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PubMed2004

From bone biology to bone analysis.

Bone development is one of the key processes characterizing childhood and adolescence. Understanding this process is not only important for physicians treating pediatric bone disorders, but also for clinicians and researchers dealing with postmenopausal and senile osteoporosis. Bone densitometry has great potential to enhance our understanding of bone development. The usefulness of densitometry in children and adolescents would be increased if the physiological mechanisms and structural features of bone were given more consideration in the design and interpretation of densitometric studies. This review gives an overview on the most relevant techniques of quantitative noninvasive bone analysis. Furthermore it describes the relationship between bone biology, selected surrogates describing the biological processes and the possibilities of measuring these surrogates specifically and precisely by the different devices. The overall recommendation for researchers in this field is to describe firstly the biological process to be analyzed (bone growth in length, remodeling or modeling, or all together), secondly the bone parameter which describes this process, and thirdly the reason for selecting a special device.

Absorptiometry, Photon↗
PubMed1994

[Immunocytochemical detection of tumor cells in bone marrow as a prognostic factor in breast carcinoma].

In a prospective study at the University of Erlangen, Dept. Gynaecol, and Obstet., 228 patients with breast cancer during their primary surgery and 20 patients during their metastatic surgery, underwent bone marrow punctions at six punction sides, which were twice at the sternum and twice at both iliac crest. The control group was 20 patients without an invasive carcinoma. Aim of the study was to detect or exclude tumour cells in the bone marrow via examination of the biopsies with monoclonal antibodies EMA and cytokeratin and consequently to find out the meaning of the results as prognostic criteria by statistical measurements. Tumour cells in the bone marrow were detected in 46.5% (106/228) of the patients, who underwent a bone marrow biopsy during primary surgery. 21% (23/106) of the patients who were bone marrow positive, but only 5.75% (7/122) of the patients, who were bone marrow negative, developed metastases during a median follow-up of 20 months. This difference is statistically significant. 17 of the 30 patients with recurrences developed bone metastases; 16 of them were EMA-positive. The median recurrence-free interval was 5 months in the bone marrow positive group and therefore noticeably shorter, than in the bone marrow negative patient group with 11 months. Of the nodal negative patients, 2 bone marrow positive patients developed distant metastases. With the knowledge of the nodal status and bone marrow biopsy result, it was possible to predict 28 of the 30 patients correctly in respect of their risk to metastasize. The result of the bone marrow puncture was proved in a multivariate analysis to be an independent prognostic factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers, Tumor↗
PubMed1985

Fusion disability of embryonic osteoclast precursor cells and macrophages in the microphthalmic osteopetrotic mouse.

Osteoclast formation in the microphthalmic osteopetrotic (mi) mouse was studied from very early embryonic to newborn stages. Embryonic and fetal milmi osteoclasts, generated during the period before bone marrow is formed in the long bones, were predominantly mononuclear and lacked ruffled borders. These cells did, however, show many osteoclastic morphologic and functional properties, such as an abundance of mitochondria, positive succinic dehydrogenase and acid phosphatase reactions, and close contact with and resorption of the calcified cartilage matrix (though diminished). These osteoclastic mononuclear cells appeared in vivo as well as in organ cultures of fetal metatarsal bones with their intact periostea. They also were observed in cocultures of periosteum-free fetal metatarsal bones, with several extraneous sources of osteoclast precursors: yolk sacs and abdominal regions of 9- and 11-day-old embryos, fetal livers, and precultured mononuclear phagocytes isolated from the fetal liver. In contrast, +/+ osteoclasts were always multinuclear, functioned normally in resorbing the calcified cartilage matrix, and had ruffled borders in vivo as well as when derived from the above-mentioned sources. Fetal liver-derived milmi macrophages also failed to form multinuclear foreign body giant cells as opposed to +/+ macrophages in granulomas on implanted pieces of Melinex. The fusion failure of cells derived from embryonic and fetal extramedullary milmi monocyte/macrophage sources contrasted with the occurrence of multinuclear osteoclasts and foreign body giant cells derived from precursors from the bone marrow in young milmi mice. We conclude that the fusion defect of milmi osteoclast precursor cells is already present in their ancestry in blood cell-forming organs of very young embryos and that these cells differentiate into mononuclear osteoclasts that function inefficiently in prenatal bone. We presume that in fully developed bone marrow, local factors are favorable for abolishing the fusion defect.

Animals↗
PubMed1993

The role of the vitamin D endocrine system in avian bone biology.

The involvement of vitamin D and its endocrine system is essential, both for the process of bone development and growth, as well as bone remodeling. Important bone cells participating in those processes include the osteoblast (bone formation), the osteoclast (bone resorption) and the growth plate chondrocyte (longitudinal bone growth). The hormonally active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], generates many of the biological responses attributed to the parent vitamin D3, including actions on osteoblasts and chondrocytes and the stimulation of the production of osteoclasts. 1,25(OH)2D3 is able to generate biological responses via both genomic and nongenomic pathways. This review provides a summary of this area.

Animals↗
PubMed1989

A composite fixation principle for modular segmental defect replacement (SDR) prostheses.

A composite fixation concept for porous-coated modular segmental bone and joint replacement prostheses was developed. Bone cement will provide immediate intramedullary stem stability, whereas autogenous bone grafts are applied over the porous-coated segmental shoulder region to achieve extracortical bone bridging and ingrowth for long-term biologic fixation. Bench tests, theoretical analyses, and animal experiments were performed to validate such a concept. Preliminary clinical trials have demonstrated extraordinary results as well as several limiting factors. Additional effort is required to perfect this innovative concept for prosthetic implant fixation.

Animals↗
PubMed1998

Development of bone morphogenetic protein receptors in the nervous system and possible roles in regulating trkC expression.

Characterization of bone morphogenetic protein receptor (BMPR) expression during development is necessary for understanding the role of these factors during neural maturation. In this study, in situ hybridization analyses demonstrate that BMP-specific type I (BMPR-IA and BMPR-IB) and type II (BMPR-II) receptor mRNAs are expressed at significant levels in multiple regions of the CNS, cranial ganglia, and peripheral sensory and autonomic ganglia during the embryonic and neonatal periods. All three BMP receptor subunits are expressed within periventricular generative zones. BMPR-IA is more abundant than the other receptor subtypes, with widespread expression in the brain, cranial ganglia, and peripheral ganglia. By contrast, BMPR-IB mRNA displays significant expression within more restricted regions, including the anterior olfactory nuclei. BMPR-II mRNA exhibits peak expression within the cerebellar Purkinje cell layer and the hippocampus, as well as within cranial ganglia. The distribution of BMP receptors within large neurons in adult dorsal root ganglia suggested a possible role in regulating expression of the neurotrophin receptor trkC. This hypothesis was tested in explant cultures of embryonic day 15 (E15) and postnatal day 1 (P1) sympathetic superior cervical ganglia (SCG). Treatment of the E15 or the P1 SCG with BMP-2 induced expression of trkC mRNA and responsiveness of sympathetic neurons to NT3 as measured by neurite outgrowth. The pattern of expression of BMP receptors in embryonic brain suggests several potentially novel areas for further developmental analysis and supports numerous recent studies that indicate that BMPs have a broad range of cellular functions during neural development and in adult life.

Animals↗
PubMed1998

Development of bone marrow erythroblastic islands in hypoxic rats with intact or damaged kidney tubules.

Keeping in mind the renal origin of erythropoietin (EPO), we designed our study in order to estimate the role of kidney damage in the development of bone marrow erythropoiesis in erythroblastic islands (EI). The experiment was performed comparing intact rats with untreated and gentamicin-pretreated rats (50 mg/kg/15 days) exposed to hypobaric pressure (42.55 kPa/6 h) to stimulate hypoxia. Blood samples were taken following a 2-week period. The study included an estimation of plasma EPO levels by RIA, the number of peripheral blood parameters and bone marrow EI (classes I to V/femur), the rate of erythroid differentiation into erythroblasts, and the rate of repeated participation of macrophages in new EI reconstruction. Plasma EPO increased to 52.88 mU/ml (p < 0.01) and 23.45 mU/ml at 0 h immediately following hypobaric exposure in untreated and gentamicin-treated rats, respectively, as compared to 14.25 mU/ml in intact animals. Bone marrow recovery patterns were markedly expressed in untreated hypoxic animals throughout the observed period. The rate of erythroid differentiation into erythroblasts in EI was increased (p < 0.01) while the number of maturing EI decreased (p < 0.01); increased reconstruction was observed in involuted EI. Less pronounced stimulation of erythropoiesis was observed in hypoxic gentamicin-treated rats. The direct impact of the hypoxic stimulus on the erythropoietic bone marrow tissue was considered significant for the erythropoietic response via activation of macrophages. These data support the hypothesis that EI central macrophages play an important role as local regulators of bone marrow erythropoiesis.

Animals↗
PubMed1993

Polymerase chain reaction analysis of parathyroid hormone-related protein gene expression in breast cancer patients and occurrence of bone metastases.

Parathyroid hormone-related protein (PTHrP) is associated with the syndrome of humoral hypercalcemia of malignancy. A high incidence of positive staining for PTHrP is observed in breast cancer and positivity is more frequent in patients who develop bone metastases. We assessed the presence of PTHrP mRNA by using the polymerase chain reaction in 38 normocalcemic breast cancer patients with long-term follow-up (minimum, 5 years) selected for the presence or absence of later bone metastasis development. In all the patients except one, the PTHrP gene was expressed in the breast tumor. The level of amplified PTHrP complementary DNA was inversely related to age (P < 0.02) and positively related to the proportion of invaded nodes (P < 0.02) but was not related to the other usual prognostic factors. The level of PTHrP mRNA was not different between the group of patients without recurrence or metastases (n = 11) and the group of patients who later developed metastases in soft tissues (n = 10). By contrast, patients who subsequently developed bone metastases (n = 17) showed higher PTHrP gene expression than patients in the other two groups (P < 0.001). This study suggests that strong PTHrP gene expression in breast tumors is associated with the onset of bone metastases.

Adult↗
PubMed1975

Periosteal new bone formation developing during haemodialysis for chronic renal failure.

Periosteal new bone formation in the pelvis is reported in five patients on maintenance haemodialysis for chronic renal failure. In two of the cases the shafts of long bones were also involved. The associated radiological and biochemical findings suggest that this unusual radiological feature may be a manifestation of secondary hyperparathyroidism. In one patient in whom the plasma phosphate and calcium X phosphate [Ca X P1] product were reduced there was partial incorporation of the periosteal new bone into the underlying cortex.

Adolescent↗
PubMed1985

Immunolocalization of gamma-carboxyglutamic acid containing proteins in developing rat bones.

The localization of a gamma-carboxyglutamic acid (Gla)-containing protein, BGP (also called osteocalcin) was examined in developing calvaria, alveolar bones and long bones of newborn rats by immunostaining with the peroxidase-antiperoxidase method. In undemineralized tissues osteoblasts of intramembranous bones stained positive; osteoid was negative, whereas young mineralized bone stained weakly. After a mild demineralization all bones stained positive; no staining was found in cartilage, muscles or soft connective tissues. In addition to the osteoblasts, osteocytes were also immunoreactive. Osteoclasts, identified by a subsequent staining for acid phosphatase activity, demonstrated no immunostaining for BGP. These data support the hypothesis that BGP is synthesized by osteoblasts and osteocytes and is subsequently deposited in the mineralizing bone.

1-Carboxyglutamic Acid↗
PubMedDate not supplied

Development of an animal model for prostate cancer cell metastasis to adult human bone.

BACKGROUND: Prostate cancer metastases to bone are associated with significant morbidity and mortality. Presently, there is little known about the biological interaction between prostate cancer cells and bone. Development of an animal model using adult human bone will enhance our ability to study the biology of prostate cancer metastasis to bone. METHODS: Bone was harvested from patients undergoing total joint arthroplasty and implanted in the hindlimbs of pre-treated SCID mice. Two months after bone implantation 4 x 104 prostate cancer cells (PC-3 or LAPC-4) were injected near the bone implantation site. The animals were sacrificed approximately 8 to 12 weeks after the injections of the cells. Complete histological analysis including immunostaining was performed. RESULTS: Both the PC-3 and LAPC-4 prostate cancer cells homed to the human bone implant, specifically the reconstituted bone marrow cavity. Analysis of the bone-tumor interaction after injection of PC-3 cells revealed strong labeling for PTHrP, TNF alpha and IL-6, consistent with osteoclast recruitment and osteoclast activity. These cells also were positively stained for CK18. After cellular injection of LAPC-4 cells, there was strong labeling for TNF alpha, IL-6, and IL-1 (osteoclast recruitment and osteolytic activity). PTHrP staining was also noted. The bone cells were strongly stained for osteocalcin, and the tumor cells for PSA. CONCLUSIONS: These data suggest that the tumor cells may induce an osteolytic response to enhance their ability to metastasize to bone. This animal model allows us to study the biologic interaction between prostate cancer cells and human bone and may enhance our understanding of the events associated with prostate cancer metastasis to bone.

Adenocarcinoma↗
PubMed2006

Regional differences in architecture and mineralization of developing mandibular bone.

The goal of this study was to investigate the mutual relationship between architecture and mineralization during early development of the pig mandible. These factors are considered to define the balance between the requirements for bone growth on the one hand and for load bearing on the other. Architecture and mineralization were examined using micro-CT, whereas the mineral composition was assessed spectrophotometrically in groups of fetal and newborn pigs. The development of the condyle coincided with a reorganization of bone elements without an increase in bone volume fraction, but with an increase in mineralization and a change in mineral composition. In the corpus, the bone volume fraction and mineralization increased simultaneously with a restructuring of the bone elements and a change in mineral composition. The growth of the condyle was reflected by regional differences in architecture and mineralization. The anterior and inferior regions were characterized by a more dense bone structure and a higher mineralization as compared to posterior and superior regions, respectively. In the corpus, growth was mainly indicated by differences between buccal and lingual plates as well as between anterior, middle, and posterior regions characterized by a more compact structure and higher mineralization in the lingual and middle regions. In conclusion, the architecture and mineralization in the condyle and corpus started to deviate early during development toward their destiny as trabecular and cortical bone, respectively. These results were compatible with those obtained with mineral composition analysis. Regional differences within condyle and corpus reflected known developmental growth directions.

Animals↗
PubMed2002

Stimulation of osteoclastic bone resorption in a model of glycerol-induced acute renal failure: evidence for a parathyroid hormone-independent mechanism.

This study was undertaken to evaluate the bone changes occurring in rats with acute renal failure (ARF). Acute renal failure was induced in rats 24 hours after dehydration by an intramuscular injection of glycerol. After induction of ARF, the rats were divided into two groups, one of which underwent parathyroidectomy (PTX). Rats with normal renal function, matched for age and weight, were used as controls and divided into two groups, one of them for PTX. At termination of the study blood and urine chemistry and bone histomorphometry were analyzed. Rats with glycerol-induced ARF developed bone changes compatible with mild hyperparathyroid bone disease, characterized mainly by increased osteoclastic bone resorption when compared with control rats having normal renal function. Rats with normal renal function following PTX developed bone disease showing complete suppression of forming and resorptive parameters. Rats with glycerol-induced ARF and PTX showed abolishment of all bone forming parameters, but a dramatic increase in osteoclastic resorption was apparent. Based on these observations we suggest that, in this model of glycerol-induced ARF, osteoclastic bone resorption may develop in the absence of parathyroid hormone, probably stimulated by other potent osteoclastogenic factors.

Acute Kidney Injury↗
PubMed1978

Induction of hemopoiesis in rat embryonic bone transplanted into adult subcutaneous connective tissue.

Five pairs of immature, non-hemopoietic femur and tibia from 17-day-old gestating female rat fetuses, whose sex was determined by chromosomal analysis of liver cells, were transplanted into subcutaneous tissues of adult male rats. The original bones were about 3 mm in length and they grew to about 17 mm length at 4 wereks after transplantation. Bone deformation was not evident after transplantation and bone marrow hemopoiesis developed. Bone marrow cytohistologic observations were made on smears, and chromosome analyses were performed on bone marrow cells. Active erythro-, myelo- and megakaryopoiesis were conducted by cells of recipient adult rats. Sex chromosome analysis of cartilage cells from the epiphyses of transplanted bones demonstrated that the growing bones were composed of cells from the grafted embryo. The results thus strongly suggest that the transition of hemopoiesis from liver to bone marrow in late embryonic development is conducted by stem cells migrating through circulating blood and settling in the bone marrow and not by in situ cells differentiating in the bone marrow stroma.

Animals↗
PubMed1992

Skeletal development and bone functional adaptation.

The role of in vivo mechanical loading histories in normal skeletogenesis is related to the process of adaptive, stress-regulated bone remodeling in the adult. The results of many previous computer models for endochondral ossification and bone modeling and remodeling are reviewed. These studies support the view that simple stress-related mathematical algorithms or "construction rules" can be used to emulate normal skeletal development and architectural construction. Such mathematical rules presumably represent the net result of biophysical phenomena influencing cell metabolism and biosynthetic activity. These rules are also successful in describing the adaptation of adult bone to changes in tissue stresses. The findings suggest that stress-related functional adaptation in mature bones may be merely the adult manifestation of the same mechanical construction rules that guide and constrain normal development.

Adaptation, Physiological↗
PubMed2003

Increased rate of brain metastasis with trastuzumab therapy not associated with impaired survival.

Trastuzumab is important for treatment of metastatic breast cancer patients with tumors that overexpress HER2/neu, but its penetration to the brain is poor. The aims of this study are to determine the prevalence of bone and brain metastasis during therapy, to compare the survival of breast cancer patients with brain metastasis who received trastuzumab to those patients not receiving trastuzumab, and to assess the impact of brain metastasis on the overall survival of trastuzumab patients. Of 103 patients treated with trastuzumab, 16 had brain metastasis and 43 had bone metastasis at the beginning of trastuzumab. The control group consisted of 196 patients with metastatic breast cancer who had never received trastuzumab. Six had brain metastasis and 75 had bone metastasis at the beginning of therapy. During therapy, only 9 of 60 trastuzumab patients (15%) developed bone metastasis, while 170 of 186 control patients (91%; c2 = 129.8, P < 0.0001) developed bone metastasis. In addition, 22 of 87 trastuzumab patients (25%) and 58 of 190 control patients (31%) subsequently developed brain metastasis. Control patients without brain metastasis experienced significantly better survival (median survival = 928 days) than those with brain metastasis (median survival = 639 days, c2 = 8.34, P < 0.005). There was no difference in survival for trastuzumab-treated patients if they acquired brain metastasis (median survival = 1400 days) or no brain metastasis (median survival > 2000 days, c2 = 0.12, P > 0.05). Patients receiving trastuzumab were unlikely to develop new bone metastasis but were as likely as control patients to develop brain metastasis. However, patients who developed brain metastasis experienced better survival compared with those patients with brain metastasis who never received trastuzumab.

Adult↗