Serum osteocalcin levels and bone alkaline phosphatase isoenzyme after oophorectomy and in primary hyperparathyroidism

Serum osteocalcin levels peaked 1 yr after oophorectomy in a prospective study of 12 women. Estrogen treatment restored serum osteocalcin to the normal range within 4 months of therapy. The changes in serum osteocalcin preceded those in bone alkaline phosphatase activity by 1-2 months, in these oophorectomized patients and during estrogen treatment. The changes in these two markers of bone formation over time were significantly different from those in urinary hydroxyproline excretion. A significant positive correlation was found between bone alkaline phosphatase and serum osteocalcin levels in patients after oophorectomy and in 18 patients with primary hyperparathyroidism. Significant positive correlations also were found between the biochemical indices of osteoblastic function and urinary hydroxyproline excretion and/or nephrogenous cAMP in primary hyperparathyroidism. In most of the patients with primary hyperparathyroidism, however, the elevation in bone alkaline phosphatase was more marked than that in osteocalcin. These data indicate that the clinical utility of serum osteocalcin as a marker of bone formation is similar but not identical to that of bone alkaline phosphatase.     

Long-term effects of dichloromethylene diphosphonate in patients with osteolytic bone metastases and coincident primary hyperparathyroidism

Dichloromethylene diphosphonate (Cl2MDP), an inhibitor of osteoclast-mediated bone resorption, lowers serum calcium in hypercalcemia associated with malignancies and with primary hyperparathyroidism. We have evaluated the effectiveness of Cl2MDP in three patients who had multiple osteolytic bone metastases due to breast cancer and coincident primary hyperparathyroidism and who refused neck exploration. Cl2MDP was added to the tamoxifen treatment and was given orally at a dose of 1600 mg/day for 12 months. All patients had a reduction in serum calcium level which was accompanied by a decline in the fasting urinary calcium and hydroxyproline excretion. Administration of Cl2MDP was not associated with any changes in parathyroid hormone levels. New bone metastases were observed neither during the treatment nor in the follow-up period. No side effects were observed.     

Interrelationships between urinary sodium, calcium, hydroxyproline and serum PTH in healthy subjects.

The effect of sodium intake on the excretion of calcium, hydroxyproline (OHP) and serum parathyroid hormone (PTH) was examined. When seven healthy males increased their sodium intake by 200 mmol/day, excretion of calcium increased by 1.70 mmol/day and that of OHP by 27%. Serum PTH, however, did not increase significantly. In a cross-sectional study of 334 healthy female subjects there were strong positive correlations between fasting urinary sodium/creatinine (Na/Cr) and calcium/creatinine (Ca/Cr) ratios (r = 0.573) and between Na/Cr and urinary OHP/Cr ratios (r = 0.246). Serum PTH was negatively correlated with Na/Cr ratio (r = -0.161). We conclude that an increase in dietary sodium causes calciuria and an increase in hydroxyproline excretion. The results do not support the hypothesis that this is mediated by PTH.     

Cardiovascular effects of parathyroid hormone: a study in healthy subjects and normotensive patients with mild primary hyperparathyroidism

The aim of the study was to evaluate: 1) the cardiovascular function and the autonomic drive to the heart in patients affected by primary hyperparathyroidism (pHPT) with no evidence of renal and cardiovascular complications; 2) the cardiovascular effects of acute administration of PTH in normal subjects. In 14 patients affected by mild asymptomatic pHPT echocardiographic assessment of cardiovascular function and of the mechanic properties of the brachial and carotid artery, heart rate variability and the dispersion of QT interval were performed before and 6 months after successful surgery. Twenty age- and sex-matched healthy subjects were included in the study. Five healthy volunteers underwent a single blind, placebo-controlled, random order, cross-over study with infusion of PTH (hPTH 1-34, 200 U in saline over 5 min) or placebo. Echocardiographic assessment of cardiovascular function, heart rate variability, and QT interval were performed between 20 and 25 min after the start of the infusion and repeated after 15 min of tilting at 60 degrees. In pHPT patients the echocardiographic parameters were normal; left ventricular isovolumetric relaxation time was always in the normal range, but significantly shorter than in control subjects, suggesting an increased sympathetic stimulation. Arterial diameters and thickness, blood pressure, and QT interval were not significantly different with respect to normal subjects and were unchanged 6 months after surgery. pHPT patients lacked the circadian rhythm of the low frequency to high frequency ratio, suggesting an increased sympathetic drive to the heart at nighttime. In normal subjects there were no significant differences in basal echocardiographic measurements during PTH infusion with respect to placebo and in the hemodynamic response to tilt. These results suggest that cardiovascular function is substantially normal in normotensive pHPT patients with mild hypercalcemia. A modulation of the adrenergic control of circulation seems to be associated with hypercalcemia and/or chronic PTH excess, but its biological relevance needs further investigations.     

Effect of fluoride therapy on nondialyzable urinary hydroxyproline,serum alkaline phosphatase,parathyroid hormone,and 25-hydroxyvitamin D

The effect of sodium fluoride therapy was studied in 40 osteoporotic male subjects, aged 50–80 yr. Twenty patients were treated with sodium fluoride (20–40 mg/day) and 20 received placebo for 107 wk. A marked increase (53%; p < 0.001) in the nondialyzable fraction of urinary hydroxyproline was found in the fluoridetreated group. Total urinary hydroxyproline levels were unchanged. The increased fraction of urinary hydroxyproline is suggestive of increased bone collagen synthesis and is consistent with the finding of a diminished rate of bone loss in the fluoride-treated group (per cent change in bone density after 107 wk was ?0.14 ± 5.28 versus ?5.24 ± 7.62 for the placebo-treated group; p < 0.02). Serum alkaline phosphatase levels were elevated in the fluoride-treated group (38%; p < 0.001) after 107 wk of treatment. This change, as well as the increased fraction of urinary hydroxyproline persisted for at least 6 mo after cessation of fluoride treatment and was not temporally related to serum fluoride levels. No significant changes in serum parathyroid hormone, 25-hydroxyvitamin D, serum calcium, and phosphorus were found after 1 yr of fluoride treatment. These findings suggest that fluoride does not alter serum 25-hydroxy-vitamin D and that the mechanism by which fluoride increases the rate of bone formation does not involve hyperparathyroidism.     

Calf and forearm blood flow in patients with primary hyperparathyroidism and in control subjects

Using a venous occlusion air-filled plethysmograph we measured the blood flow in the limbs in 10 patients with established primary hyperparathyroidism and control subjects. The patients had highly raised ionized calcium and immunoreactive parathormone levels, and the diagnosis was verified at operation. In all patients resting blood flow values in the limbs were increased compared with control subjects. Peak blood flow after 5 min of ischemia was also increased, however, not significantly. This clinical study supports previous studies on a vasoactive effect of parathormone.     

Effect of acute cimetidine administration on indices of parathyroid hormone action in healthy subjects and patients with primary and secondary hyperparathyroidism

To evaluate the acute effect of histamine H2-receptor blockade with cimetidine on PTH concentrations and its endogenous biological activity, we studied the effect of iv administration of cimetidine (50-mg bolus followed by 500 mg/60 min infusion) in normal subjects and patients with primary and secondary hyperparathyroidism. No significant changes in serum concentrations of calcium, phosphate, or immunoreactive C-terminal PTH were found in any group. However, the control group had decreased calciuria, increased phosphaturia, and decreased tubular reabsorption of phosphate, while the primary hyperparathyroid group had increased phosphaturia, increased nephrogenous cAMP excretion, and decreased tubular reabsorption of phosphate. In both of these groups, the finding suggest an increase in PTH-like biological activity. These findings suggest that cimetidine is not useful in the diagnosis or medical management of hyperparathyroidism. In fact, the changes in renal calcium and phosphorous excretion indicative of PTH-like biological activity along with a decrease in creatinine clearance in the primary hyperparathyroid group suggest a relative contraindication to the use of this drug in these patients.     

Serum levels of intact parathyroid hormone and alkaline phosphatase correlate with cortical and trabecular bone loss in primary hyperparathyroidism.

We examined the relationship between bone loss and several biochemical indices in 38 patients with primary hyperparathyroidism. Bone mineral density was reduced by 12 +/- 4.0% in the lumbar spine, 18 +/- 4.2% at the distal radius and 21 +/- 2.8% at the proximal radius (mean +/- SEM). There were significant negative correlations between the serum concentrations of intact parathyroid hormone (PTH) and the Z-scores of the bone mineral content at the proximal and distal radius. In the lumbar spine, bone mineral density was greater in patients with mildly elevated PTH and less in patients whose PTH levels exceeded 8.6 pmol/l. We also observed a strong association between increased levels of serum alkaline phosphatase and low bone mineral Z-scores. Our data thus indicate that cortical and, with the exception of mild primary hyperparathyroidism, trabecular bone loss is proportional to the concentration of circulating PTH and the severity of PTH-induced bone turnover. For the individual patient, however, the usefulness of intact PTH and alkaline phosphatase measurements for assessing bone loss associated with primary hyperparathyroidism seems to be only limited.     

Circulating levels of 1,25 dihydroxyvitamin D, alkaline phosphatase, hydroxyproline, and osteocalcin associated with antler growth in white-tailed deer

Alkaline phosphatase, hydroxyproline, osteocalcin, and 1,25(OH)2D were measured in biweekly serum samples obtained from 6 adult (greater than 4 years), 4 juvenile (1-4 years) and 4 fawn (less than 1 year) male white-tailed deer from Oct. 1983 to Oct. 1984. Antler length, from the pedicle to the tip, was measured at the time of serum sampling. Serum alkaline phosphatase activity and levels of hydroxyproline and osteocalcin were higher (P less than 0.05) in fawns compared with juveniles and adults reflecting increased bone metabolism in the younger deer. In adult deer serum alkaline phosphatase activity and hydroxyproline levels were elevated (P less than 0.05) during the period of antler growth, whereas serum osteocalcin and 1,25(OH)2D increased (P less than 0.05) during antler mineralization. Similar but less pronounced trends occurred in juvenile deer, possibly a reflection of skeletal growth in the younger animals. The data lend support for utilization of the deer antler cycle as a model for studies of bone disorders. Further work is needed to help clarify the role of hydroxyproline, osteocalcin, and 1,25(OH)2D in the antler cycle.     

The immune response to alkaline phosphatase and other immunogens in patients with primary biliary cirrhosis

BACKGROUND/AIMS: Primary biliary cirrhosis is a potentially lethal hepatobiliary disorder in which 90% of the patients are women. Histologically, the disease is characterized by a progressive destruction of intrahepatic bile ducts by autoreactive T lymphocytes. Although the underlying etiology remains unknown, potential hypotheses must take into account; a) the predilection of the disease for women of childbearing age, b) the frequent coexistence of bone and intestinal involvement, and c) the high prevalence of autoantibodies directed towards intracellular enzymes. With these considerations in mind, we hypothesized that exposure to P-ALP (placental alkaline phosphatase) during pregnancy results in autoreactivity directed towards all human tissues harboring the ALP enzyme (liver, bone and intestine) in genetically predisposed individuals. METHODOLOGY: To test this hypothesis, we stimulated peripheral blood mononuclear cells of primary biliary cirrhosis patients (n = 17) cholestatic liver disease controls (n = 6) and healthy controls (n = 14) with P-ALP, polyclonal activators (phytohemagglutinin [PHA], anti-CD3) and recall antigens (tetanus toxoid, streptokinase). We then determined their proliferative and cytokine responses by 3H-thymidine incorporation and ELISA assays for Il-10, IL-6, tumor necrosis factor-alpha and interferon-gamma, respectively. RESULTS: The results of the study revealed that the proliferative response to P-ALP was similar in peripheral blood mononuclear cells from primary biliary cirrhosis patients, cholestatic and healthy controls. Although the proliferative responses to PHA (P < 0.001) and anti-CD3 (P < 0.001) were decreased in peripheral blood mononuclear cells from primary biliary cirrhosis patients when compared to both control groups, responses to the recall antigens; tetanus toxoid and streptokinase were similar in the three groups. Cytokine production following exposure to P-ALP, polyclonal activators or recall antigens in peripheral blood mononuclear cells from primary biliary cirrhosis patients was similar to that of cholestatic and healthy controls. CONCLUSIONS: The results of the above experiments suggest that P-ALP is unlikely to be the target autoantigen in primary biliary cirrhosis. The results also support the findings of other investigators that primary biliary cirrhosis patients have suppressed proliferative responses to polyclonal stimulation.     

原发性甲状旁腺功能亢进症患者的心血管改变

原发性甲状旁腺功能亢进症(甲旁亢)患者的死亡率明显增高,而其主要死亡原因为心血管系统疾病.目前,原发性甲旁亢的临床谱已经发生了明显变化,无症状原发性甲旁亢的比例逐渐增加.然而,即使在疾病早期原发性甲旁亢患者也会发生-系列心血管异常,包括:左室肥厚、瓣膜钙化、血管反应受损、高血压、血糖及血脂代谢异常等,而这些心血管病变在手术后可以得到一定程度的改善.     

Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatase z-scores in different types of rickets

Objective: Serum alkaline phosphatase (ALP) levels show great variation with age and sex in children and adolescents. Additionally, different buffers used even in the same method cause variable results. This detail is not usually taken into account in the evaluation. We aimed to study pediatric age- and sex-specific reference ranges for ALP by colorimetric assay using p-nitrophenyl phosphate as substrate and diethanolamine as buffer and also to compare the ALP levels in patients with different types of rickets. Methods: 1741 healthy children and adolescents (904 girls) were included in the study for normative data. 77 different ALP measurements from 38 nutritional rickets (NR), 7 vitamin D-dependent rickets (VDDR) and 8 hypophosphatemic rickets (HR) patients were included. Results: Reference values for ALP were constructed. ALP levels demonstrated a tetraphasic course with two peaks at infancy and puberty. There was no difference in ALP levels between boys and girls until puberty. However, higher ALP levels were noted at 10-11 years in girls (p=0.02) and at 12-13, 14-15, 16-17 years in boys (p<0.001). ALP levels start to decline after age 12 and 14 in girls and boys, respectively. Serum ALP levels were highest in the VDDR group and lowest in the HR group (median z-score values in HR, VDDR and NR were 3.6, 10.4 and 6.5, respectively; p<0.001). Similarly, plasma parathormone(PTH) levels ranged from highest to lowest in the VDDR, NR and HR groups (median values: 525, 237 and 98 pg/mL, respectively; p<0.001). Conclusions: This normative data will provide a basis for better evaluation of ALP levels determined by the described method. Furthermore, use of z-scores gives a more precise assessment of changes in ALP levels in rickets and other bone disorders. Conflict of interest:None declared.     

Pancreatitis in patients with primary hyperparathyroidism.

Records of patients undergoing parathyroidectomy at our institute in the period 1991-2003 were retrospectively analyzed. Pancreatitis was associated in six of 87 patients (6.8%) with primary hyperparathyroidism (PHPT). Pancreatitis was the presenting symptom in five patients, while it developed postoperatively in one case. All patients with a past history of pancreatitis had suffered two or more attacks. All patients had a history of renal stone disease. Four patients also had overt bone disease with multiple fractures. Parathyroid adenoma (4) or carcinoma (1) was the cause in all patients. All five patients who underwent successful parathyroidectomy had resolution of pancreatitis on conservative management and no further attacks during a mean follow up of 28 months (3-84 months). Surgical exploration for parathyroid adenoma failed in one patient; this patient has had further attacks of pancreatitis. Repeat surgical exploration for parathyroidectomy has been advised. Hyperparathyroidism is a rare but treatable cause of pancreatitis. Parathyroidectomy has a salutary effect on the course of pancreatitis.     

Bone mineralization and bone mineral content in primary hyperparathyroidism

The degree of bone mineralization and the bone mineral content (BMC) was evaluated in 6 patients with primary hyperparathyroidism. The degree of bone mineralization was estimated as the phosphorus/hydroxyproline ratio (P/Hypro) in bone biopsies; BMC was estimated by photon absorptiometry on both forearms. The mena values of both parameters were significantly lower than normal (P less than 0.001 for P/Hypro; P less than 0.02 for BMC). As no significant correlation was found between P/Hypro and BMC in hyperparathyroidism, the findings of low values of P/Hypro and of BMC in patients with elevated serum calcium point to primary hyperparathyroidism.