bluuebunny/crossref_metadata_2025_split huggingface dataset:
BM 21.0955, a potent new bisphosphonate to inhibit bone resorption
Authors: Mühlbauer R.C. , Bauss F. , Schenk R. , Janner M. , Bosies E. , Strein K. , Fleisch H. 
Published: February 2010

Abstract
A total of 300 new bisphosphonates were screened for their effect on bone resorption in the rat. Among these, 1-hydroxy-3-(methylpentylamino)propylidenebisphosphonate (BM 21.0955) was selected for detailed investigation. It inhibited arotinoid-stimulated bone resorption as assessed by calcemia in thyroparathyroid-ectomized rats at a SC dose as low as 0.001 mg P (0.016 μmol) per kg body weight per day. The compound was thus about 2, 10, 50, and 500 times more potent than risedronate, alendronate, pamidronate, and clodronate, respectively. Intravenous administration was as effective as subcutaneous, and oral administration was 100 times less effective. The effect after one administration decreased with time but was still measurable after 2 weeks. Nonstimulated bone resorption assayed by the urinary excretion of radiolabeled tetracycline from lifelong prelabeled animals was also inhibited. This effect started 3 days after a single dose and was still maximal after 7 days. Histomorphometric analysis of the tibial metaphysis in growing intact rats also showed an inhibition of bone resorption along with an increase in bone mass. The number of osteoclasts increased in animals treated with 0.01 and 0.1 mg P per kg (0.16 and 1.6 μmol/kg) body weight SC but decreased in animals given 1 mg P per kg (16.1 μmol/kg), showing that the inhibition of bone resorption was not due to an inhibition of osteoclast recruitment. No inhibition of mineralization occurred. This new bisphosphonate appears to have great potential for use in human bone disease.
Effect of caffeine on parameters of osteoblast growth and differentiation of a mineralized extracellular matrix in vitro
Authors: Tassinari Melissa S. , Gerstenfeld Louis C. , Stein Gary S. , Dr. Lian Jane B. 
Published: February 2010

Abstract
The effects of caffeine exposure on bone formation were examined using a chick osteoblast culture system. Secondary cultures of normal diploid osteoblasts were exposed to chronic doses of 0, 0.1, 0.2, or 0.4 mM caffeine beginning on day 0 through day 28. Neither the rate of cell proliferation nor cell number, as measured by total DNA, was decreased for any of the doses examined. In contrast, osteocalcin levels, alkaline phosphatase activity, and total calcium levels showed a dose-related decrease in cultures treated with caffeine. These parameters were significantly decreased at the highest dose of 0.4 mM. The reduction in total protein levels ranged rom 29 to 66% of control values and was independent of dose. In contrast, total collagen levels were more affected by the dose of caffeine used. Inhibition of collagen levels was most apparent on days 17 and 21, time points during the period of active formation of the matrix immediately preceding the deposition of mineral. By day 28 collagen levels in cultures exposed to the lower doses of caffeine had returned to control levels, and only the cultures exposed to the highest dose (0.4 mM) remained significantly inhibited with respect to both collagen and mineral. Histochemically, alkaline phosphatase and mineral staining of day 28 cultures mirrored the biochemical events with the 0.4 mM caffeine exposure. The results indicate that one of the effects of caffeine on bone development is to inhibit the formation of a competent extracellular matrix during the osteoblast differentiation sequence, which results in the inhibition of mineralization analogous to the delayed ossification observed in fetal animals after prenatal caffeine exposure.
Polyarginine, polylysine, and protamine mimic the effects of high extracellular calcium concentrations on dispersed bovine parathyroid cells
Authors: Brown Edward M. , Katz Craig , Butters Robert , Kifor Olga 
Published: February 2010

Abstract
We investigated the effects of the basic peptides polyarginine, protamine, and polylysine on dispersed bovine parathyroid cells. All three peptides produced a dose-dependent inhibition of dopamine-stimulated cAMP accumulation, with half-maximal inhibition at 4 × 10−8, 1.5 × 10−7, 3 × 10−7, and 2 × 10−6 M, respectively, for polyarginine, protamine, and two preparations of polylysine of molecular weights 10,200 and 3800. The inhibition of cAMP accumulation was reversible and was blocked by preincubating the cells overnight with 0.5 μg/ml of pertussis toxin. The same peptides also inhibited PTH release at similar concentrations, markedly stimulated the accumulation of inositol phosphates at two- to threefold higher concentrations, and produced transient increases in the cytosolic Ca2+ concentration (Cai) in fura-2-loaded parathyroid cells. The polylysine-evoked spike in Cai persisted despite the removal of extracellular Ca2+, indicating that it arose from intracellular Ca2+ stores. Exposure of the cells to elevated extracellular magnesium (Mg2+) concentrations elicited a similar spike in Cai but blocked the Cai transient in response to subsequent addition of polylysine, or vice versa. Thus, Mg2+ and polylysine mobilize Ca2+ from the same intracellular store(s). These results indicate that highly basic peptides closely mimic the effects of polyvalent cations on parathyroid function, suggesting that both agents may regulate parathyroid function via similar biochemical pathways.
Effect of 1,25-dihydroxyvitamin D3 on prostaglandin E2 production in cultured mouse parietal bones
Authors: Klein-Nulend Jenneke , Pilbeam Carol C. , Dr. Raisz Lawrence G. 
Published: February 2010

Abstract
1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] was tested for its effects on prostaglandin E2 (PGE2) production and bone resorption in cultured mouse parietal bones. We found that at 24 h 1,25-(OH)2D3 increased 45Ca release but did not affect PGE2 production. However, at 48 h 1,25-(OH)2D3 produced a dose-related increase in PGE2 production. PGE2 production was increased with 1,25-(OH)2D3 at 10−10-10−8 M, and 45Ca release was increased with 1,25-(OH)2D3 at 10−11-10−8 M. The effects of 1,25-(OH)2D3 on PGE2 production persisted in the presence of cortisol (10−8 M), and the effects were greater in the presence of arachidonic acid (10−5 M) or fetal bovine serum (10%). Human interleukin-1α (IL-1, 1 ng/ml) and bovine parathyroid hormone-(1–34) (PTH, 10 ng/ml) increased PGE2 production earlier and to a greater extent than 1,25-(OH)2D3. The PGE2 response to IL-1 and PTH was not affected by 1,25-(OH)2D3 at 24 h, but at 48 h 1,25-(OH)2D3 (10−8 M) increased the PGE2 response to both IL-1 and PTH. The stimulation of 45Ca release at 48 h by high concentrations of 1,25-(OH)2D3, PTH, or IL-1 was similar, and there was no evidence for an additive effect. To test for an effect of 1,25-(OH)2D3 on endogenous IL-1 production, experiments were performed in the presence of an IL-1 receptor antagonist (IL-1Ra, 1000 ng/ml), which has been found to block selectively IL-1 effects on bone resorption and PG production. We found that IL-1Ra blocked the stimulatory effect of 1,25-(OH)2D3 (10−8 M) on PGE2 production but not on 45Ca release. We conclude that 1,25-(OH)2D3 at high concentrations is a stimulator of PGE2 release from bone and can enhance the response to PTH and IL-1. Its effect is smaller and occurs later than that of PTH and IL-1. The effect of 1,25-(OH)2D3 on PGE2 production could be mediated by endogenous IL-1.
No evidence for an effect of lactase deficiency on bone mass in pre- or postmenopausal women
Authors: Dr. Slemenda Charles W. , Christian Joe C. , Hui Siu , Fitzgerald Joseph , Johnston Conrad C. 
Published: February 2010

Abstract
The potential role for lactase deficiency in the development of low bone mass was examined in 342 adult female twins. Diminished lactase activity, defined as greater than 20 ppm increase in expired hydrogen at 2 or 2.5 h after an oral lactose load, was examined: (1) by comparing bone mass between members of twin pairs discordant for lactase activity; (2) by examining the linear association between bone mass and total expired hydrogen gas; and (3) by comparing all lactase-deficient individuals to those with persistent lactase activity. Among members of discordant (primarily DZ) pairs, the lactase-deficient member had greater bone mass 54% of the time. The correlations between the increase in expired hydrogen and bone mass at various sites were between −0.02 (femoral neck) and 0.11 (midshaft radius), suggesting no association between these variables. Finally, all lactase-deficient subjects were compared with those with normal lactase activity, regardless of twin status, and at each skeletal site the differences in bone mass were 1% or less. Thus, all primary hypotheses were not supported by these data; that is, in this large sample we could find no evidence of a detrimental effect of lactase deficiency on adult bone mass. However, baseline expired hydrogen was consistently and positively associated with bone mass at all sites, independently of age, suggesting the possibility that some aspect of intestinal function related to the activity of bacterial anaerobes may be positively associated with bone mass.
Bone morphogenetic protein-2b stimulation of growth and osteogenic phenotypes in rat osteoblast-like cells: Comparison with TGF-β1
Authors: Chen Theresa L. , Bates Rebecca L. , Dudley Andrew , Hammonds Glenn R. , Amento Edward P. 
Published: February 2010

Abstract
The biologic effects of recombinant human bone morphogenetic protein-2b (BMP-2b = BMP-4) were studied and compared with transforming growth factor-β1 (TGF-β1) in fetal rat osteoblast-like (ROB) cells. Similar to the effects of TGF-β1, BMP-2b stimulated DNA and collagen synthesis as well as protein accumulation. Unlike TGF-β1, which inhibited alkaline phosphatase activity, BMP-2b enhanced enzyme activity eight-to ninefold over the control level. The present study demonstrates direct actions of BMP-2b on bone-associated cells to stimulate osteogenic phenotypes in vitro and provides a cellular mechanism for the induction of bone formation by BMP-2b in vivo.
Journal of Bone and Mineral Research
Authors: Nussbaum Samuel R. , Potts John T. 
Published: February 2010

Abstract
The two most frequent causes for hypercalcemia are primary hyperparathyroidism and hypercalcemia associated with malignancy. Elevated or inappropriately high PTH serum levels are the hallmark of hyperparathyroidism. Sensitive immunometric assays for the secreted, biologically active, intact parathyroid hormone molecule, PTH-(l-84), employ two populations of region-specific antibodies, take advantage of saturation kinetics rather than competitive binding, and have many technical advantages over conventional radioimmunoassay. Approximately 90% of patients with primary hyperparathyroidism have elevated serum levels of PTH-(l-84) by immunometric assay; the remainder have inappropriately elevated values of PTH for the serum calcium concentration. Clinical correlation studies comparing measurements of PTH using antisera that recognize the carboxyl, midregion, or amino terminus of PTH with PTH levels determined by immunometric assays demonstrate elevated values in equivalent numbers of hyperparathyroid individuals. Immunometric assays for PTH-O-84) have their greatest value in separating patients with hyperparathyroidism from those with hypercalcemia of malignancy. In earlier studies using region-specific antisera, there was virtually always an overlap of serum PTH levels in hyperparathyroidism and hypercalcemia associated with malignancy. In contrast, analysis of results using PTH-(l-84) immunometric assays in several hundred reported patients shows a complete separation of PTH values. Clinical judgment, combined with measurement of PTH in the setting of hypercalcemia, can lead to the diagnosis of hyperparathyroidism with confidence in essentially all patients.
Journal of Bone and Mineral Research
Authors: Marcus Robert 
Published: February 2010

Abstract
One of the common dilemmas in clinical endocrine practice is the management of patients with hyperparathyroidism (HPT) who either cannot or will not undertake definitive surgical treatment. Therapeutic decisions would be simplified by the availability of a nonsurgical approach to control biochemical abnormalities and forestall the consequences of this condition. In the short term, oral phosphorus salts can be safe and effective. For chronic therapy, only estrogens and progestins have been examined in sufficient detail to merit discussion. Estrogens normalize serum and urinary calcium in the majority of older women with HPT. Biochemical control is generally maintained for as long as patients continue treatment. The data support the view that estrogen inhibits the actions of PTH, particularly on bone, but does not reduce the abnormal PTH secretion. Androgenic progestins may also lower serum and urinary calcium in HPT, but current data suggest that normalization of serum calcium levels is more likely to occur with estrogen. Although reduction in urinary calcium excretion should prove effective in preventing nephrolithiasis, it is unclear whether hormone therapy provides protection against fracture. Whether or not hormone replacement is prescribed, nonsurgical management requires a highly committed patient who is willing to undergo extensive and prolonged follow-up.
The osteocalcin propeptide is not secreted in vivo or in vitro
Authors: Gundberg Caren M. , Clough Mary E. 
Published: February 2010

Abstract
Osteocalcin is initially synthesized as an 11 kD molecule consisting of a 23-residue translocation signal peptide that is cleaved during translation, a 26-residue propeptide that targets the protein for gamma-carboxylation, and the 49-residue mature protein. Although the majority of newly synthesized osteocalcin is deposited into bone matrix, a small amount can be detected in blood, and it is this characteristic that has led to its current clinical use as a specific index of osteoblastic activity. Nothing is known, however, about the fate of the propeptide. If osteocalcin and the propeptide are cosecreted, then the concentration of the propeptide could also be useful as a marker of osteoblastic function and, further, may be superior to osteocalcin because it would be unaffected by binding to bone. To test this hypothesis, we synthesized a peptide corresponding to 21 residues of the osteocalcin propeptide from humans and produced a polyclonal antibody to this peptide. Human sera were screened for the presence of the propeptide, and the human osteosarcoma cell line MG-63 was tested for secretion of the propeptide. We could not detect any osteocalcin propeptide in sera from normal adults or individuals with renal failure or primary hyperparathyroidism or those on long-term coumadin therapy. Likewise there was no propeptide present in media from cells grown in the presence of vitamin K, l,25-(OH)2D3, warfarin, or warfarin plus 1,25-(OH)2D3. In contrast, the cell extract, characterized by high-performance liquid chromatography, contained mature osteocalcin, free propeptide, and the proosteocalcin precursor when cells were grown in the presence of 1,25-(OH)2D3 alone. When warfarin was added to the culture, only proosteocalcin precursor was detected in the cell extract. These data establish that the osteocalcin propeptide is not secreted in vitro or in vivo and verify that carboxylation is not required for the conversion of the precursor to osteocalcin.
Transforming growth factor β1 stimulates type II collagen expression in cultured periosteum-derived cells
Authors: Izumi Toshihiro , Scully Sean P. , Heydemann Ahlke , Bolander Mark E. 
Published: February 2010

Abstract
Chondrogenesis can occur during a bone repair process, which is related to several growth factors. Transforming growth factor β1, (TGF-β1,) downregulates the expression of type II collagen by chondrocytes in vitro, but injection of TGF-β1, into the periosteum in vivo increases type II collagen mRNA levels and initiates chondrogenesis.(1) We examined the effect of TGF-β1, on collagen gene expression in a bovine periosteum-derived cell culture system to evaluate its direct effect on the periosteum. Cultured cells expressed alkaline phosphatase and collagen proα1,(I) and proα1(II) mRNAs. A low level of type II collagen synthesis was demonstrated by immunoprecipitation. TGF-β1, had no effect on periosteal cell proliferation. Expression of collagen proα1(I) mRNA did not change with TGF-β1, treatment, but alkaline phosphatase mRNA showed a dose-dependent decrease. Expression of collagen proα1(II) mRNA was stimulated 2.7-fold by TGF-β1. TGF-β1, also caused a 2.6-fold increase in type II collagen synthesis by immunoprecipitation. These findings indicate that TGF-β1 is an enhancer of the expression of the chondrocyte phenotype of the periosteal cells and suggest that TGF-β1, is important in initiating and promoting cartilage formation in vivo.
Comparison of bone mineral content among Japanese, Koreans, and Taiwanese assessed by dual-photon absorptiometry
Authors: Sugimoto Toshitsugu , Tsutsumi Masaharu , Fujii Yoshio , Kawakatsu Mitsuru , Negishi Hirokuni , Lee Myung Chull , Tsai Keh-Sung , Fukase Masaaki , Fujita Takuo 
Published: February 2010

Abstract
Throughout the world the diagnosis and management of osteoporosis currently involves the measurement of bone mineral content. There are, however, no studies comparing bone mineral content among Asian people. This cross-sectional study was designed to quantify spine and femur bone mineral density (BMD) in Japanese and compare BMD among Asian people (Japanese, Koreans, and Taiwanese) using the same model dual-photon system (Norland Model 2600). Following a peak BMD in the third and fourth decades, the Japanese BMD values of the lumbar spine and femoral neck showed a clear decrease (annual loss of 0.99 and 0.74%, respectively) with age in females. On the other hand, Japanese BMD values were stable in males until the fifth decade. There was some decrease in BMD with age after the fifth decade, which was much less obvious than that in females. An age-dependent loss of BMD was clearly observed in Japanese and Korean but not in Taiwanese females. Korean males seemed to have a clearer age-dependent loss of BMD compared to Japanese males. Our findings indicate that differences may exist in the BMD of Asian people and that in addition to the quantitative determination of individual BMD, dual-photon absorptiometry may be useful for the comparison of BMD among different ethnic and cultural groups.
Defective bone formation by hyp mouse bone cells transplanted into normal mice: Evidence in favor of an intrinsic osteoblast defect
Authors: Ecarot Brigitte , Glorieux F.H. , Desbarats M. , Travers R. , Labelle L. 
Published: February 2010

Abstract
The hypophosphatemic (Hyp) mouse is an animal model for human hypophosphatemic vitamin D-resistant rickets. We have reported that bone cells isolated from Hyp mice born to homozygous mutant females produce abnormal bone when transplanted into normal mice. To test whether an environmentally acquired defect of the mutant cells contributed to the impaired bone formation observed in transplants, periostea and osteoblasts from normal and Hyp littermates were transplanted intramuscularly into normal animals. To test more specifically for an hypophosphatemia-induced cell alteration before transplantation, bone cells isolated from phosphate-depleted normal mice were transplanted into normal animals. The bone nodules formed in 2 week transplants were characterized by measuring their osteoid thickness and volume. Impaired bone formation was evidenced in Hyp transplants compared to normal littermate transplants by increased osteoid thickness and volume. In contrast to cells from mutant mice, cells isolated from normal mice with comparable hypophosphatemia produced normal bone. These results indicate that the inability of Hyp osteoblasts to produce normal bone when placed in a normal environment is not the consequence of prior exposure to an altered environment but likely of an intrinsic cellular abnormality. These observations add further support to the concept that the osteoblast is an important target for the Hyp mutation.
Physicochemical action of potassium-magnesium citrate in nephrolithiasis
Authors: Dr. Pak Charles Y. C. , Koenig Karl , Khan Rubina , Haynes Sharon , Padalino Paulette 
Published: February 2010

Abstract
Effect of potassium-magnesium citrate on urinary biochemistry and crystallization of stone-forming salts was compared with that of potassium citrate at same dose of potassium in five normal subjects and five patients with calcium nephrolithiasis. Compared to the placebo phase, urinary pH rose significantly from 6.06 ± 0.27 to 6.48 ± 0.36 (mean ± SD, p &lt; 0.0167) during treatment with potassium citrate (50 mEq/day for 7 days) and to 6.68 ± 0.31 during therapy with potassium-magnesium citrate (containing 49 mEq K, 24.5 mEq Mg, and 73.5 mEq citrate per day). Urinary pH was significantly higher during potassium-magnesium citrate than during potassium citrate therapy. Thus, the amount of undissociated uric acid declined from 118 ± 61 mg/day during the placebo plase to 68 ± 54 mg/day during potassium citrate treatment and, more prominently, to 41 ± 46 mg/day during potassium-magnesium citrate therapy. Urinary magnesium rose significantly from 102 ± 25 to 146 ± 37 mg/day during potassium-magnesium citrate therapy but not during potassium citrate therapy. Urinary citrate rose more prominently during potassium-magnesium citrate therapy (to 1027 ± 478 mg/day from 638 ± 252 mg/day) than during potassium citrate treatment (to 932 ± 297 mg/day). Consequently, urinary saturation (activity product) of calcium oxalate declined significantly (from 1.49 × 10−8 to 1.03 × 10−8 M2) during potassium-magnesium citrate therapy and marginally (to 1.14 × 10−8 M2) during potassium citrate therapy. Moreover, the formation product of calcium phosphate (brushite), indicative of inhibition against spontaneous nucleation, rose more prominently during potassium-magnesium citrate treatment (from 4.62 × 10−7 to 8.78 × 10−7 M2) than during potassium citrate therapy (to 6.08 × 10−7 M2). The inhibition against agglomeration of calcium oxalate increased marginally (p = 0.02) during potassium-magnesium citrate therapy, whereas it did not change significantly during potassium citrate treatment. Thus, potassium-magnesium citrate (at same dose of potassium) is more effective than potassium citrate in inhibiting the crystallization of uric acid and calcium oxalate in urine.
Bisphosphonate Space Measurement in Paget's Disease of Bone Treated with APD
Authors: Stone M. D. , Marshall D. H. , Hosking D. J. , Perkins A. C. , Evans A. J. , Wastie M. L. 
Published: February 2010

Abstract
The bisphosphonate space (BPS) is a quantitative measurement of skeletal uptake of 99mTc-HMDP. We measured BPS in 36 patients with Paget's disease of bone, both before and 6 months after treatment with intravenous APD (disodium pamidronate) infusions. BPS fell after treatment, but proportionally less than serum alkaline phosphatase (ALP) and fasting urinary hydroxyproline/creatinine (HYPRO). There was no dose-response relationship between the dose of APD given and the percentage reduction in ALP and HYPRO at 6 months. Log dose of APD/pretreatment BPS, however, predicted the percentage reduction in ALP and HYPRO very well, and from the respective regression equations it was possible to predict the dose of APD needed to achieve normal values of ALP and HYPRO. In the 10 patients who achieved a normal ALP and 9 patients a normal HYPRO after more than 6 months treatment with APD (range 7–18 months), the predicted dose of APD agreed closely with the actual dose. In conclusion, our data support the idea that log dose APD/pretreatment BPS is a valid predictor of biochemical response in Paget's disease.