Age and sex dependency of the biochemical indices of bone remodelling

The values for the bone isoenzyme of serum alkaline phosphatase peak in the first two years of age, between 6 and 7 years of age, before the end of puberty and in the postmenopause. A population between the ages of 29 and 45 provides a reference population to which all other age groupings can be compared. A significant positive correlation was found between bone isoenzyme of serum alkaline phosphatase and urinary hydroxyproline excretion in children as well as after puberty. However, in the children the urinary hydroxyproline excretion was significantly higher when compared with the bone isoenzyme of alkaline phosphatase. A significant positive correlation was found between the bone isoenzyme of alkaline phosphatase and plasma tartrate-resistant acid phosphatase, irrespective of age and sex. The biochemical indices of bone remodelling correlated significantly with the growth rate in children and adolescents. The results are in good agreement with the concept of the coupling of bone formation to bone resorption.     

Relationship of the activity of the bone isoenzyme of serum alkaline phosphataseto urinary hydroxyproline excretion in metabolic and neoplastic bone diseases

A significant correlation between the activity of the bone isoenzyme or serum alkaline phosphatase and the urinary hydroxyproline excretion in osteomalacia, osteoporosis, primary hyperparathyroidism with osteodystrophy, Paget's disease, secondary bone tumours, and in a control group was found (P less than 0.001). This close correlation was not observed between these variables in patients with active acromegaly. Diagnosis determined from these indices of formation and turnover of bone matrix agreed with that established by histological and histochemical examination of bone, by X-ray investigation of the skeleton, and by the radionuclear 85Sr test. The relationship between the activity of bone isoenzyme and urinary hydroxyproline excretion differed in metabolic bone diseases with a high bone turnover, in patients with osteoporosis and in patients with early osteoclastic bone metastases.     

Bone isoenzyme of serum alkaline phosphatase in acromegaly.

In 37 patients with active acromegaly and in 15 patients with inactive acromegaly, activity of bone isoenzyme of serum alkaline phosphatase correlated (P less than 0.001) with serum concentration of immunoreactive growth hormone. By using stepwise regression analysis, the predication of serum growth hormone values based on serum levels of bone isoenzyme of serum alkaline phosphatase, gamma-glutamyl transferase and calcium in these patients with acromegaly was within 1 S.D. range in 37 patients and in only 2 patients was it out of 2 S.D. range. By using discriminant analysis, based on bone and liver isoenzymes of serum alaline phosphatase and urinary hydroxyproline excretion, 87%, 60% and 97% of the classification of patients with active and inactive acromegaly and healthy adults, respectively, was correct. The multivariate approach offers a quantitative appraisal of the biochemical parameters of peripheral growth hormone action used as an indicator of growth hormone concentration in patients with acromegaly.     

The effects of long term feeding of Solanum glaucophyllum to growing rats on Ca, Mg, P and bone metabolism.

The effects of the long term ingestion of Solanum Glaucophyllum leaves (SG) by the rat was investigated in two series of experiments; the animals were fed a normal (for 8 weeks) or a low Ca diet (for 5 weeks). With both diets, the intestinal absorption of Ca was increased and the endogenous fecal Ca excretion was decreased by SG treatment. Added to a normal Ca diet, SG increased the urinary excretion of Ca, Mg and P and reduced the excretion of hydroxyproline and pyrophosphate. At the histological level, SG induced a higher rate of bone tissue synthesis on trabecular and endosteal surfaces. The bone content of hydroxyproline and citrate increased significantly. The total alkaline phosphatase activity of plasma decreased as a function of SG intake due to a decreased in the activity of the intestinal isoenzyme, which was not compensated by the increase in the bone isoenzyme activity. The Mg absorption was decreased by SG inducing lower Mg balances and lower plasma Mg levels. Added to a low Ca diet, SG increased the severity of the secondary hyperparathyroidism induced by the diet. The urinary excretion of hydroxyproline and the plasma alkaline phosphatase activity (both isoenzymes) were significantly increased. The Na and K content of bone decreased as a function of SG intake. 45Ca kinetic experiments revealed that SG increased the rate of Ca resorption and the rate constant of the fast exchangeable Ca pool, in both diets.     

Bone mass and biochemical parameters of bone metabolism in men with spinal osteoporosis

With advancing age both sexes have an increased incidence of osteoporotic fractures, although fractures are more common in women than in men. Whereas in women several potential risk factors have been identified, less is known about osteoporosis in men. A total of 27 Austrian men (mean age: 65 +/- 2 years) with atraumatic spine fractures were studied. In all patients, medical history gave no evidence of disease or medications causing osteoporosis. Peripheral bone mass was determined by single-photonabsorptiometry on the distal non-dominant forearm; lumbal bone density was measured by quantitative computed tomography. Serum levels of calcium, phosphate, alkaline phosphatase, osteocalcin, testosterone, estrogen, parathyroid hormone and 25-hydroxy-vitamin D as well as 2-h-urinary-OH proline and calcium excretion were measured. All data were compared with those of an age and sex matched control group consisting of 19 healthy males. A significant difference in mean peripheral and axial bone mass (SPA: P less than 0.004; QCT: P less than 0.0001) was observed between osteoporotic men and controls. When compared to controls, serum levels of alkaline phosphatase (P less than 0.012), urinary OH proline (P less than 0.05) and urinary calcium excretion (P less than 0.003) were significantly higher in the osteoporotic males. Additionally, there was a significant positive correlation between serum alkaline phosphatase and urinary OH proline excretion (r = 0.32; P less than 0.04) in the osteoporotics. All other biochemical parameters showed no significant differences. Our results may lead to the assumption that osteopenia in men is related to increased bone turnover.     

Measurements of whole body retention of diphosphonate and other indices of bone metabolism in 125 normals: dependency on age, sex and glomerular filtration

Measurements of 24-h whole body retention of 99m-Tc-MDP (WBR) has been performed in 125 normal volunteers, together with determinations of serum alkaline phosphatase, urinary hydroxyproline excretion and creatinine clearance. WBR decreased slightly from the 3rd to the 4th decade, after which it increased gradually in the older age-groups. Serum alkaline phosphatase followed an identical pattern, while the urinary hydroxyproline excretion demonstrated a marked but temporary rise in the post-menopausal age-groups. Finally, the creatinine clearance decreased gradually in the older age groups. Analysis of variance demonstrated that WBR varied independently with serum alkaline phosphatase and creatinine clearance, while no relationship between WBR and the hydroxyproline excretion was found. It seems likely that the increasing retention of diphosphonate in elderly persons reflects rising osteoblastic activity as well as decreasing glomerular filtration.     

Clinical and biological effects of low doses of (3 amino-1 hydroxypropylidene)-1,1-bisphosphonate (APD) in Paget''s disease of bone

Abstract. At doses varying between 500 and 1500 mg/day, the disodium salt of (3 amino-1 hydroxypro-pylidene)-1,1-bisphosphonate (APD) has been shown to induce rapid and complete biochemical responses in Paget's disease of bone, but a short-lived and self-limited fever has been observed in 30–40% of patients. The present study is an open and unrandomized trial, performed to explore the use of lower doses of APD (250 and 50 mg/day) given for 6 months to fourteen patients suffering from Paget's disease of bone. Subjective clinical improvement and complete biochemical remission (as assessed by normalization of urinary hydroxyproline excretion and plasma alkaline phosphatase concentration) was observed in ten out of eleven patients given 250 mg/day, but fever did not occur. Thus, a significant decrease in urinary hydroxyproline excretion was noted as early as 15 days after the beginning of the treatment (from 4.5 to 1.3 μmol/l GF; P > 0.05) whereas plasma alkaline phosphatase concentration fell significantly only 1 month later (from 330 to 195 IU/ml; P > 0.05). Both mean (± SEM) urinary hydroxyproline excretion (0.98 ± 0.08 μmol/l GF) and plasma alkaline phosphatase concentration (70 ± 8 IU/ml) were in the normal range after 6 months of treatment. Plasma calcium and phosphorus concentration, urinary calcium excretion and TmP/GFR decreased whereas plasma immunoreactive parathyroid hormone concentration increased. These changes were statistically significant (P < 0.05) only transiently and disappeared at the time when bone formation (assessed by plasma alkaline phosphatase) returned to normal. An increase in total body retention of ⁴⁷Ca during the second month of treatment was documented in five patients (P < 0.05), compatible with a positive calcium balance. Plasma immunoreactive calcitonin did not change (P > 0.05). After 6 months of treatment at 50 mg/day, APD also induced significant decreases in urinary hydroxyproline excretion (from 4.23 to 1.73 μmol/l GF; P < 0.05) and plasma alkaline phosphatase concentration (from 360 to 162 IU/ml; P < 0.05) but biochemical remissions were not complete and these two variables were significantly higher than the corresponding values in the group of patients receiving 250 mg APD/day. Less marked changes were also noted in all the other variables measured. Biological and clinical tolerance was good in all the patients. It is concluded that 250 mg/day of APD is an effective dose schedule, capable of reducing to normal levels the indirect indices of bone turn-over, but in contrast with higher doses, without inducing fever.     

Changes in bone turnover and deoxypyridinoline levels in epileptic patients.

In this study, we evaluated bone turnover in 52 epileptic patients receiving chronic anticonvulsant therapy and in 39 healthy volunteers whose ages matched those of the patients. We determined serum osteocalcin and total and bone alkaline phosphatase levels as markers of bone formation, and urinary deoxypyridinoline and urinary calcium levels as markers of bone resorption. Statistical comparison of the levels of these markers between sexes in epileptic patients and their control groups revealed that total alkaline phosphatase levels were significantly increased in patients from both sexes compared with those of their controls. Urinary deoxypyridinoline levels of male epileptic patients were significantly increased compared with those of their controls. On the other hand, 25-hydroxyvitamin D levels of the male patients were significantly reduced compared with those of their controls. Serum osteocalcin, bone alkaline phosphatase, and urinary calcium levels of epileptic patients were not statistically different from those of the controls. We found that urinary deoxypyridinoline levels of male epileptic patients were increased, however, we observed no difference in serum osteocalcin and bone alkaline phosphatase levels. The lack of difference may be attributed to the fact that only the resorption phase of bone turnover is affected during chronic anticonvulsant therapy.     

Biochemical measurements in Paget''s disease of bone

In a group of eighty-three patients with untreated Paget's disease of bone, plasma alkaline phosphatase activity (AP), plasma non-protein-bound hydroxyproline concentration (PHP) and urinary excretion rate of total hydroxyproline (THP) were closely correlated with each other but not with fasting plasma concentrations of calcium or inorganic phosphate. Probit plots of AP and THP showed log-normal distributions overlapping the normal ranges.     

Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases

Analyses of the urinary concentration relative to creatinine of the collagen crosslinks, pyridinoline (Pyd) and deoxy-pyridinoline (Dpd) were made in 47 patients with metabolic bone diseases to assess the validity of these assays as indicators of bone resorption. The mean values for patients with Paget's disease of bone, primary hyperparathyroidism and osteomalacia were significantly higher (P less than 0.001) than those for age-matched healthy individuals. During treatment of Paget's disease with bisphosphonates, there was a steady decline in the urinary concentration of the crosslinks to the normal range; this change occurred earlier than for serum alkaline phosphatase. There were significant correlations (P less than 0.01) between the concentrations of both crosslinks and the corresponding values for hydroxyproline. At lower crosslink concentrations, however, these relationships were less marked due to large variations in hydroxyproline values. The results show that measurements of urinary Pyd and Dpd provide clinically applicable indices of bone resorption that are more specific than other markers.     

The properties and clinical significance of some electrophoretically slow forms of alkaline phosphatase.

Sera from 8 patients with a marked slow-moving alkaline phosphatase band on electrophoresis were investigated. Inhibitor studies and treatment with neuraminidase showed that all the patients had slow bands with alkaline phosphatase properties resembling those of the liver or bone isoenzyme. In no case did the slow band resemble the intestinal isoenzyme. Immunoelectrophoretic and molecular weight studies indicated that the slow band consisted of an IgG-alkaline phosphatase complex of molecular weight 540 000. Serum from a patient with the slow band was able to bind liver or bone, but not intestinal, alkaline phosphatase from other patients to form the slow band. Serum from patients with the slow band probably contains an abnormal IgG molecule which can bind alkaline phosphatase in the ratio 2:1. No clinical condition was common to all 8 patients although most of them had either intestinal or lung disease.     

Effect of sex hormones on bone in primary osteoporosis

The effect of sex hormones on bone tissue was studied in 12 osteoporotic patients. Surfaces of bone undergoing formation and resorption were determined by quantitative microradiography of iliac crest biopsy samples before and after treatment with estrogens in 11 postmenopausal women and with testosterone in one gonadally competent man. Before treatment, bone resorption was greater than normal in all but one patient and bone formation was normal. After treatment, bone resorption decreased to within the normal range in all patients, and bone formation did not change significantly. Biochemical studies showed significant decreases in serum calcium, phosphorus, and alkaline phosphatase levels and in urinary excretion of calcium and hydroxyproline. These changes are believed to be the consequence of the effect of the hormones on bone. The data indicate that the major effect of sex hormones in osteoporosis is an inhibition of bone resorption.     

Formation of an alkaline phosphatase-immunoglobulin G complex in human sera.

An electrophoretically slow-moving band of alkaline phosphatase (ALP) isoenzyme was found in four patients with chronic liver disease and in one with ulcerative colitis. Immunoelectrophoretic studies revealed that the slow band was a complex containing alkaline phosphatase and an immunoglobulin G of the lambda class. Its molecular weight was approximately 280 000. A complex molecule consisting of one molecule of immunoglobulin G and one molecule of alkaline phosphatase was proposed. The complex was similar to the liver and bone alkaline phosphatases in functional properties. Serum containing the complex was capable of binding liver and bone alkaline phosphatase isoenzymes but not the intestine or placenta alkaline phosphatase isoenzymes from normal controls. The presence of an abnormal immunoglobulin which binds liver and bone alkaline phosphatases appears to be responsible for the development of the complex. In one case of chronic liver disease, the complex disappeared after a few months.     

Skeletal blood flow in Paget's disease of bone and its response to calcitonin therapy

1. Blood flow to the skeleton was measured by the 18F clearance method of Wooton, Reeve & Veall (1976) in 24 patients with untreated Paget's disease. In every patient but one, resting skeletal blood flow was increased. There was a significant positive correlation between skeletal blood flow and serum alkaline phosphatase and between skeletal blood flow and urinary total hydroxyproline excretion. 2. Fourteen patients were re-studied after they had received short-term (7 days or less) or long-term (7 weeks or more) calcitonin. Skeletal blood flow, alkaline phosphatase and urinary hydroxy-proline excretion fell towards normal in every case. There was some evidence from the short-term studies that calcitonin produced a more rapid fall in skeletal blood flow than in alkaline phosphatase. 3. Glomerular filtration rate appeared to increase transiently in response to calcitonin.     

Biochemical markers of bone formation in patients with plasma cell dyscrasias and benign osteoporosis

BACKGROUND: Myeloma-induced bone loss is related to an uncoupling of bone formation and bone resorption. The aim of the present study was to assess the potential clinical value of biochemical markers of bone formation in the work up of patients with plasma cell dyscrasias. METHODS: Serum total alkaline phosphatase, bone-specific alkaline phosphatase (BAP), and osteocalcin (OC) were measured in 43 patients with newly diagnosed multiple myeloma (MM), in 40 patients with monoclonal gammopathy of undetermined significance (MGUS), in 40 patients with untreated benign vertebral osteoporosis (OPO), and in 48 healthy adults. RESULTS: In MM and MGUS patients, serum BAP, but not serum OC, was lower than in healthy controls (P<0.05). Serum OC was higher in patients with OPO than in healthy controls (P<0.05). The strongest associations between markers were found in OPO patients and in healthy adults. MM patients with early-stage disease or without detectable osteolysis had decreased serum BAP values (P<0.05). Serum OC was higher in MM patients with stage III disease (P<0.05) than in healthy controls. MM patients with OPO-like bone involvement had lower BAP values than sex- and age-matched MGUS patients with OPO-like bone involvement and patients with benign OPO (P<0.05). CONCLUSIONS: In patients with plasma cell dyscrasias, serum BAP, rather than serum OC, appears to reflect a suppressed bone formation rate and may be helpful in the differentiation between benign and myeloma-induced OPO. However, the overall clinical use of biochemical markers of bone formation in patients with plasma cell dyscrasia appears limited.     

Estimation of whole body bone resorption rate: a comparison of urinary total hydroxyproline excretion with two radioisotopic tracer methods in osteoporosis

In 37 female patients with primary osteoporosis, urinary hydroxyproline excretion, determined in 18 24-h consecutive complete urine collections was compared with two radioisotopic measurements of bone resorption rate measured simultaneously using 85Sr. A somewhat better fit was obtained when the kinetically determined bone resorption rate was corrected for long-term exchange processes within bone. Regression analysis showed that the intercept of the regression of hydroxyproline excretion on resorption rate, corrected or uncorrected for exchange, was significantly higher than zero at about 100 mumol/day. This is consistent with a substantial fraction of urinary hydroxyproline arising from non-bony sources. Fifteen paired studies were analysed and the results suggested that intra-individual variability in these relationships (when studies were separated by a year or more) were similar to inter-individual variability. We calculated the precision with which an estimate of bone resorption could be determined based on the calculated regressions. As a means of non-invasive quantitation of whole body bone resorption rate, the excretion rate of hydroxyproline, measured over 5 days, for example, appeared competitive with isotopic methods making no correction for exchange and relatively little worse than our exchange corrected method.     

Primary hyperparathyroidism and hyperuricaemia are associated but not correlated with indicators of bone turnover

Urate metabolism was studied in 53 patients with primary hyperparathyroidism. They had compared to controls significantly higher serum urate and reduction of the clearance of urate. In 14 of the tested patients with primary hyperparathyroidism serum urate was increased above normal limits. Six months after parathyroidectomy serum urate fell significantly from 365.3 ± 75.7 μmol/l to 265.7 ± 48.3 μmol/l, in 26 patients where urate measurements were available before as well as after surgery. Serum urate levels in our patients with primary hyperparathyroidism did not correlate with clearance of urate. Levels of serum urate cannot be entirely explained by the decrease in renal clearance of urate. Serum urate levels did not correlate with severity of skeletal changes expressed by serum B-ALP and urinary excretion of hydroxyproline. These results suggest that parathormone does not increase the part of the urate pool coming from the nucleic acids of the increased bone metabolism.     

Biochemical markers of bone turnover in women with surgically treated carcinoma of the breast

Abstract. Biochemical markers of bone turnover were measured in fasting urine and blood samples obtained from 38 postmenopausal women with previous surgi cal treatment of breast cancer combined with adjuvant chemotherapy, tamoxifen, or placebo. Significantly elevated urinary pyridinoline as nmol mmol^-1 creatinine (47.5 and 42.5 in tamoxifen and placebo treated patients compared with 26.3 in normal controls, both P <0.001) and deoxypyridinoline (11.9 and 10.5 com pared with 6.3, P <0.001 and P =0.002 respectively) were found with unchanged urinary hydroxyproline, serum alkaline phosphatase and procollagen I carboxyterminal peptide (PICP). These findings suggest enhanced bone resorption resulting from the humoral osteoclast activating effect of the previous breast cancer or underlying carcinoma recurrence. Alternatively the raised pyridinium excretion might indicate an altered cross linking composition of bone collagen. No specific effect on bone metabolism was found with tamoxifen treatment as all measured parameters were similar in both tamoxifen ex-users and non-users. This confirmed the safety of tamoxifen therapy with respect to bone.     

早期功能锻炼对脊髓损伤患者骨质疏松的预防作用

目的探讨早期肢体被动功能锻炼对脊髓损伤患者骨质疏松的预防作用。方法将26例外伤性脊髓损伤所致截瘫患者随机分为实验组和对照组,每组13例,实验组进行早期肢体功能锻炼,对照组按照外伤瘫痪患者护理常规进行。常规x线片观察两组患者锻炼前后（入组时和4个月后）腰椎及股骨近端的松质骨密度变化,同时分别检测两组患者锻炼前后（入组时和4个月后）血清碱性磷酸酶、血钙、尿Ca／Cr及尿羟脯氨酸含量。结果腰椎及股骨近端的松质骨密度实测值与入组时比较,锻炼后（4个月后）两组均有下降趋势,但均无统计学意义（P〉0．05）,两组间差异也无统计学意义（P〉0．05）。与入组时比较,锻炼后（4个月）实验组血清碱性磷酸酶无统计学差异（P〉0．05）,血钙、尿Ca／Cr及尿羟脯氨酸均有统计学意义（P〈0．05）;对照组血清碱性磷酸酶血钙、尿Ca／Cr及尿羟脯氨酸均无统计学意义（P〉0．05）。锻炼后（4个月）两组间除血清碱性磷酸酶差异无统计学意义（P〉0．05）,血钙、尿Ca／Cr及尿羟脯氨酸差异均有统计学意义（P〈0．05）。结论早期肢体功能锻炼对脊髓损伤患者骨质疏松具有一定的预防作用。     

Effects of disodium dichloromethylene diphosphonate on hypercalcemia produced by bone metastases.

The aim of this study was to determine the ability of disodium dichloromethylene diphosphonate (Cl2MDP) to reduce the hypercalcemia secondary to skeletal metastases and induced by stimulation of bone resorption by malignant cells. Five patients with hypercalcemia due to bone metastases of breast or renal cancer were treated orally for 4 wk with 3,200 mg of Cl2MDP and 4 wk with a placebo in a double blind, crossover study. During the Cl2MDP period of administration four patients experienced a rapid and significant decrease in serum calcium and urinary calcium excretion together with an increase in alkaline phosphatase. In the remaining patient who developed a sudden paraplegia at the onset of the therapy followed by a marked increase in serum calcium levels and urinary calcium excretion, Cl2MDP was able to reverse this worsening of hypercalcemia or to reduce serum and urinary calcium to normal values. For all patients, urinary hydroxyproline excretion was unchanged during the Cl2MDP period when compared with the prestudy or placebo periods. From these results, and because of the rapid relapse of hypercalcemia during the placebo period or after withdrawal of the treatment, we can conclude that Cl2MDP is capable of reducing excessive mobilization of calcium resulting from bone metastases.