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This study provided data relevant to three major goals. It confirmed that both COLLOSS and COLLOSS E contain osteo- and chondro-inductive BMPs as shown by their ability to produce new bone in an ectopic location in rats. Second, based on the area of bone produced in standardized implant sections by osteoinductive growth factors in GFm, COLLOSS , and COLLOSS E and their respective collagenous carrier matrices, the study showed that COLLOSS was 0.1, and COLLOSS E 0.3 time as potent as 10 microg of GFm. Finally, the study showed that ordinary and accelerated endochondral bone formation were more frequent in response to GFm than to COLLOSS and COLLOSS E, whereas membranous bone formation was more frequent in response to COLLOSS E than to COLLOSS or GFm.

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Synovial cysts occur throughout the body and are generally benign lesions with limited clinical consequences. Juxtafacet cysts of the spine, in contrast, often press on a nerve root as it exits in the foramen, causing radiculopathy. Synovial tissue that emanates from the facet joint but extends medially, is an additional important cause of spinal stenosis. Over the past 5 years, neurosurgeons at our institution have operated on a large number of patients with back pain, with removal of abnormal synovial tissues. Histological examination of these tissues distinguishes the different types of pathologic processes responsible for producing symptoms. Juxtafacet cysts may be either mucin-filled ganglion cysts devoid of cyst lining or true synovial cysts with watery content and lined by synovial cells. Ganglion cysts arise in degenerated ligament at the facet joint, and occasionally within synovial stroma. Synovial cysts arise within synovium and, unlike synovial cysts in the extremities, have a thick wall containing granulation tissue, numerous histiocytes and giant cells. This hyperplastic, irritated synovium of the spine, which we term "synovial excrescences", is voluminous and this reactive part overshadows the cystic portion of the lesion in most instances. Iron pigment deposition and inflammation are mild to absent, making synovial excrescences different from pigmented villonodular synovitis. Synovial excrescences of the spine are an important cause of spinal stenosis, predominantly in elderly patients. Surgical removal of excrescences protruding into the spinal canal provides prompt and durable relief of symptoms, usually without the need for extensive bony laminectomy or spinal fusion. Several patients in our study had both spinal ganglion cysts and synovial excrescences, suggesting common risk factors for both lesions.

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Cholesterol granulomas (CGs) are tumor-like lesions seldom encountered by neuropathologists. CGs develop in reaction to localized hemorrhage, often occurring in bony sites with possible impaired drainage of blood and blood products. The most common bony location is the petrous apex, although orbital, frontal sinus, and maxillary sinus sites have been reported. We compare and contrast three recent cases seen at our institution that illustrate the spectrum of clinical, radiographic, and pathologic features that can be seen with these mass lesions. One case demonstrated the unique pathological features of Gamma-Gandy body formation, epithelioid histiocytes heavily encrusted with iron pigments, and extensive tophi. The latter most likely represented aggregates of calcium pyrophosphate crystals associated with extensive iron deposition.

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This article describes preliminary in vivo studies evaluating the osteogeneic potential of bone morphogenetic proteins (BMPs) delivered from an absorbable puttylike polymer matrix. In the first study, bovine-derived bone morphogenetic proteins were incorporated in an polymer matrix consisting of 50:50 poly(DL-lactide-co-glycolide) dissolved in N-methyl-2-pyrrolidone. The matrix was implanted in an 8 mm critical-size calvarial defect created in the skull of adult Sprague-Dawley rats (n = 5 per treatment group). After 28 days, the implant sites were removed and examined for new bone formation, polymer degradation, and tissue reaction. Gamma-irradiated polymer matrices appeared to give more bone formation than nonirradiated samples (histological analysis; 2. 76 + 1.34 mm(2) of bone versus 1.30 + 0.90 mm(2) of bone, respectively and x-ray analysis; 27.2 + 15.9 mm(2) of bone versus 20. 7 + 16.7 mm(2) of bone, respectively) and less residual polymer (0.0 + 0.0 versus 0.2 + 0.4, respectively). The polymer implants with bone morphogenetic protein also gave less inflammatory response than the polymer controls (gamma irradiated polymer/BMP = 1.8 + 0.4 and nonirradiated polymer/BMP = 1.2 + 0.4 versus polymer only = 3.0 + 1. 2, respectively). However, despite trends in both the x-ray and histological data there was no statistical difference in the amount of new bone formed among the four treatment groups (P > 0.05). This was most likely due to the large variance in the data scatter and the small number of animals per group. In the second animal study, bovine-derived BMPs and the polymeric carrier were gamma irradiated separately, at doses of 1.5 or 2.5 Mrad, and their ability to form bone in a rat skull onlay model was evaluated using Sprague-Dawley rats (n = 5 per treatment group). Histomorphometry of skull caps harvested 28 days after implantation showed no significant differences as compared to non-irradiated samples, in implant area, new bone area, and percent new bone (P > 0.05). These results suggest gamma irradiation may be useful in sterilization of the bovine-derived BMPs and the polymeric carrier for potential bone repair and/or regeneration applications.

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Down Syndrome (DS) is the most common of the chromosomal disorders and manifests abnormalities in several organ systems. While mental retardation, skull and brain anomalies, and the development of Alzheimer-type neuropathological changes in patients greater than age 40 years are well recognized by neurologists and neuropathologists, less appreciated are the various cervical spine abnormalities that can occur. Widening of the anterior atlanto-odontoid distance (AAOD) and atlantooccipital instability occur in up to 21% and 63% of DS patients, respectively, but neurologic complaints are uncommon and rarely are severe enough to contribute to the patient's demise. We present a case of 49-year-old DS patient whose triplegia, subacute progressive respiratory failure, and death could be attributed to severe degenerative joint disease of the cervical spine with osteophyte formation and severe spinal canal stenosis. We provide the first detailed correlation study between pre-mortem magnetic resonance imaging (MRI) and extensive autoptic dissection in an adult DS patient with cervical spine abnormalities, as well as a review of the literature.

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During embryonic development, cartilage formation involves the condensation of mesenchymal stem cells and a series of maturation steps that ultimately results in the mineralized hypertrophic chondrocyte. The embryonic, murine, mesenchymal stem cell line, C3H/10T1/2, is pluripotent; exposure to azacytidine or to bone morphogenetic protein-2 or -4 results in low rates of differentiation to three mesengenic lineages. In contrast to previous studies, we report conditions for 10T1/2 differentiation specifically to the cartilage lineage and at high yields. These conditions include high cell density micromass cultures, a purified mixture of osteoinductive-proteins (BP; Intermedics Orthopedics, Denver, CO), a serum substitute, 50 micrograms/ml ascorbic acid, and 10 mM beta-glycerophosphate. The cartilagenous fate was confirmed by 1) histological detection of sulfated proteoglycans, 2) electron microscopic detection of proteoglycan and rounded cells separated by extracellular matrix containing short, disorganized collagen fibrils, 3) morphological detection of chondrocytes surrounded by a territorial matrix and encompassed within a distinct perichondrium, and 4) immunocytochemical detection of type II collagen and link protein. After 4 weeks in culture, mature although unmineralized cartilage was observed, as indicated by hypertrophic morphology, immunocytochemical detection of osteocalcin, and histological detection of lacunae. These conditions promote overt chondrogenesis for most of the treated cells and preclude lineage determination to the fat, muscle, and bone lineage, as assayed by electron microscopy and histomorphology. The faithful recapitulation of cartilage differentiation that we have established in vitro provides a versatile alternative to the use of chondrocyte and limb bud explant cultures. We propose this as a model system to study the factors that regulate commitment to the chondrogenic lineage, exclusion to related mesengenic pathways, and maturation during chondrogenesis.

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OBJECTIVES: To investigate the histological features of bone, the turnover status of bone remodeling in postmenopausal women with osteopenia. To observe the influence of age on the changes of bone turnover. METHODS: Two hundred ninety three bone biopsies were obtained from posterior iliac crests of postmenopausal white women with osteopenia after taking fluorescence-labelled tetracyclin. All these specimens were embedded in methacrylate, the nondecalcified sections were stained routinely and measured by computerized histomorphometry. RESULTS: The mean trabecular bone volume was 10.6% +/- 5.47%, which is 29.3% less than the low limit of normal range (15%) established in our laboratory. There were 186 cases (63.5%) in normal turnover status, 75 cases (25.6%) in high turnover, and 32 cases (10.9%) in low turnover. In comparison with the normal turnover group, the osteoclast number, corrected bone mineralization rate and bone formation rate were elevated and mineralization lag time was reduced in the high turnover group (P < 0.01). In contrary, all the above parameters in the low turnover group were on the opposite (P < 0.05-0.01). Comparison of three age groups (51-60, 61-70, > 70 years) showed that the bone volume and osteoid volume decreased as the age increased. The proportion of high and low turnover types began to increase in the 51-60 age group, peaked in the 61-70 age group and dropped to nadir in the > 70 age group. CONCLUSIONS: Bone histomorphometry examination is not only valuable in distinguishing osteoporosis from osteomalacia, but also beneficial for determination of the bone turnover status and, therefore, is useful for the direction of clinical treatment in patients with postmenopausal osteopenia.

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OBJECTIVE: To compare the efficacy of butyl-2-cyanoacrylate tissue glue (TG) for the repair of skin lacerations in rats with the efficacy of standard closure with sutures. METHODS: In a prospective study, eight rats were anesthetized and an 8-cm dorsal incision was made on each side of the midline. One wound was closed with a single layer of interrupted 5-0 Prolene suture and one by application of TG. The time required to close each wound was recorded. Sutures were removed at seven days; the TG was allowed to fall off spontaneously. The animals were sacrificed after 20 days and the wounds were judged for cosmetic outcome. Four I x 3-cm strips of skin were excised from each wound; one strip for histologic analysis and three for load extension testing using a tensiometer. Specimens were loaded to wound failure while displacement (D) and energy absorption (EA) were recorded. The paired t-test was used for comparisons and reported as mean +/- SE. No significant difference between TG and suture was found in D (6.5 +/- 0.4 vs 5.2 (1.4 mm), EA (0.18 +/- 0.01 vs 0.17 +/- 0.03 kg x mm/cm2), or histologic features. The closure time was significantly less using TG (66 +/- 5 vs 401 +/- 17 sec; p < 0.0001). CONCLUSIONS: 1) Sutures and TG in rat skin repair result in similar wound strengths (EA), amounts of stretch (D), and histologic feasures. 2) Wound closure is accomplished much more rapidly with TG.

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STUDY DESIGN: This study is a prospective histomorphometric evaluation of human spinal fusion bone using video dimensional analysis. OBJECTIVES: Little information exists regarding the biology of fusion mass (FM) and the effect that instrumentation has on FM quality. Concerns regarding potential for "stress shielding" of FM with rigid implants have arisen. The goal of this study was to determine what effect spinal implants have on the quality and metabolism of FM bone. METHODS: Fifty-six patients underwent surgeries to remove spinal implants or extend a fusion after pulse-dose labeling with fluorochrome. Twelve patients had undergone fusions without instrumentation. Duplicate biopsies of FM and iliac crest (IC) were obtained and evaluated blindly for mineralized volume, trabecular thickness, mineralization rate, and bone formation rate. Iliac crest, instrumented FM, and noninstrumented FM were compared. RESULTS: Instrumental FM had superior material properties relative to noninstrumented FM or IC. No significant difference in metabolic activity was present. CONCLUSION: Instrumentation does not lead to FM "stress-shielding."

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The aims of this study were twofold: (1) to evaluate the ability of pathologists to recognize infiltration of bone marrow core biopsy specimens by breast carcinoma, particularly lobular carcinoma, using routine hematoxylin-eosin (HE) sections; and (2) if indicated, to determine the reasons for difficulties in diagnosis. Thirty-six bone cores obtained before bone marrow harvest were involved by breast carcinoma and were confirmed by pancytokeratin immunostains. Thirty of the 36 were ductal carcinomas and six were lobular carcinomas. Fourteen negative bone core biopsy specimens (from patients with breast cancer or lymphoma) were included as controls. These 50 bone cores were reviewed by three surgical pathologists. Lobular carcinoma was correctly identified in only 39% of positive specimens as compared with 88% for ductal carcinoma. After instruction, sensitivity for the detection of lobular carcinoma improved to 61% but at the expense of an unacceptably high rate of false-positive diagnoses (18%). None of the three pathologists was able to achieve both high sensitivity and high specificity in recognizing lobular carcinoma in the bone marrow. Lobular carcinoma was difficult to detect because of tumor cell size similar to hematopoietic cells, infiltration as single cells, presence of bland cytological features, and paucity of tissue reaction to the tumor. Although the number of cases of bone marrow involved by lobular carcinoma is small, these findings suggest that pancytokeratin stains should be performed routinely in the evaluation of bone core biopsy specimens from patients with lobular carcinoma, and probably from patients with ductal carcinoma whose HE-stained bone core biopsy specimens are considered negative for tumor.

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The purpose of this study was to examine bone histomorphometry before and after 2 yr of a double blind trial of etidronate to determine whether etidronate was associated with the development of osteomalacia and to clarify the mechanism of action. Sixty-eight postmenopausal women with vertebral compression fractures from 3 clinical centers received 1 g phosphate or placebo twice daily on days 1-3, 400 mg etidronate or placebo daily on days 4-17, and 0.5 g calcium daily on days 18-91. This cycle was given eight times. Iliac crest bone was biopsied after tetracycline labeling. None of the patients developed osteomalacia. The placebo/placebo group lost significantly more bone volume than the other groups. The change in mineralizing surface was significantly different among groups due to the decrease in the placebo/etidronate group. Within groups, placebo/placebo showed a decrease in bone volume without other changes. Phosphate/placebo showed no changes. Placebo/etidronate showed decreases in osteoid volume, osteoid surface, mineralizing surface, bone formation rate, and activation frequency. The only change in phosphate/etidronate was a decrease in osteoid surface. We conclude that 2-yr treatment with cyclical etidronate does not cause osteomalacia and that the mechanism for the increased bone mass is probably a decreased activation frequency.

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OBJECTIVE: To ascertain the effects of low-dose methotrexate (MTX) on bone metabolism and histomorphometry in rats. METHODS: Female Sprague-Dawley rats (6 months old, n = 42) were divided into the following 4 groups: intraperitoneal (IP) injections of MTX, with and without ovariectomy, and IP saline (controls), with and without ovariectomy. Injections were given for 16 weeks. The MTX dose was equivalent to a standard dose for rheumatoid arthritis in humans that would yield similar serum MTX levels (0.6 +/- 0.1 mumoles). RESULTS: Bone formation (assessed by serum alkaline phosphatase and osteocalcin levels and histomorphometry) was significantly lower in the MTX groups, and bone resorption (assessed by urinary hydroxyproline levels and histomorphometry) was increased in the MTX groups. Bone mass was significantly diminished in the MTX groups. CONCLUSION: Prolonged administration of low-dose MTX in rats causes significant osteopenia via suppression of osteoblast activity and stimulation of osteoclast recruitment, which results in increased bone resorption.

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Semiautomated methods are used to measure elongated, curved and complex branching profiles and isolated perimeter segments in monochrome video images with a general-purpose analysis system. These methods are used to make the major primary measurements of bone histomorphometry. Accuracy and reproducibility of the image acquisition, processing and measurement system is documented by measuring a semicircular standard of known dimensions. Semiautomated applications of the Ar/Le method for measuring areas and perimeters, and calculating lengths and widths of osteoid seams, lengths of mineralization labels and mineral apposition rate, wall width, indirect measurements of eroded, osteoclastic and osteoblastic perimeters without tracing, and measurement of mineralized or total cancellous bone area and perimeter gave values comparable to measurements of the same parameters by tracing or grid counting techniques with equal or better reproducibility and much greater efficiency. Intraindividual variation in measuring multiple bone biopsies methods. Major sources of variability for semi-automated methods were image magnification and selection of profile edges by thresholding, and sources of variability for manual methods are image magnification, numbers of orthogonal intercepts, tracing speed and accuracy of the algorithm used to measure traced pixels. Semiautomated methods are accurate, reproducible and rapid methods suitable for bone histomorphometry.

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Al-treated or untreated decalcified sections of bone matrix were implanted subcutaneously into the abdominal wall of parathyroidectomized (PTX) or control rats for 21 or 28 days. The bone remodeling and Al, Ca content in the implants were measured by using histomorphometry and atomic absorption spectrum method. The results showed that bone area, osteoclast number, osteoblast number and bone mineralization rate of Al-treated or untreated bone in PTX rats and of Al-treated bone in control rats were significantly lower than those of untreated bone in control rats (P < 0.05). There was no marked difference between these parameters of Al-treated bone in control rats and untreated bone in PTX rats (P > 0.05), and these of Al-treated bone in PTX rats were the lowest (P > 0.05- < 0.05). Ca contents were consistent with the histological parameters. Bone Al removing rate between PTX and control rats was not markedly different. In conclusion, both PTX and Al impair bone formation and mineralization, bone biopsy and removal of Al from bone is necessary before PTX treatment in uremic patients with secondary hyperparathyroidism.

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Bone biopsy was performed in 429 cases of uremic bone disease and they were classified histologically into 3 groups--high turnover 129 (30%), low turnover 102 (24%) and mixed type 198 (46%) cases. The histological features of the high turnover type were increased corrected mineralization rate (CMR) and osteoclast member and decreased mineralization lay time (MLT), while those of the low turnover type were on the contrary. In the mixed there were decrease of CMR and increase of MLT and osteoclast number. Bone aluminum positive rate was determined; it was 75% and 80% respectively in the low turnover and mixed type and 29% in high turnover. Biochemical study showed that significantly higher levels of serum PTH and alkaline phosphate in the high turnover type and low levels of serum 1,25(OH)2D3 and 25(OH)D3 in the low turnover. These results suggested that high turnover uremic bone disease is caused by secondary hyperthyroidism and low turnover mainly related to aluminum toxicity or other causes such as vitamin D deficiency.

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Orthogonal intercepts from random test lines (OIr), uniformly distributed intercepts (OIu), and areas and lengths (Ar/Le) were measured manually and by computer to determine individual profile and sample widths of artificial profiles and human osteoid seams. Individual widths were equal by Ar/Le and OIu methods. The means of individual profile widths (all methods), of all orthogonal intercepts (OIu and OIr), or of profile widths weighted in proportion to their lengths (Ar/Le) were also equal. Ar/Le and OIu had smaller variance than OIr. Discrepant individual OIu and Ar/Le widths in digitized images were corrected by thresholding and did not significantly affect sample means. Unweighted Ar/Le sample means were 15-44% lower than weighted means. Distributions of osteoid seam widths were not normal, and all but one had more than one mode. We conclude that the Ar/Le method is comparable to direct orthogonal intercept methods and suitable for automated histomorphometry.

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The effect of aluminum on the bone inductive properties of implanted bone matrix was studied in rats. After decalcification femur sections were placed in either 0.1 or 0.01 M AlCl3 or a solution of similar pH without Al for 24 hours. Following 28 days of implantation in subcutaneous pouches the aluminum content was 3232 +/- 1020 and 51 +/- 6 mg/kg in the matrix pretreated with 0.1 and 0.01 M AlCl3. At the same time period following implantation the matrix calcium content was 794 +/- 539 and 3038 +/- 692 mmol/kg in the 0.1 and 0.01 M AlCl3 pretreated groups versus 4252 +/- 579 mmol/kg in the control group (P less than 0.01). In the control group bone histology showed extensive osteoblastic and osteoclastic remodeling, tetracycline labeling and bone formation. In contrast all of these histological features were virtually absent in aluminum treated matrix. Aluminum-induced resistance of bone matrix to collagenase degradation and restoration of bone inductive properties with chelation suggests that aluminum forms intermolecular cross links between collagen fibrils. Aluminum-induced cross links of collagen fibrils and/or its effects on bone inductive proteins present in bone matrix could explain the mechanism by which aluminum induces osteomalacia.

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