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PubMed1993

Serum markers of type I collagen formation and degradation in metabolic bone disease: correlation with bone histomorphometry.

Type I collagen makes up more than 90% of bone matrix. Therefore, analysis of antigens related to collagen formation and degradation in bone should provide good and specific estimates of both bone resorption and bone formation rates. In this study we measured serum levels of the pyridinoline cross-linked telopeptide domain of type I collagen (ICTP) as a marker of bone resorption and serum carboxy-terminal propeptide of type I procollagen (PICP) as a marker of bone formation. Serum levels of the two antigens were correlated to histomorphometric indices of bone resorption and bone formation calculated from iliac crest bone biopsies in a group of 18 individuals with high- and low-turnover bone disease (myxedema, primary hyperparathyroidism, and thyrotoxicosis). After logarithmic transformation the regression of S-ICTP on volume-referent resorption rate (BRs/R/BV) was significant (r = 0.61, p < 0.01, SEM/Y = 56%). S-ICTP also showed a significant regression on the volume-referent cancellous bone balance (r = -0.45, p < 0.05, SEM/Y = 412%). S-PICP was significantly correlated to the mineral appositional rate (r = 0.53, p < 0.05) and volume-referent bone formation rate (r = 0.61, p < 0.01, SEM/Y = 48%). The correlation to bone turnover as expressed in the activation frequency was also highly significant (r = 0.61, p < 0.01, SEM/Y = 51%). No significant correlation with wall thickness or bone balance was demonstrable per remodeling cycle. Thus, assays employing antigens that reflect collagen formation and degradation are useful instruments for the evaluation of rates of bone remodeling in metabolic bone disease.

Adult↗
PubMed1993

Changes in markers of bone formation and resorption in a bed rest model of weightlessness.

To study the mechanism of bone loss in physical unloading, we examined indices of bone formation and bone resorption in the serum and urine of eight healthy men during a 7 day -6 degrees head-down tilt bed rest. Prompt increases in markers of resorption--pyridinoline (PD), deoxypyridinoline (DPD), and hydroxyproline (Hyp)/g creatinine--during the first few days of inactivity were paralleled by tartrate-resistant acid phosphatase (TRAP) with significant increases in all these markers by day 4 of bed rest. An index of formation, skeletal alkaline phosphatase (SALP), did not change during bed rest and showed a moderate 15% increase 1 week after reambulation. In contrast to SALP, serum osteocalcin (OC) began increasing the day preceding the increase in Hyp, remained elevated for the duration of the bed rest, and returned to pre-bed rest values within 5 days of reambulation. Similarly, DPD increased significantly at the onset of bed rest, remained elevated for the duration of bed rest, and returned to pre-bed rest levels upon reambulation. On the other hand, the other three indices of resorption, Hyp, PD, and TRAP, remained elevated for 2 weeks after reambulation. The most sensitive indices of the levels of physical activity proved to be the noncollagenous protein, OC, and the collagen crosslinker, DPD. The bed rest values of both these markers were significantly elevated compared to both the pre-bed rest values and the post-bed rest values. The sequence of changes in the circulating markers of bone metabolism indicated that increases in serum OC are the earliest responses of bone to head-down tilt bed rest.

Acid Phosphatase↗
PubMed1995

Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget's disease.

Clinical biochemical markers of bone turnover are usually increased in Paget's disease. However, the analysis of "new" markers, such as serum bone alkaline phosphatase (BAP), carboxy-terminal propeptide of type I procollagen (PICP), tartrate-resistant acid phosphatase (TRAP), telopeptide carboxy-terminal propeptide of type I collagen (ICTP), and urinary pyridinoline (PYR) and deoxipyridinoline (D-PYR), may improve the diagnostic efficacy and the evaluation of Paget's disease compared with conventional markers, such as serum total alkaline phosphatase (TAP) and urinary hydroxyproline (HYP). To evaluate the diagnostic accuracy and the changes of biochemical markers of bone turnover according to Paget's disease activity, we measured the levels of all these markers in three groups of pagetic patients classified according to their serum TAP activity: G-I, patients with serum TAP lower than 250 U/l (upper limit) (n = 15); G-II, patients with serum TAP between 251 and 500 U/l (n = 18); and G-III, patients with serum TAP greater than 501 U/l (n = 26). Serum TAP and BAP showed the highest diagnostic accuracy among the markers of bone formation with a sensitivity of 78% and 84%, respectively, when the specificity was 100%. Urinary PYR was the most sensitive marker of bone resorption. Also, urinary PYR showed the highest proportion of increased values in pagetic patients (73%) compared with urinary HYP (64%), urinary D-PYR (60%), serum ICTP (41%), or serum TRAP (39%). In pagetic patients with normal serum TAP activity (G-I), serum BAP concentration was increased in 60% of patients, and urinary PYR was increased in 40% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Phosphatase↗
PubMed1995

The effects of recombinant human insulin-like growth factor (rhIGF)-1 and rhIGF-1/IGF binding protein-3 administration on rat osteopenia induced by ovariectomy with concomitant bilateral sciatic neurectomy.

We compared the effect of administration of recombinant human insulin-like growth factor-1 (rhIGF-1) alone or the rhIGF-1/IGF binding protein-3 (IGFBP-3) complex on osteopenia in rats. Female Sprague-Dawley rats (8 months old) underwent combined ovariectomy and bilateral sciatic neurectomy (OVX-NX) or sham operation only. After 2 months, the OVX-NX animals were injected subcutaneously with rhIGF-1 alone or with rhIGF-1A IGFBP-3 equimolar complex for 4 weeks. The IGF-1 contents and dose were 0.3 mg/kg of body weight (BW) three times/week, 3 mg/kg of BW once/week, or 3 mg/kg of BW three times /week. At the end of the experiment, the 4th and 5th lumbar vertebrae (L4, L5) and the proximal tibiae were removed after tetracycline labeling, and histomorphometrical analyses were performed on undecalcified sections using Villanueva's staining. The cancellous bone volume at L5 significantly increased by thickening of the trabecular width in rats treated with the complex. However, the increase in the values at the proximal tibia was not significant. The bone formation rates (BFR/BS) in the lumbar vertebrae of rats treated with the complex three times a week at doses of 0.3 mg/kg of BW and 3 mg/kg of BW were both significantly increased but the parameter increase was less marked with the dose of 3 mg/kg of BW once/week. The BFR/BS did not increase significantly in animals treated with IGF-1 alone. These findings clearly demonstrated that the effect of systemically administered rhIGF-1 on bone formation was markedly potentiated when combined with IGFBP-3 in estrogen deficiency combined with reduced activity. The action of IGF-1 was less potent on the bone in paralyzed limbs. The action of rhIGF-1/IGFBP-3 on trabecular bone appeared to depend not only on the dose but also on the frequency of administration and the parts of the skeleton in rats.

Analysis of Variance↗
PubMed1996

An acute intake of phosphate increases parathyroid hormone secretion and inhibits bone formation in young women.

We studied the effects of a single oral phosphate (Pi) dose as well as those of three consecutive oral phosphate doses on calcium and bone metabolism. In the first part of the study (P1 study) 10 female volunteers were given orally 1500 mg of Pi in water, as a single dose, or plain water in randomized order at two different sessions. In the second part of the study (P3 study), 10 female volunteers were given orally 1500 mg of Pi, as three separate 500 mg doses in water, or plain water in randomized order. Calcium and bone metabolism was monitored for 24 h by measuring the concentrations of serum ionized calcium (S-iCa), urinary calcium, serum phosphate (S-P), urinary P, serum intact parathyroid hormone (PTH), serum carboxy-terminal propeptide of type I collagen (PICP), serum osteocalcin (BGP), serum carboxy-terminal telopeptide of type I collagen (ICTP), urine deoxypyridinoline (DPD) and bone-specific alkaline phosphatase activity (B-ALP). The S-P increased (p = 0.00005 and p = 0.0005, in the P1 and P3 studies, respectively), the S-iCa concentration declined significantly only in the P1 study (p = 0.0014), the urinary calcium excretion decreased (p = 0.02 and 0.013, in the P1 and P3 studies, respectively), and the PTH concentration rose (p = 0.0083 and p = 0.014, in the P1 and P3 studies, respectively) during the phosphate experiment as compared with the control session. Of the three markers of bone formation studied, PICP declined in the P1 study (p = 0.04), and B-ALP declined in both parts of the study (p = 0.027, p = 0.026, in the P1 and P3 studies, respectively) after phosphate administration, whereas there was no significant change in BGP in either of the studies. The markers of bone resorption, ICTP and DPD, were unaffected by the phosphate load in both studies. In conclusion, acute ingestion of phosphate leads to an increase in S-P, a decrease in S-iCa, and an increase in intact PTH secretion. Our results indicate that these events may lead to an acute inactivation of the early phases of bone formation. In this setting, there was no indication of enhanced bone resorption despite the increase in PTH secretion, which could be due to the combined effect of phosphate and PTH on bone resorption.

Administration, Oral↗
PubMed2007

Hyaline cartilage formation and enchondral ossification modeled with KUM5 and OP9 chondroblasts.

What is it that defines a bone marrow-derived chondrocyte? We attempted to identify marrow-derived cells with chondrogenic nature and immortality without transformation, defining "immortality" simply as indefinite cell division. KUM5 mesenchymal cells, a marrow stromal cell line, generated hyaline cartilage in vivo and exhibited enchondral ossification at a later stage after implantation. Selection of KUM5 chondroblasts based on the activity of the chondrocyte-specific cis-regulatory element of the collagen alpha2(XI) gene resulted in enhancement of their chondrogenic nature. Gene chip analysis revealed that OP9 cells, another marrow stromal cell line, derived from macrophage colony-stimulating factor-deficient osteopetrotic mice and also known to be niche-constituting cells for hematopoietic stem cells expressed chondrocyte-specific or -associated genes such as type II collagen alpha1, Sox9, and cartilage oligomeric matrix protein at an extremely high level, as did KUM5 cells. After cultured OP9 micromasses exposed to TGF-beta3 and BMP2 were implanted in mice, they produced abundant metachromatic matrix with the toluidine blue stain and formed type II collagen-positive hyaline cartilage within 2 weeks in vivo. Hierarchical clustering and principal component analysis based on microarray data of the expression of cell surface markers and cell-type-specific genes resulted in grouping of KUM5 and OP9 cells into the same subcategory of "chondroblast," that is, a distinct cell type group. We here show that these two cell lines exhibit the unique characteristics of hyaline cartilage formation and enchondral ossification in vitro and in vivo.

Animals↗
PubMed2005

Regulation of proliferation and migration in retinoic acid treated C3H10T1/2 cells by TGF-beta isoforms.

UNLABELLED: Proliferation of mesenchymal precursors of osteogenic and chondrogenic cells and migration of these precursors to repair sites are important early steps in bone repair. Transforming growth factor-beta (TGF-beta) has been implicated in the promotion of bone repair and may have a role in these processes. Three isoforms of TGF-beta, TGF-beta1, -beta2, and -beta3, are expressed in fracture healing, however, their specific roles in the repair process are unknown. Differential actions of the TGF-beta isoforms on early events of bone repair were explored in the multipotent mesenchymal precursor cell line, C3H10T1/2. Cell migration was determined using a modified Boyden chamber in response to concentrations of each isoform ranging from 10(-12) to 10(-9) g/ml. All three isoforms demonstrated a dose-dependent chemotactic stimulation of untreated C3H10T1/2 cells. Checkerboard assays indicated that all three isoforms also stimulated chemokinesis of the untreated cells. C3H10T1/2 cells treated with all-trans-retinoic acid (ATRA) and expressing relatively higher levels of osteoblastic gene markers such as alkaline phosphatase and collagen type I, lower levels of chondrocytic gene markers collagen type II and aggrecan, and unchanged levels of the adipose marker adipsin did not demonstrate significant chemokinesis or chemotaxis in response to TGF-beta1 or -beta3 at concentrations ranging from 10(-12) to 10(-9) g/ml. In the ATRA-treated cells, TGF-beta2 stimulated a significant increase in chemotaxis only at the highest concentration tested. Cell proliferation was assessed by mitochondrial dehydrogenase activity and cell counts at TGF-beta concentrations from 10(-11) to 10(-8) g/ml. None of the TGF-beta isoforms stimulated cell proliferation in untreated or ATRA-treated C3H10T1/2 cells. Analysis of TGF-beta receptors (TGF-betaR1, -betaR2, and -betaR3) showed a 1.6- to 2.8-fold decrease in mRNA expression of these receptors in ATRA-treated cells. IN CONCLUSION: (1) while all three TGF-beta isoforms stimulate chemotaxis/chemokinesis of multipotent C3H10T1/2 cells, TGF-beta1 and -beta3 do not stimulate chemotaxis in C3H10T1/2 cells treated with ATRA while TGF-beta2 stimulated chemotaxis only at the highest concentration tested. (2) TGF-beta isoforms do not appear to stimulate cell proliferation in C3H10T1/2 cells in either a multipotent state or after ATRA treatment when expressing higher levels of alkaline phosphatase and collagen type I gene markers. (3) Decrease in mRNA expression for TGF-betaR1, -betaR2, and -betaR3 upon ATRA treatment could potentially explain the lack of chemotaxis/chemokinesis in these cells expressing higher levels of alkaline phosphatase and collagen type I.

Animals↗
PubMed2003

Does vitamin D administered to children with asthma treated with inhaled glucocorticoids affect short-term growth or bone turnover?

Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover. We utilized a randomized, double-blind, two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration. The setting was an Outpatient clinic in a secondary referral center. Subjects included 14 boys and 3 girls with a mean age of 11.7 (range, 6.1-14.4) years. Interventions included 15 microg (600 IU) 25-OH-vitamin D (cholecalciferol) in one tablet ABCDin(R) once daily in the morning. Primary outcome measures were: lower leg growth rate, serum osteocalcin, and serum markers of type I collagen turnover, i.e., the amino terminal propeptide of type I procollagen (PINP), the carboxy terminal propeptide of type I procollagen (PICP) (formation markers), and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) (degradation markers). Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment (NS). Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment, respectively, PINP 574 and 565 microg/l, PICP 381 and 382 microg/l, and ICTP 11.5 and 11.1 microg/l, respectively (NS). Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l, respectively (P < 0.001). There were no statistically significant differences in measures of pulmonary function. In conclusion, administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily.

Administration, Inhalation↗
PubMed1993

Bone turnover in asthmatic children treated with oral prednisolone or inhaled budesonide.

Biochemical markers of bone turnover were studied in prepubertal school children with asthma in two randomized double-blind crossover trials with run-in, treatment, and wash-out periods of 2 weeks. One group (n = 11) was treated with 2.5 and 5.0 mg prednisolone, the other (n = 14) with 200 and 800 micrograms inhaled budesonide per day. Serum osteocalcin, serum total alkaline phosphatase, fasting urinary excretion of hydroxyproline and calcium, serum 25-hydroxyvitamin D, and 1,25 dihydroxyvitamin D were assessed. A dose-related reduction of serum osteocalcin (Page's test for trend: P = 0.04; z = -2.3) and of the fasting urinary hydroxyproline:creatinine ratio (Page's test for trend: P = 0.05; z = -2.0) was found in the children who were treated with prednisolone. Inhaled budesonide was not associated with statistically significant effects on any of the biochemical markers. Short-term treatment with low daily doses of prednisolone may cause a suppression of bone turnover in children with asthma. To reduce the risk of adverse effects on bone turnover, doses of inhaled budesonide up to 800 micrograms daily may be preferable to low doses of prednisolone. Bone turnover remains to be evaluated during long-term treatment.

25-Hydroxyvitamin D 2↗
PubMed2004

Analytical, practical and regulatory issues in prevention studies.

Prevention studies, as distinguished from studies investigating treatments for established disease, present some distinct challenges. Perhaps the most extensive experience with preventive agents is in the area of infectious diseases; vaccines have been extremely effective in preventing many such diseases. Vaccines have been, and continue to be, studied in other disease areas such as certain cancers, but as yet have not achieved success outside of infectious disease prevention. One obvious and important feature of prevention studies is that they enroll healthy individuals; thus such studies require particularly high standards for the safety of those enrolled (and those who might ultimately receive the product being tested). Prevention studies often need to be quite large, as the types of diseases most important to prevent tend to be uncommon. Large studies usually require simplified approaches; to ensure high quality of data on the key variables it may be necessary to compromise on the amount of data collected, frequency of data collection, and other aspects of trial design. The reliability of randomization and blinding may be especially important in these large studies, as bias could easily overwhelm the small effects that are usually sought. Often, biomarkers thought to indicate developing but as yet subclinical disease, will be important to evaluate; whether such markers can serve as primary endpoints in prevention studies has been a contentious issue in many contexts. Studies in older populations, such as those at risk for Alzheimer's Disease, raise challenges such as accounting for competing risks, and considering potential interactions of preventive agents with multiple medications often used by the elderly.

Clinical Trials as Topic↗
PubMed1995

PTH and 1,25(OH)2 vitamin D priming to growth factors differentially regulates the osteoblastic markers in MBA-15 clonal subpopulations.

The functional modulation of enzymatic activities of alkaline phosphatase (ALK-P) and neutral endopeptidase (CD10/NEP) in MBA-15.4 and MBA-15.6 marrow stromal osteoblastic cells was studied. The hormonal effects of parathyroid hormone (PTH) and 1,25 (OH)2D3 combined with various growth factors (bone morphogenic protein [BMP-2 and BMP-3], TGF beta and IGF-I) on these cells were monitored. The cell responses of MBA-15.4, a preosteoblastic cell, and MBA-15.6, a more mature osteoblastic cell, to the growth factors and the hormonal challenge were measured by changes of the enzymatic activities (ALK-P and CD10/NEP). The cellular response was not uniform and revealed a differential pattern.

Alkaline Phosphatase↗
PubMed1996

Comparative inhibition of enzymes of human erythrocytes and plasma in vitro by agricultural chemicals.

Farm workers generally are exposed to a combination of synthetic agricultural chemicals and natural products while working in the fields. These biologically active compounds control infestation of tobacco by insects, and plant growth. We have investigated, in vitro, the effects of acephate (AP), cadmium (Cd), methamidophos (MAP), maleic hydrazide (MH), and nicotine (NI) on the activities of the erythrocyte enzymes delta-aminolevulinic acid dehydratase (ALAD), superoxide dismutase (SOD), and plasma cholinesterase (CHE). ALAD, SOD, and plasma CHE were assayed, using aminolevulinic acid, pyrogallol, or butyryl thiocholine as substrates, respectively. Different concentrations of the above chemicals were used to obtain minimum and maximum inhibition of the enzymes, and for the development of inhibition dose response curves. These curves were used to determine the concentration of each chemical required to inhibit 50% of enzyme activity (I50). The I50 concentrations of various chemicals for each enzyme were determined in mM for ALAD: AP=95.5, Cd=1.4x10(-3), MH=2.8, MAP=7.1, NI=60.8; for SOD: AP=1.2, Cd=0.8x10(-7), MH=0.04, MAP=0.42, NI=0.81; for CHE: AP=5.6, Cd=18. 8x10(-5), MAP=18.4x10(-4); CHE was not inhibited by MH and NI. Our data indicate that AP inhibited both SOD and CHE to a maximum of 91 and 87%, while MH inhibited both SOD and ALAD to a maximum 78 and 90%. However, SOD was the enzyme that was most sensitive to all the agricultural-chemicals tested in this study. The inhibition of these enzymes will enable the development of a sensitive biomarker and the assessment of long term health risks in farm workers.

Agrochemicals↗
PubMed1995

Changes in serum carboxyterminal telopeptide of type I collagen in an experimental model of canine osteomyelitis.

Blood biochemical indices of bone turnover were followed up for 1 month in six dogs with experimental osteomyelitis. The bone infection resulted in significant increase in parameters of bone formation (serum bone alkaline phosphatase and serum osteocalcin) and bone resorption [serum carboxyterminal telopeptide of type I collagen (i-ICTP)] as early as the end of the second week after the operation and inoculation. There was strong evidence that serum i-ICTP levels could be useful for the early diagnosis of postoperative complications in veterinary orthopedics, such as posttraumatic osteomyelitis.

Alkaline Phosphatase↗
PubMed1995

Indicators of bone formation in weight lifters.

Physical activity has been suggested to be one of the determinants of bone turnover and to prevent age-related bone loss. To examine this we measured the serum levels of osteocalcin (bone Gla-protein, BGP), C-terminal procollagen peptide (PICP), serum alkaline phosphatase, bone-specific alkaline phosphatase, and S-calcium as indices of bone formation in 19 actively performing and 15 ex-lifters. All were nationally or internationally ranked male athletes. Their values were compared with those from 38 age- and gender-matched controls. Actively performing weight lifters had 35% higher (P < 0.05) serum concentration of osteocalcin than the controls. The ex-lifters did not differ from the age-matched controls. Also serum calcium was elevated in active lifters (6%) (P < 0.01) but not in ex-lifters. No difference was found for serum-ALP, B-ALP, or PICP in either of the groups. Our study indicates that in addition to an already documented and well-known higher bone mineral density in heavily exercising athletes, they have an indication of higher bone formation as measured by biochemical markers. In athletes who have retired from competitional training, however, the bone formation does not differ from that of more sedentary controls.

Adult↗
PubMed1995

Phenytoin and fluoride act in concert to stimulate bone formation and to increase bone volume in adult male rats.

We have recently demonstrated that phenytoin is an osteogenic agent at low doses. The present paper describes observations that a mitogenic dose (i.e., 20 microM in BGJb medium) of fluoride significantly augments the phenytoin-dependent stimulation of normal human bone cell proliferation and alkaline phosphatase (ALP) activity in cell culture. Additionally, the present study was designed to investigate whether fluoride and phenytoin would interact to increase bone formation in rats in vivo. Four groups of weight-matched adult male rats received daily I.P. injection of (1) vehicle (10% DMSO), (2) 5 mg/kg/day phenytoin, (3) 5 mg/kg/day phenytoin and 50 ppm NaF, and (4) 50 ppm NaF and vehicle, respectively, for 36 days. Sodium fluoride (NaF) was delivered in drinking water. Blood samples were drawn weekly and analyzed for serum osteocalcin, ALP, calcium, phosphorus, and 25(OH)D3. Rats were labeled with tetracycline at day 21 and 30 and histomorphometric analysis was carried out on the tibia at the end of the experiment. Neither agent by itself or together affected the serum calcium, phosphorus, or 25(OH)D3 levels. All measures of bone formation, i.e., serum osteocalcin level and ALP activity, bone ALP specific activity, mineral apposition rate, bone formation rate, and % bone formation surface, were increased by each agent. Fluoride and phenytoin together produced bigger increases in each parameter than did each agent alone. Trabecular bone volume was increased in the tibial metaphysis by fluoride or phenytoin alone; and when administered together, the two agents produced a greater increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1993

Evaluation of bone turnover in type I osteoporosis using biochemical markers specific for both bone formation and bone resorption.

The aims of the study were to evaluate the use of bone-specific biochemical markers of turnover in type I osteoporosis, to test for evidence of heterogeneity of bone turnover in this condition, and to attempt to devise an 'uncoupling index' by using the relationship between bone-specific biochemical markers of bone formation and bone resorption. In women with type I osteoporosis (mean age 64 years, SD 5; n = 63) the mean level of serum osteocalcin, a specific biochemical marker of bone formation, was 9.9 ng/ml (SD 2.0), which was higher than the level in normal postmenopausal women (mean age 65 years, SD 6; n = 8.9 ng/ml (SD 2.0; p < 0.01). The variance of serum osteocalcin levels in the two groups was similar. Compared with this 11% increase in the biochemical marker for bone formation, the markers of bone resorption, total urinary deoxypyridinoline (bone-specific), pyridinoline and hydroxyproline were increased by 40% (p < 0.0001), 61% (p < 0.0001) and 25% (p < 0.01), respectively. Furthermore, these biochemical markers of bone resorption had greater variance in women in type I osteoporosis than in the normal postmenopausal women (p < 0.01). The urinary excretion of the free crosslinks deoxypyridinoline, pyridinoline and glycosylated pyridinoline were increased by 26% (p < 0.001), 17% (p < 0.01) and 13% (NS) respectively. An 'uncoupling index' was calculated for the difference between urinary deoxypyridinoline and serum osteocalcin using the results from the normal women and expressed as z-scores. We conclude that the pyridinium crosslinks of collagen enable better discrimination between normal and osteoporotic women than does hydroxyproline.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1999

In vitro effects of zinc on markers of bone formation.

Zinc deficiency is associated with a reduced rate of bone formation that can be corrected by supplementation of the deficient diet with adequate amounts of zinc. This study was conducted to examine the effects of zinc on bone cell parameters associated with bone formation. Tibiae were removed from 19-d-old chicken embryos and incubated for 48 h in Dulbecco's modified Eagle's medium supplemented with antibiotics, bovine serum albumin, and HEPES. The addition of zinc (25-200 g/dL) to tibial cultures resulted in a concentration-dependent increase in alkaline phosphatase activity, an increase in the incorporation of proline into bone protein and an increase in the post-translational oxidation of proline to peptidyl hydroxyproline. These effects of zinc were all diminished by the addition of 2,6-pyridine dicarboxylic acid, a chelator of zinc. The addition of either cycloheximide (10(-5)M), dactinomycin (10(-8)M), or hydroxyurea (10(-3)M) to tibial cultures also attenuated the effects of zinc. The effect of zinc on bone cell DNA synthesis was measured by following the incorporation of 3H-thymidine into DNA and by fluorometric measurement of cellular DNA content. These methods revealed that the addition of zinc to cultured tibiae resulted in a concentration-dependent increase in tibial DNA content and synthesis rate. The magnitude of the zinc-induced DNA increase was similar to the magnitude of the zinc-induced increases in alkaline phosphatase activity, proline incorporation, and hydroxyproline synthesis. Normalization of these latter responses to tibial DNA content yield data indicating that the effect of zinc on bone formation results from a zinc-induced increase in bone cell proliferation.

Alkaline Phosphatase↗
PubMed2005

Strontium ranelate: a novel mode of action optimizing bone formation and resorption.

Strontium ranelate has been shown to decrease the risk of fractures in postmenopausal women. Its efficacy in clinical studies results from its unique mode of action, on both bone resorption and bone formation. Pharmacological studies in animals have shown that strontium ranelate decreases bone resorption and increases bone formation, resulting in increased bone mass. In ovariectomized rats, strontium ranelate prevented the reduction in bone mineral content and the decrease in trabecular bone volume induced by estrogen deficiency. In this model, strontium ranelate decreased bone resorption, whereas bone formation was maintained at a high level as documented by plasma biochemical markers and histomorphometric indices of bone formation. In the model of osteopenia induced by hind-limb immobilization in rats, strontium ranelate reduced histomorphometric parameters of bone resorption and partially prevented long-bone loss, as assessed by bone mineral content, bone volume, and biochemical indices of bone resorption. In intact mice, strontium ranelate increased bone formation and vertebral bone mass. In intact growing rats, strontium ranelate increased the bone trabecular volume without alteration of mineralization. The unique mode of action of strontium ranelate on bone formation and resorption was supported by in vitro studies. In rat calvaria culture systems and rat osteoblastic cell cultures, strontium ranelate enhanced preosteoblastic cell replication and increased collagen synthesis by osteoblasts. Moreover, strontium ranelate decreased bone resorption in organ cultures and decreased the resorbing activity of isolated mouse osteoclasts. The assessment of bone markers in a clinical trial [Spinal Osteoporosis Therapeutic Intervention (SOTI)] supports the mode of action of strontium ranelate: bone alkaline phosphatase levels increased and C-telopeptide of type I collagen levels decreased in treated patients compared with the placebo group at all time points. Thus, pharmacological and clinical studies suggest that strontium ranelate optimizes bone resorption and bone formation, resulting in increased bone mass, which may be of great value in the treatment of osteoporosis.

Alkaline Phosphatase↗