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Pubertal bone growth in the femoral neck is predominantly characterized by increased bone size and not by increased bone density--a 4-year longitudinal study.

Fragility fractures are correlated to reduced bone size and/or reduced volumetric bone density (vBMD). These region-specific deficits may originate from reduced mineral accrual and/or reduced skeletal growth during the first 2 decades of life. Before pathological development can be defined, normal skeletal growth must be described. To evaluate growth of bone size, accrual of bone mineral content (BMC), areal bone mineral density (aBMD) and vBMD in a population-based cohort, 44 boys and 42 girls were followed by annual measurements from the age of 12 to 16 (attendance rates 90-100%). Segmental bone length, bone width, BMC, aBMD and vBMD were measured by dual-energy X-ray absorptiometry (DXA). Data were compared with predicted adult peak, as determined in 36 men aged 27.7+/-4.6 years and 44 women aged 26.8+/-4.9 years. Growth in width of the femoral neck precedes accrual of BMC in the femoral neck in both genders up to age 15. The girls were at all ages closer to their predicted adult peak in both bone width and BMC compared with the boys except in the femoral neck. As femoral neck vBMD had reached its predicted adult peak already at 12 years in both genders, the increase in femoral neck BMC and femoral neck aBMD from age 12 to 16 was most likely to be explained by the increase in bone size. In boys the peak velocity growth was recorded at ~14 years for BMC, height, width and lean mass. Growth from the age of 12 to 16 seems to build a bigger but not a denser skeleton in the femoral neck.

Adolescent↗

Methotrexate maintains bone mass by preventing both a decrease in bone formation and an increase in bone resorption in adjuvant-induced arthritic rats.

We examined the effects of low doses methotrexate (MTX) and indomethacin (IND) on bone mass and turnover in normal male Sprague-Dawley rats and those with adjuvant-induced arthritis. Normal and the adjuvant (heat-killed mycobacterium)-injected rats, 6 weeks of age, were given MTX at daily doses of 0.05, 0.1, or 0.2 mg/kg body weight (BW) or IND at a daily dose of 1.0 mg/kg BW. Rats were killed at the start, or at 14 and 28 days. In normal rats, the administration of these agents did not change the lumbar and femoral BMD values, nor did the serum osteocalcin or urinary deoxypyridinoline (D-Pyr) levels. Lumbar trabecular osteoclast number (Oc.N/BS) and osteoclast surface (Oc.S/BS) were decreased in the rats given IND. In the arthritic rats, the administration of MTX did not prevent an early increase of paw edema in the adjuvant-injected limb, but late inflammatory edema was alleviated in the non-injected limb. However, MTX administration at a dose of 0.1-0.2 mg/kg BW maintained an age-dependent increase in the lumbar and femoral BMD values. While serum osteocalcin levels were decreased and urinary D-Pyr values were increased in the arthritic control rats, these bone markers remained at the levels of the normal rats. Decreases in mineral apposition rate (MAR) and bone formation rate (BFR/BS) and increases in the trabecular Oc.N/BS and Oc.S/BS values were prevented by MTX. While IND almost completely prevented inflammatory paw edema, it did not improve the parameters of bone formation. An increase in osteoclasts was prevented and the osteopenia in the lumbar and the femoral bone was only partially prevented by IND. These data suggest that MTX improves bone mass and turnover in the arthritic rat, in which several cytokines that affect bone cells are involved. An increase in bone resorption may be due to prostaglandins, but bone formation defect was suggested to be due to other cytokines such as IL-1, IL-6, and TNF-alpha in this model.

Animals↗

Bone induction and bone repair by composites of bone morphogenetic protein and biodegradable synthetic polymers.

We developed adequate delivery systems for bone morphogenetic protein (BMP) to express its bone-inducing activity by combining it with biodegradable synthetic polymers, these causing no unfavorable tissue reaction or anti-BMP effect. Their efficacy was tested for ectopic bone formation in mice and reconstruction of large segmental bone defects of the tibiae in rabbits. Composites of semipurified BMP and polylactic acid--polyethylene glycol block copolymer (PLA-PEG), and composites of BMP, PLA-PEG and lactic acid--glycolic acid copolymer (PLGA) were implanted under the fasciae of the dorsal muscles of mice. Three weeks after implantation, both the BMP/PLA-PEG and BMP/PLA-PEG/PLGA composites were completely absorbed and replaced by newly induced bone with hematopoietic marrow. Because the BMP/PLA-PEG composite is a viscous semiliquid and the BMP/PLA-PEG/PLGA composite is a plastic and moldable, the former can be used as an injectable bone-inducing material and the latter as a plastic mold. The BMP/PLA-PEG/PLGA composites were implanted in large segmental bone defects in the tibiae in rabbits. Twelve weeks after implantation, the bone defect was completely restored by a newly formed bone mass of the original thickness and structure.

Animals↗

Bone marrow plays a role in bone metabolism: histomorphometry of iliac bone in postmenopausal women.

We conducted a histomorphometrical study on the role of the bone marrow in cancellous bone metabolism using iliac bone specimens from 79 postmenopausal women. A gradual decrease in hematopoietic tissue of the bone marrow was proportionate to the decrease in cancellous bone and the ratio of osteoid perimeter/bone perimeter regardless of age. On the other hand, the ratio of eroded perimeter/bone perimeter remained almost steady until hematopoietic tissue decreased significantly. These findings suggest that a change in the bone marrow, that is, a decrease in hematopoietic tissue, causes an imbalance in bone formation and resorption and leads to bone loss.

Aged↗

In vivo bone-forming capacity of human bone marrow-derived stromal cells is stimulated by recombinant human bone morphogenetic protein-2.

In the present study, we investigated whether the in vivo bone-forming capacity of human bone marrow-derived stromal cells (HMSCs) could be enhanced by recombinant human bone morphogenetic protein-2 (rhBMP-2). The HMSCs obtained from seven donors (5-54 years of age) were passaged three to six times. Passaged HMSCs exhibited the osteoblastic phenotype in vitro, including: (a) an increase in alkaline phosphatase (ALP) activity in response to dexamethasone, ascorbic acid, and beta-glycerophosphate: and (b) mRNA expression for markers of osteoblastic lineage (ALP, osteopontin, osteocalcin, and parathyroid hormone-receptor) and BMP-2, -4, and -6 detected by reverse transcription-polymerase chain reaction. For the in vivo assay, transplants were subcutaneously implanted into nude mice as follows: group A (vehicle); group B (rhBMP-2); group C (HMSCs with vehicle); and group D (HMSCs with rhBMP-2). Transplants were obtained 2 and 4 weeks after implantation. Correlated radiographic findings, histological observations, and in situ hybridization using species-specific probes showed that the group B transplants contained bone tissue of mouse origin, which was observed at the periphery of the transplants. Four weeks after implantation, small amounts of HMSCs-derived bone tissue were detected at the periphery in two of seven transplants in group C. In contrast, five of seven group D transplants exhibited HMSCs-derived bone tissue, which was located at the center of the transplants and was surrounded by mouse bone tissue. Furthermore, HMSCs-derived chondrogenesis was detected in two of seven group D transplants. The results of the present study demonstrate that culture-expanded HMSCs preserve the osteoblastic phenotype, and the in vivo bone-forming capacity can be promoted by rhBMP-2.

Adolescent↗

The influence of screw omission on construction stiffness and bone surface strain in the application of bone plates to cadaveric bone.

Biological fracture repair is becoming an increasingly popular means of fracture fixation. This technique involves a reduction in the amount of surgical trauma thereby preserving vascular supply and soft-tissue integrity combined with the implantation of less hardware. The aim is the stimulation of callus formation as the means by which fracture union occurs. This paper describes the mechanical effect of the symmetrical omission of screws on construction stiffness and bone surface strain following the application of bone plates to cadaveric bone. The influence of the pattern of screw omission was evaluated in both intact and osteotomized bone specimens. The application of bone plates using certain patterns of screw omission did not significantly effect the stiffness of the final construction whilst inherent bone surface strain was increased. It was concluded that the omission of screws in certain defined patterns for a given plate-bone construction may meet the criteria for 'biological fixation'. There was no apparent deleterious effect on structural stiffness following the omission of 40% of the total screw complement from a plate-bone construction.

Animals↗

Bone mineral density and bone metabolism in children treated for bone sarcomas.

In adolescent bone sarcoma patients, bone mass acquisition is potentially compromised at a time in which it should be at a maximum. To evaluate the problem we measured bone mineral density (BMD) and serum markers of bone formation and resorption in a series of pediatric patients with bone tumors. BMD was measured by dual-energy x-ray absorptiometry, at clinical remission, for lumbar spine and the neck of the femur in 38 osteosarcoma and 25 Ewing's sarcoma patients. Mean age was 20.65 and 19.13 y respectively. Serum markers of bone metabolism were: OC, PICP, ICTP, 25-OH vit D and 1,25-(OH)(2) vit D, IGF-I, IGFBP-3 and intact PTH. Serum was sampled throughout anti-tumoral treatments and follow-up. We analyzed 85 samples from 59 osteosarcoma patients and 54 samples from 36 Ewing's sarcoma patients. Patients had decreased lumbar and femoral BMD. The decrease was more pronounced in pubertal patients compared with those who had completed pubertal development at the time of disease diagnosis. Multivariate analysis indicated that sex, age, weight and BMI were significant in lumbar BMD depletion. Weight and BMI were significant in femoral BMD depletion. Serum markers of bone formation (PICP and OC) and resorption (ICTP) were, throughout, lower than reference values. Significant alterations in other markers were also observed. Up to a third of osteosarcoma and Ewing's sarcoma patients in clinical remission had some degree of BMD deficit. The corresponding increased risk of pathologic bone fractures constitutes a reduction in future quality of life.

Adolescent↗

Changes of bone metabolic markers in patients with bone metastases: clinical significance in assessing bone response to chemotherapy.

To determine the changes in bone metabolism in response to combined chemotherapy in patients with bone metastases (BM), we examined osteocalcin (BGP), alkaline-phosphatase (ALP), hydroxyproline (HYP), pyridinoline (PYR), and/or deoxypyridinoline (D-PYR) in 25 cancer patients. In patients without BM, serum BGP was normal and not affected by chemotherapy. In patients with BM, however, BGP was often abnormally high or low, and some patients reacted to chemotherapy with a BGP increase at 4 weeks after initiation of therapy. Such an increase was observed in the group of patients who responded favorably to therapy as judged by a decrease in bone pain and tumor-associated biochemical markers. Urine HYP, PYR, and D-PYR were high in patients with BM before therapy; D-PYR decreased transiently at 2 weeks and increased thereafter. We assume that increased bone-resorption markers along with increased bone formation markers after therapy would indicate recovery of coupled bone metabolism, as the deranged bone remodeling is improved by tumor-regression. This study suggests that BGP and D-PYR can be useful early markers to predict favorable bone response to chemotherapy in patients with BM.

Adult↗

Utilization of type I collagen gel, demineralized bone matrix, and bone morphogenetic protein-2 to enhance autologous bone lumbar spinal fusion.

Autologous bone grafts are currently considered "gold standard" material for achieving long-term spinal arthrodesis. The present study was performed to determine whether demineralized bone matrix (DBM), type I collagen gels, or bone morphogenetic protein-2 (BMP-2) can improve autologous bone spinal fusions. Using a unilateral decompression-contralateral fusion technique in dogs, each of these materials was added to an autologous bone graft. Volumetric analysis, histological analysis, and biomechanical testing were performed to assess the effectiveness of each material. The DBM had an inhibitory effect on solid bone fusion of the spine, whereas the type I collagen gels improved the bony interface between the graft and the host spine. The BMP-2 strongly enhanced the amount of bone deposition at the fusion site and increased the number of intervertebral levels that were solidly fused. This study strongly supports the use of BMP-2 as an additive to autologous bone grafts in spine stabilization.

Animals↗

Bovine bone activin enhances bone morphogenetic protein-induced ectopic bone formation.

A 25-kDa homodimeric protein was purified from demineralized bovine bone extract and identified as activin A. The bovine bone activin enhanced formation of ectopic bone in rat subcutis when implanted in combination with partially purified bovine bone morphogenetic protein (BMP-2, BMP-3) in collagen/ceramic carrier. The implants, removed at 14 days, contained markedly elevated levels of alkaline phosphatase activity. Histological examination revealed an extensive formation of woven bone with very little cartilage. In contrast, a combination of transforming growth factor-beta 2 and BMP promoted formation of bone with an abundance of cartilage. The implants with BMP alone exhibited some osteoinductive activity, while the implants with activin alone showed no activity. These results demonstrate that bone is a rich source of activin and that activin plays an important role in modulating bone formation.

Activins↗

Bone lesions following renal transplantation. Bone mineral density and amount of trabecular bone.

24 renal transplanted patients who developed post-transplant bone complications (aseptic necrosis of bone of spontaneous fractures) were studied and compared with a control material of age- and sexmatched renal transplanted (RT) patients. The bone mineral concentration in the forearm, histomorphometric measurements of iliac crest biopsies, and the parathyroid function were investigated. A significant reduction in the bone mineral concentration was found in the group of RT patients with bone complications compared to RT patients without. The amount of cancellous bone in the bone biopsies was reduced in patients with aseptic necrosis of bone. No significant differences in the biochemical values were found.

Adult↗

[Quantitative whole-body bone scintigraphy. III. Clinical significance for the diagnosis of bone metastases, systemic bone diseases and diseases of the joint (author's transl)].

Quantitative whole-body bone scans were performed on 277 patients with bone metastases, diseases of the joint and systemic bone diseases in order to evaluate the clinical significance of quantitative and kinetic data in bone imaging. Metastases and other focal bone diseases are recognizable and quantifiable by the method; however, sensitivity and specificity of bone imaging are not enhanced. In metabolic bone diseases, with the exception of osteoporosis, kinetic data facilitate the analysis of bone scans. Typical signs of osteomalacia, hyperparathyroidism and renal osteodystrophy--increased retention of the activity in the skeleton and increased bone/soft tissue ratios as well as a generally changed distribution of radioactivity--are only recognizable by quantitative imaging.

Adolescent↗

Remodeling of large bone defects in the treatment of space-occupying lesions. Curettage without bone graft for treating benign bone tumors.

Curettage without bone graft was performed in 17 patients with benign bone tumors and tumor-like lesions. New bone formation with uniformly increased radiodensity appeared in serial plain radiographs within 3 months after the operation. The average period before full weight could be borne on the lower extremities was 14 weeks. Computed tomography revealed that the central part of the bone lesions persisted without bone formation. The thickening of cortical bone was predominant. These data indicate that enough mechanical strength for daily activity will be recovered by bone within 4 months after curettage without any filler, although remodeling continues for over a year. It is suggested that bone graft and implantation of "biomaterials" are not necessary in patients, especially younger ones, with benign bone tumors or tumorous conditions.

Adolescent↗

Estimation of bone mineral density and bone loss by means of bone metabolic markers in postmenopausal women.

We have examined healthy women (51 premenopausal women and 30 postmenopausal women; age 28-59) for lumbar bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) and assessed metabolic bone markers, such as type I procollagen carboxy-terminal propeptide (P1CP), pyridinoline (PYR), deoxypyridinoline (DPYR), osteocalcin (BGP) and alkaline phosphatase (ALP). BMD was assessed once a year in three consecutive years. Correlations among the BMD, BMD changes and levels of bone markers in samples at the first DXA assessment were studied. In pre-menopausal women, none of the biochemical markers were correlated with the BMD or changes in BMD. In contrast, BMD in post-menopausal women correlated (negatively) well with levels of P1CP, DPYR, PYR and ALP declining in this order, and a significant positive correlation was observed between the rate of bone loss in postmenopausal women and the P1CP concentration. PYR and DPYR also had a tendency to correlate. Combinations of several bone markers improved the correlation. These results show that by measuring several bone specific biochemical markers in postmenopausal women, one can estimate their rates of bone loss as well as their present BMDs. The measurement of biochemical bone markers will therefore be very useful in evaluating bone status and would be applicable in screening postmenopausal osteopenia.

Adult↗

[Effect of beta-TCP containing the bone-growth promoting compound, TAK-778, on the vertex bone of rat--change of volmetric bone formation corresponding to the containing volume of TAK-778].

PURPOSE: This study was conducted to histomorphologically determine the quantity of bone formation induced by TAK-778, a 3-benzothiepin derivative, (Takeda Pharmaceutical Co.Ltd.), in various amounts, using b-tricalcium phosphate granules (beta-TCP; OLYMPUS Corp.) as a carrier for the osteogenetic agent. METHODS: Ten-week-old female SD rats were used. An incision was made over the parietal region of the head. The cranial periosteum was ablated and a titanium tube was fixed with an adhesive resin cement to the central part of the head, through which a mixture of TAK-778 and beta-TCP was implanted under various conditions. Tissue specimens were prepared at 4, 8, and 16 weeks after the implantation for histomorphological examination, and the proportion of new bone formation was compared at fixed time points using the NIH imaging software. The amount of new bone formation was examined every week after the implantation of TAK-778 at various doses, and the mean values were compared using Fisher's PSLD test (P< 0.05). RESULTS: The histomorphological observations revealed new bone formation in all the groups, irrespective of the amount and the duration of implantation of TAK-778. A comparative study revealed that the amount of new bone formation was the largest at 16 weeks following the implantation of a mixture of beta-TCP and 100 mg of TAK-778. CONCLUSIONS: 1. The present study confirmed the acceleration of new bone formation soon after TAK-778 implantation. 2. The results suggested that the action of TAK-778 could be maintained over time if the agent was used in combination with beta-TCP. 3. The time-course of bone formation differed depending on the proportion of TAK-778 and beta-TCP in the mixture used. 4. TAK-778 at the dose of 10 mg or 50 mg was more effective than that at the dose of 100 mg for the early formation of new bone. These results indicate that TAK-778 accelerates the formation of new bone and that beta-TCP is a useful carrier for TAK-778.

Animals↗

Dog bone less osteogenetic than rat bone. Bone-matrix transplants in nude rats.

Demineralized bone matrix and bone-matrix gelatin prepared from cortical rat bone, and from cortical and cancellous canine bone were implanted into muscle pouches of nude rats for 6 weeks. Evaluation was done by histology, histomorphometry, and determination of alkaline phosphatase. Rat matrix consistently induced new bone and high phosphatase levels. Canine matrix induced but small amounts of bone and lower phosphatase levels, with cortical matrix somewhat more inductive than cancellous matrix; demineralized cancellous bone matrix from the dog was the only material tested not showing any inductivity. Irrespective of bone type or species, gelatin had clearly higher induction capacity than demineralized bone matrix.

Alkaline Phosphatase↗

Content of bone morphogenetic protein-4 in human demineralized bone: relationship to donor age and ability to induce new bone formation.

BACKGROUND: Bone morphogenetic proteins (BMPs) are also called growth and differentiation factors (GDFs) and form a subfamily of related proteins within the TGF-beta superfamily. BMP-4 is one ofmultifuntional growth factors with pleiotropic roles in many different cell types and is predominantly present in human bone tissue. OBJECTIVES: To analyze the content of extractable BMP-4 in human demineralized bone as a function of age. MATERIAL AND METHOD: Bone samples were ground and demineralized by exposure to 0.5 N HCl and then extracted by collagenase digestion. Extractable BMP-4 was analyzed using a commercially available enzyme-linked immunosorbent assay (ELISA). RESULTS: 63 samples of demineralized bone matrix (DBM) derived from 36 men and 27 women between the ages of 15-65 years. The extractable BMP-4 content appears to be age-dependent, with DBM from younger donors being most likely to have higher BMP-4 quantity. In addition, DBM with high osteoinductivity contained greater amounts of extractable BMP-4 than DBM samples with low osteoinductivity. CONCLUSION: The BMP-4 in demineralized bone undergoes age-related decrease that may contribute to the reduction of bone volume observed with aging.

Adolescent↗

Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women. The OFELY study.

INTRODUCTION: Vitamin D status is considered as an important determinant of bone health but supplementation trials with vitamin D(3) have yielded conflicting results. The aim of this study was to investigate the associations between serum 25-hydroxyvitamin D (25-OH D), bone turnover markers, bone mineral density (BMD), radius bone loss and incidence of fracture in postmenopausal women. METHODS: 669 postmenopausal women (mean age: 62.2 years) belonging to a population-based cohort were followed prospectively for a median of 11.2 years. At baseline, 25-OH D levels, BMD, bone turnover markers and clinical risk factors of osteoporosis were assessed. BMD loss at the radius was estimated by annual measurements of BMD and all incident fractures which occurred in 134 women were confirmed by radiographs. RESULTS: 73% and 35% of women had serum 25-OH D levels below 75 and 50 nmol/l which correspond respectively to the median and lowest optimal values recently proposed for fracture prevention. 11% of women had levels below 30 nmol/l. Serum 25-OH D correlated modestly with intact PTH (r(2)=0.023, p<0.0001), but not with bone turnover markers or BMD at the hip and radius after adjustment for age. When levels of 25-OH D were considered as a continuous variable, there was no significant association between 25-OH D levels and radius BMD loss or fracture risk. After adjustment for age, there was no significant difference in incidence of fracture, BMD, radius BMD loss, bone turnover markers, grip strength and the percentage of fallers in the previous year between women with 25-OH D levels below or above 75, 50 or 30 nmol/l. CONCLUSIONS: In a population of home-dwelling healthy postmenopausal women with few of them with severe vitamin D deficiency, vitamin D status may not be an important determinant of bone health.

Absorptiometry, Photon↗