the wide distribution of collagen, Pyr is present in bone and cartilage, but not in significant amounts in other connective tissues, and D-Pyr appears to be specific for bone tissue. Therefore, the urinary excretion of Pyr and D-Pyr might be a sensitive marker of bone matrix degradation. Using a specific high pressure liquid chromatography assay we have measured Pyr and D-Pyr cross-links in a 24-h and a fasting urine sample in 60 early postmenopausal women and 19 premenopausal women matched for age. Menopause induced a 62% increase in Fu Pyr (49.8 +/- 18.7 vs. 30.8 +/- 8.0 pmol/mumol creatinine; P less than 0.001) and an 82% increase in Fu D-Pyr (8.2 +/- 3.4 vs. 4.5 +/- 1.4 pmol/mumol creatinine; P less than 0.001). In 20 postmenopausal women on hormone replacement therapy, urinary Pyr and D-Pyr returned to premenopausal levels within 6 months, contrasting with unchanged levels during placebo treatment. The 24-h excretion of Pyr and D-Pyr was significantly lower than the fasting excretion, but was similarly decreased after hormone replacement therapy. Pyr and D-Pyr excretion measured in the same urinary sample were highly correlated (r = 0.85 for fasting and 0.83 for 24-h sampling), but correlations between fasting and 24-h values were weak (D-Pyr, r = 0.30; Pyr, r = 0.29; P less than 0.05 for both). Correlations between urinary cross-links and other markers of bone turnover (Fu hydroxyproline/creatinine and plasma osteocalcin) were significant but low (Pyr vs. osteocalcin, r = 0.29, P less than 0.05; Pyr vs. hydroxyproline, r = 0/.34; P less than 0.01; D-Pyr vs. osteocalcin, r = 0.39; P less than 0.01), except for D-Pyr vs. hydroxyproline (r = 0.24; P = 0.07), suggesting that these markers reflect different events of bone metabolism. Finally, a single measurement of the fasting excretion, but not of the 24-h excretion, of cross-links was significantly correlated (Pyr, r = 0.34; P less than 0.05; D-Pyr, r = -0.46; P less than 0.01), with the subsequent spontaneous rate of bone loss assessed by repeated measurements of the radial bone mineral content in 37 postmenopausal women.(ABSTRACT TRUNCATED AT 400 WORDS)     

Efficacy of intranasal human calcitonin in patients with Paget's disease refractory to salmon calcitonin

PURPOSE: A cause for the resistance to intranasal salmon calcitonin (sCT) therapy in patients with Paget's disease is the occurrence of neutralizing antibodies to sCT. As a result, a new formulation of intranasal human calcitonin (hCT) was developed, and the efficacy investigated in patients treated earlier with sCT. PATIENTS AND METHODS: Twelve patients with Paget's disease were treated twice daily for 6 months with 1 mg synthetic hCT administered intranasally. Five patients demonstrated low-titer antibodies to sCT, and four of the patients did not respond previously to 1-year therapy with intranasal sCT. The hypocalcemic effect of 3 mg hCT was compared to that of 0.1 mg sCT before and after the intranasal hCT therapy. Serum alkaline phosphatase and the ratio between the urinary excretion of hydroxyproline and creatinine were measured before and during intranasal hCT treatment. RESULTS: The hypocalcemic response to 3 mg intranasal hCT (-6.60 +/- 0.67%, mean +/- standard error) was similar before and at the end of intranasal hCT therapy (-5.92 +/- 0.80%, p greater than 0.1). Intranasal sCT (0.1 mg) lowered serum calcium less effectively (-2.86 +/- 0.76%) than 3 mg intranasal hCT (p less than 0.05). The presence of low-titer antibodies to sCT did not affect the hypocalcemic response to sCT or hCT. As a result of the 6-month intranasal hCT regimen, serum alkaline phosphatase and urinary hydroxyproline/creatinine ratio were reduced to 62 +/- 5% (p less than 0.001) and 80 +/- 7% (p less than 0.05) respectively, of pretreatment levels. In four patients previously resistant to intranasal sCT therapy because of neutralizing antibodies to sCT, serum alkaline phosphatase was similarly lowered by intranasal hCT to 66 +/- 6% of pretreatment levels (p less than 0.05). CONCLUSION: A new formulation of intranasal hCT effectively lowered serum calcium levels, alkaline phosphatase concentrations, and urinary hydroxyproline excretion in patients with Paget's disease, some of whom were previously resistant to intranasal sCT because of neutralizing antibodies.     

The effect of infliximab on bone metabolism markers in patients with rheumatoid arthritis

OBJECTIVE: The aim of this study was to evaluate urinary excretion of N-telopeptide of type I collagen (NTX) and deoxypyridinoline (DPD), markers of bone resorption, and serum bone alkaline phosphatase (BAP) level, a marker of bone formation and an early marker of osteoblast differentiation, in patients with rheumatoid arthritis (RA) treated with infliximab. METHODS: Seventeen male and female patients (age 60.7+/-2.53 yr; mean disease duration 12.9+/-3.01 yr; Steinbrocker's class II-IV) with RA, diagnosed according to the criteria of the American College of Rheumatology (ACR), took part in the study between March 2003 and January 2005. None of the patients had a history of oestrogen replacement therapy. All patients were treated with infliximab combined with methotrexate. Infliximab was infused intravenously at 3 mg/kg at baseline, 2 and 6 weeks, then every 8 weeks. To evaluate disease activity, ESR, CRP, the numbers of swollen and tender joints, modified Stanford Health Assessment Questionnaire (mHAQ) score and ACR score were measured. Levels of NTX and DPD in urine and BAP in serum were measured in all patients. RESULTS: ESR, CRP, the number of swollen joints and tender joints, and mHAQ score had decreased significantly 6 weeks after initial treatment and were still low 6 months after initial treatment. NTX levels had decreased significantly 6 weeks after the initial treatment and were still low 6 months after initial treatment. DPD levels had decreased 6 months after initial infusion. Mean serum BAP level did not differ significantly among the three time points. NTX levels were statistically corresponding with the number of swollen joints and mHAQ scores. DPD levels were statistically lower corresponding with ESR. CONCLUSION: Infliximab therapy may inhibit generalized bone loss in patients with RA. NTX is a more sensitive marker than DPD.     

Melatonin, Cortisol, Prolactin, and Calcitonin Secretion in Primary Hyperparathyroidism Before After Surgery

The aim of the present study was to determine the diurnal secretion of melatonin, cortisol, prolactin, and calcitonin during chronic parathyroid hormone-dependent hypercalcemia. Eight women, aged 40-76 years, with primary hyperparathyroidism (PHPT) were studied before and after surgical removal of a parathyroid adenoma. The hormone concentrations in blood were determined at 08, 12, 16, 22, 02, 04, and 06 h. Concomitantly, the excretion of melatonin and cortisol in urine between 07-19 h and 19-07 h, and the clearance of calcium and creatinine were measured. Nyctohemeral serum prolactin and calcitonin were unaffected by moderate parathyroid hormone-dependent hypercalcemia. In contrast, serum cortisol and melatonin were significantly higher during active disease than after surgical cure. Mean 24-h variation of serum cortisol was 349 +/- 34 nmol/liter vs. 223 +/- 17 nmol/liter and mean serum melatonin was 0.13 +/- 0.04 nmol/liter vs. 0.06 +/- 0.02 nmol/liter. Endogenous creatinine clearance was similar before and after surgery, while the clearance of melatonin and cortisol significantly increased after surgery, indicating an increased tubular reabsorption of both hormones during active disease. Fasting morning glucose concentrations were also significantly decreased after successful surgery, 6.1 +/- 0.6 vs. 5.2 +/- 0.5 mmol/liter. It is suggested that the relative hypercortisolism may be the cause of the glucose intolerance in primary hyperparathyroidism. Three to 4 months after surgical cure the serum melatonin levels were significantly lower than those seen in age-matched controls, indicating a melatonin insufficiency in patients successfully treated for PHPT. The meaning of this finding is not yet understood but might be of importance in the development of primary hyperparathyroidism.     

Reactivity to norepinephrine and effect of sodium on blood pressure during weight loss

Eighteen moderately obese middle-aged men with untreated mild hypertension were randomized to two groups and placed on a low energy diet regimen for 9 to 11 weeks. In Group I (n = 10) the amount of sodium chloride in the diet maintained the urinary sodium excretion at the predieting level. Mean body mass was reduced by 9.1 +/- 0.7 (SEM) kg. Mean intra-arterial pressure showed no significant change. There were significant decreases in heart rate (p less than 0.05) and urinary norepinephrine excretion (p less than 0.05) but not in plasma concentration of norepinephrine. In Group II (n = 8) energy as well as sodium intake was restricted, with a 95 +/- 22 mmol/24 hour reduction of urinary sodium excretion. Body mass decreased by 9.3 +/- 1.1 kg, and mean arterial pressure decreased by -18.9 to -4.3 mm Hg (95% confidence interval). There were also significant reductions in heart rate (p less than 0.001) and plasma norepinephrine concentrations (p less than 0.01) but not in urinary norepinephrine excretion. The pressor response (mean arterial pressure) to norepinephrine infusion at different dose rates was significantly elevated (p less than 0.05) in Group I during dieting in comparison with baseline. The blood pressure response to norepinephrine during dieting in patients in Group II was not changed from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone.

OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).     

Evaluation of free and peptide bound collagen crosslink excretion in different skeletal diseases

OBJECTIVE: To investigate urinary fractions of free and peptide forms of collagen crosslinks in patients with rheumatoid arthritis (n=50), osteoarthrosis (n=38), psoriatic arthritis (n=38) and in healthy volunteers (33 adults, 17 children). METHODS: Pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high performance liquid chromatography. RESULTS: In rheumatoid arthritis (RA) all fractions of PYD and DPD were significantly raised compared with osteoarthritis, psoriatic arthritis, and healthy controls. PYD and DPD correlated with disease activity in RA. In RA the collagen degradation resulted in primarily peptide bound forms. CONCLUSION: The correlation between total peptide bound or free collagen crosslinks in different chronic joint diseases varies; however, this variation does not allow for a reliable differentiation between inflammatory and degenerative joint diseases.     

Metabolism of calcium and phosphorus in Cushing syndrome with osteoporosis

52 patients with Cushing syndrome were studied. According to the appearance of X-ray film of bones, they were divided into three groups: (I) Without osteoporosis, 12 cases (23.1%), (II) Mild osteoporosis, 17 cases (32.7%), (III) Severe osteoporosis with fractured ribs and/or wedge-shaped vertebrae, 23 cases (44.2%). It was found that the mean level of serum calcium in the patients was significantly lower than that in 94 normal subjects (mean +/- S 2.3 +/- 0.2 versus 2.4 +/- 0.1 mmol/L P less than 0.001). The mean concentrations of blood alkaline phosphatase and parathyroid hormone in the patients were much higher than those in normal subjects (65.0 +/- 27.6 versus 42.6 +/- 15.6 IU/L P less than 0.001, 44.6 +/- 22.4 versus 20.6 +/- 8.0 pg/ml P less than 0.001 respectively). The mean level of serum 25 (OH)-D in the patients was significantly lower than that in controls (10.9 +/- 5.6 versus 16.2 +/- 4.6 ng/ml P less than 0.001). Urinary calcium excretion increased in the patients as compared with that in controls (P less than 0.01). The urinary calcium excretion correlated well with the blood total cortisol and urinary free cortisol. It is suggested that hypercalciuria might cause decrease of serum calcium. Thus the parathyroid glands were stimulated and the parathyroid hormone (PTH) secretion was increased. Excess of PTH stimulates bone resorption. All of these factors are involved in the pathogenesis of osteopenia in Cushing's syndrome.     

Mineral metabolism in postmenopausal women with active rheumatoid arthritis

Serum and urinary variables of bone mineral metabolism were studied in 49 postmenopausal women with rheumatoid arthritis (RA). Results were compared to those in a sex, age and menopausal age matched control group. No patient took corticosteroids, or had any disease other than RA which might affect bone. Total serum calcium was low in patients with RA compared to controls (9.0 +/- 0.5 mg% vs 9.3 +/- 0.3 mg%, p less than 0.005), but was normal when corrected for albumin (9.5 +/- 0.6 mg% vs 9.3 +/- 0.4 mg%, NS). Serum phosphorus was significantly higher in patients with RA than in controls (3.6 +/- 0.3 mg% vs 3.3 +/- 0.4 mg%, p less than 0.001) as well as serum alkaline phosphatase activity (107.6 +/- 27.2 IU/l vs. 9.6 +/- 28.91 IU/l). Serum creatinine, vitamin D and parathyroid hormone levels were comparable in both groups. Urinary hydroxyproline and mucopolysaccharide excretions were higher in patients with RA than controls, both for fasting (respectively 0.089 +/- 0.028 vs 0.039 +/- 0.023, p less than 0.001 and 0.072 +/- 0.027 vs 0.047 +/- 0.019, p less than 0.001) and for 24 h values (50.3 +/- 17.9 mg vs 36.2 +/- 15.4 mg, p less than 0.001 and 54.6 +/- 26.0 mg vs 41.7 +/- 16.5 mg, p less than 0.05). Urinary calcium excretion was comparable in the 2 groups. Our findings of raised serum phosphorus and alkaline phosphatase activity, raised urinary hydroxyproline and mucopolysaccharides excretion suggest that in patients with RA there is a higher metabolic activity of bone. In none of the patients could any indication of osteomalacia or of parathyroid overactivity be found.