Bone Gamma-carboxyglutamic Acid-containing Protein Research Articles

Serum Human \(\beta\) Defensin (HBD-2) and Osteocalcin Levels in Menopausal Iraqi Women with Osteopenia

Background and Purpose: Osteopenia (OP) is a chronic and advanced condition that is often described by diminished bone mineral density (BMD), deteriorated bone tissue microarchitecture, and an elevated risk of fracture. The low molecular weight antimicrobial peptides known as Human Defensin (HBD-2) proteins are produced locally by keratinocytes in various tissues, including skin, mucosa, and bones. Osteocalcin, often called bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a tiny (49 amino acids) noncollagenous protein hormone in bone and dentin. It was initially discovered to be a calcium-binding protein. Material and Methods: Prospective study to evaluate the osteoblast's ability to produce and release osteocalcin makes it a noncollagenous protein, and has primary physiological roles include calcium ion homeostasis, maintaining an average rate of bone mineralization, preventing the aberrant development of hydroxyapatite crystals, and participating in bone remodeling via a negative feedback loop. In menopausal women with osteopenia, this study evaluates the osteocalcin and human beta-defensin 2 for their diagnostic potential. A small amount of venous blood, about 5 ml, was added to the tube and centrifuged for five minutes at a speed of 3 \(\times\) 103 rpm. The serum was put into an Eppendorf tube and stored in a freezer at -20 \(^\circ\)C before being tested. With the help of the specified equation, the body mass index is determined. Findings and Conclusion: Increasing serum HBD 2, osteocalcin levels in postmenopausal women with osteopenia plays an essential role in developing osteopenia to osteoporosis. Differences in serum levels of alkaline phosphatase were seen among patients (as a sample) and controls; serum levels of HBD2 and osteocalcin were considerably lower in controls than in patients (p 0.01).

In vitro biological evaluation of epigallocatechin gallate (EGCG) release from three-dimensional printed (3DP) calcium phosphate bone scaffolds.

Three-dimensional printed (3DP) tricalcium phosphate (TCP) scaffolds can guide bone regeneration, especially for patient-specific defect repair applications in low-load bearing sites. Epigallocatechin gallate (EGCG), a green tea compound, has gained attention as a safer alternative treatment for bone disorders. The 3DP TCP scaffold is designed for localized EGCG delivery, which can enhance in vitro osteogenic ability, anti-osteoclastogenic activity, vascularization formation, and chemoprevention. In the cocultures of human bone marrow-derived mesenchymal stem cells (hMSCs) and monocytes (THP-1), EGCG release enhances osteogenic differentiation of hMSCs at day 16 compared to the control; this is indicated by a 2.8- and 4.0-fold upregulation of Runt-related transcription factor 2 (Runx2) and bone gamma-carboxyglutamic acid-containing protein (BGLAP), the early and late osteoblast differentiation marker expressions. However, EGCG significantly downregulates the receptor activator of nuclear factor-κB ligand (RANKL) expression by 7.0-fold, indicating that EGCG suppresses RANKL-induced osteoclast maturation. EGCG also stimulates endothelial tube formation at as early as 3 hours when human umbilical vein endothelial cells (HUVECs) grow on Matrigel. It reduces human osteosarcoma MG-63 cell viability by 66% compared to the control at day 11. An in vitro release kinetics study demonstrates that EGCG shows a ∼64% release within a day followed by a sustained release in the physiological environment (pH 7.4) because its phenolic hydroxyl groups are easily deprotonated at physiological pH. These findings contribute to developing a multifunctional scaffold for the treatment of low load-bearing patient-specific bone defects after trauma and tumor excision.

Anti-Osteoporotic Effects of the Herbal Mixture of Cornus officinalis and Achyranthes japonica In Vitro and In Vivo.

Osteoporosis is a porous bone disease caused by bone density loss, which increases the risk of fractures. Cornus officinalis (CO) and Achyranthes japonica (AJ) have been used as traditional herbal medicine for various disorders in East Asia. Although the anti-osteoporotic effects of single extract of CO and AJ have already been reported, the synergistic effect of a combined mixture has not been studied. In this study, we investigated the effects of a CO and AJ herbal mixture on osteoporosis in in vitro and in vivo models. The results demonstrate that treatment with the CO and AJ mixture significantly promoted osteoblast differentiation of MC3T3-E1 mouse preosteoblasts through the upregulation of osteoblastic differentiation-associated genes such as alkaline phosphatase (Alpl), runt-related transcription factor 2 (Runx2), and bone gamma-carboxyglutamic acid-containing protein (Bglap), while the mixture significantly inhibited differentiation of osteoclasts isolated from primary-cultured mouse monocytes. In addition, oral administration of CO and AJ mixture significantly prevented bone mineral density loss and trabecular bone structures in an ovariectomy-induced osteoporotic mouse model. These results suggest that the combination treatment of CO and AJ mixture might be a beneficial therapy for osteoporosis.

Nano-hydroxy apatite/chitosan/gelatin scaffolds enriched by a combination of platelet-rich plasma and fibrin glue enhance proliferation and differentiation of seeded human dental pulp stem cells

The purpose of this study was to investigate the effects of Fibrin Glue (FG) and activated platelet-rich plasma (a-PRP) on the proliferation and osteogenic differentiation of human dental pulp stem cells (h-DPSCs). Therefore, we planned to investigate in vitro behavior of porous composite scaffolds based on chitosan-gelatin/nanohydroxyapatite (CS–G/nHA) treated with FG and a-PRP. The porous structure of CS–G/nHA was prepared using combination of particle leaching and freeze-drying methods. The a-PRP was prepared from the centrifugation of whole blood activated with calcium chloride. Four groups of composite scaffolds were fabricated to seed h-DPSCs: (1) a-PRP–FG/CS–G/nHA; (2) FG/CS–G/nHA; (3) a-PRP/CS–G/nHA; (4) CS–G/nHA. The 14 days SEM image reveled organized fibrin network on scaffolds surface. All groups treated with FG and a-PRP, showed improved adhesion of seeded h-DPSCs compared to CS–G/nHA. Cytotoxicity of the composite scaffolds was assessed by MTT. Alizarin red staining confirmed the formation of bone minerals by h-DPSCs after 21 days of cell seeding. In addition, the a-PRP–FG treated scaffolds exhibited significantly elevated bone gamma-carboxyglutamic acid-containing protein (BGLAP), bone morphogenetic protein 2 (BMP2), and runt-related transcription factor 2 (RUNX2) gene expression. The present result the composite scaffolds treated with FG and a-PRP showed a fibrin network, preferentially on the surface of composite scaffold increasing the mineralization and osteoblastic differentiation of harvested cells. In addition, a-PRP–FG/ CS–G/nHA scaffold increased bone marker gene expressions from day 7 to day 21.

Antimicrobial activity of commercial calcium phosphate based materials functionalized with vanillin

Infections represent one of the most frequent causes of arthroplasty revision. Thus, design of new antimicrobial scaffolds to reduce implant rejections, bone infections and associated medical costs is highly desired. In recent years, essential oil components (EOCs) have merged as compounds with significant antimicrobial activity that can be attached to specific surfaces to enhance and prolong their antimicrobial effect. Herein calcium phosphate CaP regenerative materials have been coated with a vanillin derivative to combine its original bone regeneration properties with antimicrobial action of EOCs. Materials in form of microparticles and blocks were prepared and fully characterized. Clonogenic viability tests demonstrated that low concentrations of material (10 mg·mL−1) resulted effective to kill 100% of E. coli DH5α bacteria. Additionally, vanillin containing scaffolds did not display any toxic effect over cells, yet they preserve the ability to express alkaline phosphatase (ALPL), collagen type 1, chain α1 (COL1A1) and bone gamma-carboxyglutamic acid-containing protein or osteocalcin (BGLAP), which are genes typically expressed by osteoblasts. These results demonstrate that commercially available scaffolds can be functionalized with EOCs, achieving antimicrobial activity and open up a new approach for the treatment and prevention of infection. Statement of significanceDuring the last years, the interest in bone regenerative materials with antibiotic properties has increased, since prosthesis infection is one of the most usual complications in implant surgery. In this work, we report a hybrid system composed by a calcium phosphate material (powders and scaffolds) functionalized with the derivative of an essential oil component (EOC). Our purpose was to provide the calcium phosphate material with antimicrobial activity without harming its bone regenerative capability. The obtained results were encouraging, which opens up the possibility of developing new modified materials for the prevention and treatment of bone infection.

Transcriptome Analysis Identified Elevated Expression of Bone Gamma-carboxyglutamic acid-containing Protein (BGLAP) in Human Cervical Cancer Tissues

Transcriptome Analysis Identified Elevated Expression of Bone Gamma-carboxyglutamic acid-containing Protein (BGLAP) in Human Cervical Cancer Tissues

Interfacial Mineral Fusion and Tubule Entanglement as a Means to Harden a Bone Augmentation Material.

A new bone augmenting material is reported, which is formed from calcium-loaded hydrogel-based spheres. On immersion of these spheres in a physiological medium, they become surrounded with a sheath of precipitate, which ruptures due to a build-up in osmotic pressure. This results in the formation of mineral tubes that protrude from the sphere surface. When brought into close contact with one another, these spheres become fused through the entanglement and subsequent interstitial mineralization of the mineral tubules. The tubular calcium phosphate induces the expression of osteogenic genes (runt-related transcription factor 2 (RUNX2), transcription factor SP7 (SP7), collagen type 1 alpha 1 (COL1A1), and bone gamma-carboxyglutamic acid-containing protein (BGLAP)) and promotes the formation of mineral nodules in preosteoblast cultures comparable to an apatitic calcium phosphate phase. Furthermore, alkaline phosphatase (ALP) is significantly upregulated in the presence of tubular materials after 10 d in culture compared with control groups (p < 0.001) and sintered apatite (p < 0.05). This is the first report of a bioceramic material that is formed in its entirety in situ and is therefore likely to provide a better proxy for biological mineral than other existing synthetic alternatives to bone grafts.

Effect of deferoxamine on osteoblast differentiation under iron overload environment

Objective To study the influence of eferoxamine (DFO) intervention on osteoblast defferentiation under iron overload environment [using ferric ammonium citrate (FAC) to offer iron overload environment]. Methods The FAC and DFO intervention dosage was determined by method of cell counting kit-8 (CCK-8). Experiment was divided into three groups: control group, 50 μmol/L FAC intervention group, and FAC + DFO group (50 μmol/L FAC intervention + 20 μmol/L DFO). After intervention, alkaline phosphatase staining and quantitation, alizarin red staining and calcium nodule count were carried out. Real-time quantitative polymerase chain reaction detecting system (QPCR) was used to detect the osteogenesis related gene [runt related transcription factor 2 (Runx2), special protein 7 (Sp7), bone gamma-carboxyglutamic acid-containing protein (Bglap), osteoprotegerin (OPG)] mRNA expression level. Results CCK-8 showed 50 μmol/L FAC [(95.6±0.7)%], or 20 μmol/L DFO [(97.6±0.5)%] did not influence the cell viability, with the difference being not statistical differences among groups (P=0.427). As compared with control group, the expression of osteogenesis related genes (Runx2, Sp7, Bglap and OPG) was significantly decreased in the FAC group. As compared with the FAC group, the expression of osteogenesis related genes was significantly increased in the FAC + DFO group (P=0.026). As compared with the control group, the activity of alkaline phosphatase (ALP) staining and quantitation, alizarin red staining and nodule count were decreased in the FAC group. As compared with the FAC group (36±3), the nodule count in the FAC + DFO group (120±6) was increased significantly (P=0.017). Conclusion Osteoblast differentiation is restrained under the iron overload environment. DFO intervention can restore osteoblast differentiation to a certain extent under the iron overload environment. Key words: Deferoxamine; Osteoblast; Iron overload environment; Osteoporosis

Improved regeneration and de novo bone formation in a diabetic zebrafish model treated with paricalcitol and cinacalcet.

Bone changes related to diabetes have been well stablished, but few strategies have been developed to prevent this growing health problem. In our work, we propose to investigate the effects of calcitriol as well as of a vitamin D analog (paricalcitol) and a calcimimetic (cinacalcet), in fin regeneration and de novo mineralization in a zebrafish model of diabetes. Following exposure of diabetic transgenic Tg(ins:nfsb-mCherry) zebrafish to calcitriol, paricalcitol and cinacalcet, caudal fins were amputated to assess their effects on tissue regeneration. Caudal fin mineralized and regenerated areas were quantified by in vivo alizarin red staining. Quantitative real-time PCR was performed using RNA from the vertebral column. Diabetic fish treated with cinacalcet and paricalcitol presented increased regenerated and mineralized areas when compared with non-treated diabetic group, while no significant increase was observed in non-diabetic fish treated with both drugs. Gene expression analysis showed an up-regulation for runt-related transcription factor 2b (runx2b), bone gamma-carboxyglutamic acid-containing protein (bglap), insulin a (insa) and insulin b (insb) and a trend of increase for sp7 transcription factor (sp7) in diabetic groups treated with cinacalcet and paricalcitol. Expression of insra and vdra was up-regulated in both diabetic and nondiabetic fish treated with cinacalcet. In nondiabetic fish treated with paricalcitol and cinacalcet a similar increase in gene expression could be observed but not so pronounced. The increased mineralization and regeneration in diabetic zebrafish treated with cinacalcet and paricalcitol can be explained by increased osteoblastic differentiation and increased insulin expression indicating pro-osteogenic potential of both drugs.

Effect of kidney-reinforcing and marrow-beneficial Chinese medicine on bone metabolism-related factors following spinal cord injury in rats.

The present study aimed to investigate the effect of traditional Chinese kidney reinforcing and marrow-beneficial medicine (KRMB) on the prevention and treatment of abnormal bone metabolism and osteoporosis (OP) resulting from spinal cord injury (SCI). Rat models of OP following SCI were surgically established. The rats were randomly divided into five groups: Normal; sham operation + KRMB; normal + KRMB; SCI + KRMB; and SCI model group. Bone mineral density (BMD), and the expression of bone gamma-carboxyglutamic-acid containing protein (BGP), hepcidin mRNA and bone sialoprotein (BSP) were recorded at 1, 2, 4, 6, 8 and 10 weeks after the operation. BMD expression in the SCI model group was significantly lower compared with the normal, sham + KRMB and normal + KRMB groups at 4, 6, 8 and 10 weeks (P<0.01), and was significantly lower than that in the SCI + KRMB group at 6 (P<0.05), 8 and 10 weeks (P<0.01). The level of serum BGP in the SCI model group was significantly higher compared with the normal, sham + KRMB and normal + KRMB groups at each time point (P<0.01), and lower than the SCI + KRMB group (P<0.01). The SCI + KRMB group was significantly higher than the normal, sham operation + KRMB and normal + KRMB groups (P<0.01). Hepcidin mRNA expression in the rat livers in the normal, sham + KRMB and normal + KRMB group was significantly higher than that in the SCI + KRMB group and SCI model group at each time point (P<0.01). Hepcidin mRNA expression in the SCI + KRMB group was significantly higher than that in the SCI model group at 1 week (P<0.01), and significantly higher than the SCI model group at 2, 4, 6, 8 and 10 weeks (P<0.01). BSP expression in the SCI model group was significantly higher than that in the normal, sham + KRMB and normal + KRMB groups at each time point (P<0.01). BSP expression in SCI model group was higher than that in the SCI + KRMB group at 1 (P<0.05), 2, 4, 6, 8 and 10 weeks (P<0.01). In conclusion, KRMB traditional Chinese medicine may have a curative effect on secondary OP resulting from SCI.

Synergistic interaction of platelet derived growth factor (PDGF) with the surface of PLLA/Col/HA and PLLA/HA scaffolds produces rapid osteogenic differentiation

Scaffolds with structural features similar to the extracellular matrix stimulate rapid osteogenic differentiation in favorable microenvironment and with growth factor supplementation. In this study, the osteogenic potential of electrospun poly-l-lactide/hydroxyapatite/collagen (PLLA/Col/HA, PLLA/HA and PLLA/Col) scaffolds were tested in vitro with the supplementation of platelet derived growth factor-BB (PDGF-BB). Cell attachment and topography, mineralization, extracellular matrix protein localization, and gene expression of the human mesenchymal stromal cells were compared between the fibrous scaffolds PLLA/Col/HA, PLLA/Col, and PLLA/HA. The levels of osteocalcin, calcium, and mineralization were significantly greater in the PLLA/Col/HA and PLLA/HA compared with PLLA/Col. High expression of fibronectin, intracellular adhesion molecule, cadherin, and collagen 1 (Col1) suggests that PLLA/Col/HA and PLLA/HA scaffolds had superior osteoinductivity than PLLA/Col. Additionally, osteopontin, osteocalcin, osterix, Runt-related transcription factor 2 (Runx2), and bone morphogenic protein (BMP2) expression were higher in PLLA/Col/HA and PLLA/HA compared with PLLA/Col. In comparison with PLLA/Col, the PLLA/Col/HA and PLLA/HA scaffolds presented a significant upregulation of the genes Runx2, Col 1, Integrin, osteonectin (ON), bone gamma-carboxyglutamic acid-containing protein (BGALP), osteopontin (OPN), and BMP2. The upregulation of these genes was further increased with PDGF-BB supplementation. These results show that PDGF-BB acts synergistically with PLLA/Col/HA and PLLA/HA to enhance the osteogenic differentiation potential. Therefore, this combination can be used for the rapid expansion of bone marrow stromal cells into bone-forming cells for tissue engineering.

Berberine in Combination with Insulin Has Additive Effects on Titanium Implants Osseointegration in Diabetes Mellitus Rats.

This study evaluated the effects of berberine in combination with insulin on early osseointegration of implants in diabetic rats. Fifty male Sprague-Dawley rats were randomly divided into 5 groups: healthy rats were used as control (HC), and streptozotocin-induced diabetic rats were treated with insulin, berberine, berberine + insulin (IB), or no treatment. Each rat received one machined-surface cp-Ti implant into the right tibia and was given insulin injection and/or gavage feeding with berberine daily for 8 weeks until being sacrificed. Serum levels of alkaline phosphatase (ALP) and bone gamma-carboxyglutamic acid-containing protein (BGP) were analyzed in each group. Peri-implant mineral apposition was marked by fluorochrome double-labeling and osseointegration was histomorphologically examined. The ALP and BGP levels decreased in diabetic rats but were successfully corrected by insulin and berberine combined treatment. Moreover, untreated diabetic rats had less labeled mineral apposition and impaired osseointegration. In contrast, Groups I, B, and IB were observed with increased peri-implant bone formation. The combination treatment of insulin and berberine was more effective than each administrated as a monotherapy. These results suggest that berberine combined with insulin could promote osseointegration in diabetic rats, thereby highlighting its potential application to patients, though further studies are needed.

The effect of pulsed electromagnetic fields on bone loss in spinal cord injured patients

Objective To observe any therapeutic effect of pulsed electromagnetic fields (PEMFs) on bone loss in spinal cord injury (SCI) patients.Methods Fifty-five patients with SCI were divided into two groups randomly.The twenty-six patients in the control group (group B) were given only routine rehabilitation treatment; the twenty-six patients in the treatment group (group A) received PEMF therapy in addition.Results After 12 weeks of treatment,the average bone mineral density (BMD) of the proximal femur (including total,neck,Wards,inter,troch) in group A was significantly higher than in group B.The levels of bone-gamma-carboxyglutamic acid containing protein (BGP) and 1,25 (OH)2D3 in group A increased significantly,while they decreased in group B.Urine-pyridinium/crealinine (U-Pyd/Cr) levels in group A decreased significantly,while in group B they were higher than before.There were statistically significant differences between the two groups.Conclusion PEMF treatment can effectively retard bone loss in SCI patients.It has good preventive and curative effects on osteoporosis after SCI. Key words: Spinal cord injury; Bone loss; Pulsed electromagnetic fields; Osteoporosis

SOY ISOFLAVONES IMPROVE BONE METABOLISM IN POSTMENOPAUSAL JAPANESE WOMEN

1. This study examines whether the supplementation of isoflavones (ISO) exerts beneficial effects on serum and urinary biomarkers of bone metabolism. 2. A total of 102 women were randomly assigned to three groups taking either ISO (40 mg) tablets, tablets containing vitamins C (25 mg) and E (5 mg) (V) or placebo tablets (vehicle only) (P) daily for 4 weeks, in a double-blind parallel placebo controlled design. 3. Among the 67 women who completed the study (24 on ISO, 24 on V, 19 on P), only ISO tablets were proven to decrease significantly urinary deoxypyridinoline (Dpd) excretion (P < 0.05 vs before), a specific biomarker of bone resorption, but there was no significant difference in serum bone gamma-carboxyglutamic acid-containing protein (BGP), a specific serum biomarker of bone formation. 4. Among the 67, 25 women were postmenopausal (8 on ISO, 12 on V, 8 on P) and only ISO tablets decreased significantly urinary Dpd excretion (P < 0.05 vs before) in them. The reduction rate of Dpd in ISO group was also significantly greater than that in P group (P < 0.01). 5. Dietary supplementation of vitamins C 25 mg and E 5 mg did not affect urinary Dpd.

Production of monoclonal antibodies specific for human bone γ-carboxyglutamic acid containing protein

Murine monoclonal antibodies specific for human bone gamma-carboxyglutamic acid containing protein (BGP) were produced against BGP purified from young adult human long bones. The amino acid composition of purified protein corresponds with that of human BGP, and Western blot analysis revealed that the antibodies reacted most intensely with the cytoplasm of osteoblasts and less intensely with the cytoplasm of osteocytes, but did not react with any other cells, such as chondrocytes, or osteoclasts. Because of their ability to react with routinely processed tissue sections and their marked reactivity with human osteoblastic cells, the antibodies are expected to be a useful tool for studying the process of ossification in human bones and for the immunohistochemical diagnosis of human osteogenic tumours.

Serum Bone Gla Protein (BGP) During Treatment of Hyperthyroidism and Hypothyroidism

Serum bone gamma-carboxyglutamic acid-containing (Gla) protein (BGP) was measured before and with initially 2 weeks, later 4-8 weeks intervals for 20-58 weeks during treatment of patients with hyperthyroidism (n = 10) and hypothyroidism (n = 4). Biochemical euthyroidism was obtained in the hyperthyroid patients after a median of 3 weeks (range 1-8 weeks), and in the hypothyroid patients after a median of 17 weeks (range 10-27 weeks). Serum BGP levels closely followed the thyroid state, being high respectively low in the hyperthyroid and hypothyroid state and reaching a stable plateau just at the time biochemical euthyroidism was obtained. These data suggest that osteoblastic activity is enhanced in hyperthyroidism and reduced in hypothyroidism, and that normalization occurs in close conjunction with the normalization of the thyroid state, without any delay, indicating a direct effect on the function of the excisting osteoblasts by the thyroid hormones.

A Newly Established Human Osteosarcoma Cell Line With Osteoblastic Properties

A human osteosarcoma cell line, HuO9, was established from a tumor that was heterotransplanted into athymic nude mice. Antiserum against nude mouse spleen cells was added to the early passage cultures to eliminate the host fibroblastic cells. The cell line retained a high activity of liver/bone/kidney-type alkaline phosphatase (ALP) and secreted osteocalcin, i.e., bone gamma-carboxyglutamic acid-containing protein (BGP), into the medium. The addition of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) increased the ALP activity as well as the level of BGP secreted into the medium. The ALP of 1,25(OH)2D3-treated cells has the same inhibition characteristics to heat and amino acids as that of untreated cells. Synthetic human parathyroid hormone stimulated the production of intracellular adenosine 3',5'-cyclic monophosphate (cAMP) approximately 100-fold within five minutes. However, the stimulation was not observed with a synthetic human thyrocalcitonin. When HuO9 cells were transplanted into the back of a nude mouse, a tumor with an abundant osteoid formation and mineralization was produced. The results indicate that the HuO9 cell line expresses well-differentiated osteoblastic phenotypes. HuO9 is the first established human cell line to produce BGP, and it provides a useful model for the studies of osteoblasts and the regulatory mechanisms of BGP production.

Serum markers of bone formation in parenteral nutrition patients

Bone gamma-carboxyglutamic acid containing protein (BGP) has been utilized effectively as a serum marker of bone turnover in healthy normals and in individuals with a variety of metabolic bone disorders including postmenopausal osteoporosis and Paget's disease. The utility of this serum marker in other bone disorders, including that associated with the maintenance of patients on long-term parenteral nutrition, still requires definition. Because of our interest in this clinical syndrome and the availability of serum and of bone formation rates (BFR) measured directly from double tetracycline labeling in 11 long-term parenteral nutrition patients, we measured BGP levels in these patients and attempted to correlate this measure with BFR. Serum vitamin D metabolites, immunoreactive parathyroid hormone (PTH), and alkaline phosphatase (alk phos) were also measured. Serum BGP was only weakly and not significantly correlated (r = 0.24, p = NS) with bone formation rate for the group as a whole. However, in a subgroup of 10 patients without hyperparathyroidism, there was strong and significant correlation (r = 0.81, P less than 0.01) between BGP and BFR. There was also a strong correlation between bone formation rate and serum 1,25 dihydroxyvitamin D [1,25(OH)2D] levels (r = 0.89, P less than 0.01, n = 11). The mechanism of this association could not be established. A correlation of borderline significance was observed between bone formation rate and serum alk phos (r = 0.60, P = 0.05, n = 11). The current data suggest that additional studies may help to more fully define the utility of serum measurements in quantifying bone dynamics in parenteral nutrition patients, and that measures of vitamin D metabolites, BGP, and alk phos may prove useful.

Bone Gla Protein and Sex Hormone-Binding Globulin in Nontoxic Goiter: Parameters for Metabolic Status at the Tissue Level

Several patients with nontoxic goiter have reduced serum TSH levels, as measured with new sensitive assays. Whether this is a sign of subclinical hyperthyroidism, thus having the potential of adverse effects on different organs with time, is not known. We have measured serum levels of 2 markers of thyrometabolic status at the tissue level, bone gamma-carboxyglutamic acid-containing protein (BGP), reflecting the function of osteoblasts, and sex hormone-binding globulin (SHBG), reflecting the function of hepatocytes, in 44 patients (41 women and 3 men) with nontoxic goiter (11 diffuse and 33 nodular goiters; serum T4, T3, free T4, and free T3 levels had been normal and stable for at least 0.5 yr). Serum TSH levels ranged from normal to unmeasurably low values (less than 0.05 mU/L). Serum TSH levels correlated negatively to serum BGP levels (r = -0.60; P less than 0.001). Due to the postmenopausal surge in serum BGP levels, premenopausal women (n = 21) were tested separately without changing the significance (r = -0.53; P less than 0.02). Expressing serum BGP values as a percentage of the mean value in control subjects of the same age and sex did not change the correlation (r = -0.63; P less than 0.001). Six patients had serum BGP levels above the normal range, and patients with reduced serum TSH levels (less than 0.45 mU/L; n = 12) had significantly enhanced serum BGP levels [median, 1.53 nmol/L (range, 1.02-4.24) vs. 1.23 nmol/L (0.62-3.71); P less than 0.05]. Serum TSH also correlated negatively to serum SHBG levels (r = -0.56; P less than 0.001; women alone: r = -0.58; P less than 0.001). Eight patients had serum SHBG levels above the normal range, and patients with reduced serum TSH levels had significantly enhanced serum SHBG levels, expressed as a percentage of the mean control value for the relevant sex [203% (range, 75-288) vs. 120% (42-317); P less than 0.01]. It is concluded that the lower serum TSH levels in patients with nontoxic goiter, the higher are serum BGP and SHBG levels. This suggests a progressively generalized (not only pituitary) tissue overexposure to thyroid hormones, the lower the serum TSH levels. Therefore, the finding of a reduced serum TSH level in patients with nontoxic goiter might reflect supraphysiological levels of T4 and/or T3, which could possibly be harmful.

Increased circulating levels of γ-carboxyglutamic acid-containing protein and decreased bone mass in children on anticonvulsant therapy

In order to investigate the pathophysiology of anticonvulsant-induced osteopenia, circulating levels of bone gamma-carboxyglutamic acid-containing protein (Bone Gla Protein: BGP) and urinary excretion of BGP were measured in 16 children on chronic anticonvulsant therapy and in 12 control children. Using microdensitometry analysis, osteopenia was found in 25% of the anticonvulsant therapy group, but it was not observed in the control group. Serum BGP and A1-P levels were significantly increased in the anticonvulsant group compared with the control group (P less than 0.05 and P less than 0.01, respectively), and a positive correlation was found between serum BGP and A1-P levels (P less than 0.05). Urinary excretion of BGP and hydroxyproline showed an increase in the anticonvulsant group, but it was not statistically significant. On the other hand, there was no significant difference between the two groups in serum levels of vitamin D metabolites, PTH, calcitonin, Ca, or P or in urinary excretion of Ca or P. It is suggested, therefore, that the increased BGP level in children receiving anticonvulsant therapy is a reflection of high bone turnover due to anticonvulsant drug complications.