Distal Femoral Metaphysis Research Articles

Chronic effect of CLA isomers on bone mineral density, fat and lean mass in C57BL/6 female mice

Conjugated linoleic acids (CLA) are a class of positional, geometric, conjugated dienoic isomers of linoleic acid (LA). Dietary CLA supplementation results in a dramatic decrease in body fat mass and increase in lean mass as well as protects against bone loss both in mice and humans. However, little information is known of the long term effect of CLA isomers in animals as well as in humans. In order to investigate the isomer specific effects of CLA on fat and lean mass, the purified c9,t11‐CLA, (0.5%), t10,c12‐CLA (0.5%) and CLA‐mix (0.25%, c9,t11‐CLA + 0.25% t10,c12‐CLA) were fed along with 10% corn oil (CO) to 6 months old C57BL/6 female mice (n=8–10) for 6 months. All of the dietary interventions of CLA groups were compared with CO fed mice as a control group. After 6 months, mice were scanned using DEXA to measure the bone mineral density (BMD), lean and fat mass. The results revealed that, the body weights were significantly decreased in both t10,c12‐CLA, CLA‐mix groups compared to c9,t11‐CLA and 10% corn oil. Further, t10,c12‐CLA and CLA‐mix groups significantly decreased the total and abdominal fat mass compared to c9,t12‐CLA and CO group. In addition, both CLA‐mix and t10,c12‐CLA significantly increased the lean mass and also BMD in lumbar spine and distal femoral metaphysis compared to corn oil. The overall % fat of the body were decreased significantly in t10,c12‐CLA and CLA‐mix compared to c9,t11‐CLA and CO group. In conclusion, the specific effect of t10,c12‐CLA induces both significant fat mass reduction, maintains higher lean and bone mass compared to c9,t12‐CLA and CO.Research support: NIH R21 AG027562

Influence of Physical Exercise and Food Restriction on the Biomechanical Properties of the Femur of Ageing Male Rats

Background: Voluntary running in wheels as well as food reduction increase the life spans of rats. Disparate parameters such as the collagen biomarker of ageing and the development of kidney pathologies are decreased by voluntary exercise. There are few reports on the influence of physical exercise and food restriction on the skeleton of male rats. Most investigations initiated rather short-term interventions in 4- to 5-week-old animals and thus studied more the influence of growth than the influence of ageing on the skeleton. Objective: To compare the effects of physical exercise and food restriction on the biomechanical properties of bone tissue of ageing male rats with the interventions starting at the age of 5 months with the end point at 23 months. This enables the study of the influence of these interventions on the ageing of the skeleton. Methods: Five groups of male Sprague-Dawley rats were used: baseline (BL), voluntarily running in wheels (RW), food restriction to attain pair weight with RW animals (PW), forced running in treadmills (TM), and sedentary controls (SE). The biomechanical properties of femoral neck, diaphysis, and distal metaphysis were measured. Results: While the body weights and fat-free mass increased from BL to SE group, the occiput-sacrum length did not increase and the length of the femur increased marginally. These lengths were slightly retarded in RW and PW groups compared to the SE group. The strength of the distal femoral metaphysis decreased from BL to SE group. This decrease was counteracted by physical exercise (RW and TM groups) as well as by food restriction (PW group). In contrast, the strength of the femoral mid-diaphysis did not differ between BL and SE groups. Conclusions: The distal metaphysis in the male rat femur is more prone to decreasing biomechanical strength than the diaphysis during ageing. Physical exercise, when started at the age of 5 months, when the skeleton has reached its adult size, is somewhat effective in counteracting these changes. There is also some retarding effect of food restriction.

Spinal cord injury causes rapid osteoclastic resorption and growth plate abnormalities in growing rats (SCI-induced bone loss in growing rats)

Spinal cord injury causes severe bone loss. We report osteoclast resorption with severe trabecular and cortical bone loss, decreased bone mineral apposition, and growth plate abnormalities in a rodent model of contusion spinal cord injury. These findings will help elucidate the mechanisms of osteoporosis following neurological trauma. Limited understanding of the mechanism(s) that underlie spinal cord injury (SCI)-induced bone loss has led to few treatment options. As SCI-induced osteoporosis carries significant morbidity and can worsen already profound disability, there is an urgency to advance knowledge regarding this pathophysiology. A clinically relevant contusion model of experimental spinal cord injury was used to generate severe lower thoracic SCI by weight-drop (10 g x 50 mm) in adolescent male Sprague-Dawley rats. Body weight and gender-matched naïve (no surgery) rats served as controls. Bone microarchitecture was determined by micro-computed tomographic imaging. Mature osteoclasts were identified by TRAP staining and bone apposition rate was determined by dynamic histomorphometry. At 10 days post-injury we detected a marked 48% decrease in trabecular bone and a 35% decrease in cortical bone at the distal femoral metaphysis by micro-CT. A 330% increase in the number of mature osteoclasts was detected at the growth plate in the injured animals that corresponded with cellular disorganization at the chondro-osseous junction. Appositional growth studies demonstrated decreased new bone formation with a mineralization defect indicative of osteoblast dysfunction. Contusion SCI results in a rapid bone loss that is the result of increased bone resorption and decreased bone formation.

Effect of combined humanPTH(1–34) and calcitonin treatment in ovariectomized rats

We examined the combined effects of human parathyroid hormone 1–34 (hPTH) and elcatonin (ECT: a synthetic derivative of eel calcitonin) to prevent loss of bone mass, architecture and strength in ovariectomized (OVX) rats. Fifty-four female rats (aged 13 weeks) were assigned to one of nine groups: Sham (fake surgery performed), OVX, ECT (15 U/kg administered), PTH5, PTH10 and PTH20 (5, 10 or 20 μg/kg administered), and E + PTH5, E + PTH10 and E + PTH20 (15 U/kg of ECT and 5, 10 or 20 μg/kg of hPTH administered). The drug or vehicle was subcutaneously administered three times a week for 12 weeks. The femurs were removed at the completion of the experiment. The right distal femoral metaphysis was used for measuring bone mineral density (BMD), analyzing trabecular bone structure by micro-computed tomography (μCT), and conducting the bone strength test, and the left femur was used for histomorphometric analysis. Trabecular bone volume (BV/TV) and other bone mass parameters were greater in the ECT and PTH groups than in the OVX group. The number of nodes (N.Nd/TV) and trabecular number (Tb.N) were significantly greater in the ECT group, and trabecular thickness (Tb.Th) and trabecular bone pattern factor (TBPf) were significantly greater in the PTH group. These results indicate that these drugs preserve the bone architecture by different means. Analysis by means of μCT revealed that BV/TV, Tb.N, fractal D and N.Nd/TV were significantly greater in the E + PTH groups than in the PTH groups at each concentration. Trabecular separation (Tb.Sp) was significantly lower in the E + PTH5 and E + PTH10 groups than in the respective PTH5 and PTH10 groups. When the maximum load was applied in a compression test on the distal femur, the E + PTH groups had higher values than the PTH groups, however, the three point bending strength of the diaphysis of femur in the E + PTH10 and E + PTH20 groups tended to be low compared to those in the PTH10 and PTH20 groups. These results indicate that combination therapy using PTH and ECT preserves the trabecular microarchitecture better than single-drug therapy using ECT or PTH in OVX rats, however, it is necessary to optimize the calcitonin (CT) dosage and administration in order to achieve the optimal combined effect of PTH and CT.

In VivoBehavior of Zirconia—Hydroxyapatite (ZH) Ceramic Implants in Dogs: A Clinical, Radiographic, and Histological Study

The main goal of this study is to evaluate potential applications of two zirconia-hydroxyapatite composites, Z4H6 and Z6H4, as bone substitutes. Composite plugs were implanted into the distal femoral metaphysis and also onto the longissimus dorsi of 18 adult mixed-breed dogs in order to assess in vivo biocompatibility by immediate clinical and radiographic evaluation 30, 90, and 120 days after implantation. Radiographic examination revealed radiolucency on the defect site. However, a progressive increase in bone density was observed over time, reaching a radiopacity similar to that of bone 120 days after implantation. Histological study revealed that a thin layer of fibroblasts was observed at the implant-bone interface in addition to osteoblastic activity 30 days after implantation, whereas bone neoformation around the implants was detected for the subsequent implantation times (90 and 120 days). Otherwise, the histological evaluation of the implant-muscle interface showed the presence of an initially thick fibrous tissue layer 30 days after implantation, which decreased with longer investigation times (90 and 120 days). The numbers of plasmocytes, lymphocytes, and macrophages gradually reduced as a function implantation time, being completely absent 120 days after implantation with a resulting complete osteointegration process. The zirconia phase content did not affect the bioactive behavior of the implants investigated and did not induce bone formation when implanted into muscle either.

Effects of Treatment of Ovariectomized Adult Rhesus Monkeys with Parathyroid Hormone 1-84 for 16 Months on Trabecular and Cortical Bone Structure and Biomechanical Properties of the Proximal Femur

Treatment of monkeys and humans with parathyroid hormone (PTH) 1-84 stimulates skeletal remodeling, which increases trabecular (Tb) bone mineral density (BMD) but decreases cortical (Ct) BMD at locations where these bone types predominate. We report the effects of daily PTH treatment (5, 10, or 25 microg/kg) of ovariectomized (OVX) rhesus monkeys for 16 months on bone structure and biomechanical properties at the proximal femur, a mixed trabecular and cortical bone site. PTH reversed the OVX-induced decrease in BMD measured by dual-energy X-ray absorptiometry at the proximal femur, femoral neck, and distal femur. Peripheral quantitative computed tomography confirmed a significant decrease in Ct.BMD and an increase in Tb.BMD at the total proximal femur and at the proximal and distal femoral metaphyses. The decrease in Ct.BMD resulted primarily from increased area because cortical bone mineral content was unaffected by PTH. Histomorphometry revealed that PTH significantly increased the trabecular bone formation rate (BFR) as well as trabecular bone volume and number. PTH did not affect periosteal or haversian BFR at the femoral neck, but cortical porosity was increased slightly. PTH had no effects on stiffness or peak load measured using a shear test, whereas work-to-failure, the energy required to fracture, was increased significantly. Thus, PTH treatment induced changes in trabecular and cortical bone at the proximal femur that were similar to those occurring at sites where these bone types predominate. Together, the changes had no effect on stiffness or peak load but increased the energy required to break the proximal femur, thereby making it more resistant to fracture.

Changes in Osteoblast, Chondrocyte, and Adipocyte Lineages Mediate the Bone Anabolic Actions of PTH and Small Molecule GSK‐3 Inhibitor

Parathyroid hormone (PTH) and glycogen synthase kinase-3 (GSK-3) inhibitor 603281-31-8, administered once daily increased bone formation in vivo. We investigated the molecular mechanisms of the anabolic responses of PTH and 603281-31-8 in rat osteopenia model. Female 6-month-old rats were ovariectomized (Ovx) and permitted to lose bone for 1 month, followed by treatment with PTH (1-38) at 10 microg/kg/day s.c. or 603281-31-8 at 3 mg/kg/day p.o. for 60 days. Twenty-four hours after the last treatment, RNA from distal femur metaphysis was subjected to gene expression analysis. Differentially expressed genes (P<0.05) were subjected to pathway analysis to delineate relevant bio-processes involved in skeletal biology. Genes involved in morphogenesis, cell growth/differentiation, and apoptosis were significantly altered by Ovx and the treatments. Analysis of morphogenesis genes showed an overrepresentation of genes involved in osteogenesis, chondrogenesis, and adipogenesis. A striking finding was that Ovx decreased several markers of osteogenesis/chondrogenesis and increased markers of adipogenesis/lipid metabolism. Treatment with either PTH or the GSK-3 inhibitor reversed these effects, albeit at different levels. Histological analysis confirmed that osteopenia in Ovx animals was associated with three-fold increase in marrow adiposity. PTH and GSK-3 inhibitor restored bone volume, and reversed or normalized marrow adiposity. Ex vivo studies showed that PTH and GSK-3 inhibitor increased the ratio of colony forming marrow stromal progenitors (CFU-fs) that were alkaline phosphatase positive (putative osteoblasts). Our results suggest that the bone anabolic actions of PTH and GSK-3 inhibitor in vivo involve concerted effects on mesenchymal lineages; osteoblasts, chondrocytes, and adipocytes.

Total femoral prosthesis replacement in management of femoral malignant bone tumor

To discuss the indications of reconstruction with total femoral prosthesis for the patients with a majority of femur infiltrated by malignant bone tumor, and to evaluate the functional outcome and complication. Between October 1996 and October 2002, 17 patients with malignant bone tumor were treated with total femoral prosthesis replacement. The patients included 8 males and 9 females, whose age was from 12 to 34 years, with the average of 16 years. The lesions were located in the proximal femur metaphysis in 1, the distal femur metaphysis in 6, the femur shaft in 10, pathologic fracture in 2, skip lesions in 3. The extent of lesions was 23-28 cm (a majority of femur infiltrated by malignant bone tumor). Preoperative pathologic diagnosis were established by open biopsy (2 cases) or needle biopsy (15 cases). All patients were osteosarcoma. According to Enneking surgical staging system, the cases were 12 IIB and 5 IIIB. Seventeen cases received preoperative chemotherapy and 15 cases received postoperative chemotherapy. Seventeen cases were followed up with a mean time of 45 months (range 9-120 months). Local recurrence was observed in 3 (17.6%) after operation 6-14 months. In 12 IIB cases, 4 cases (33%) developed pulmonary metastasis and died. Eight cases remained continuously disease-free for average 75 months (range 50-120 months). In 5 IIIB cases, all with a mean survived term of 13 months (range 9-20 months) died. Fifteen patients (88%) could walk. The patients had maintained average 74% (range 40% - 93%) limb function scores evaluated by ISOLS criteria. Four cases had complications of paralysis of common peroneal nerve (3 cases) and dislocation of hip joint (2 case). No infection took place. Total femoral prosthesis replacement could be used in the treatment of the patients with a majority of femur infiltrated by malignant bone tumor and could effectively recover their limb function to a great extent. The procedure can effectively improve the quality of life for the patients with malignant bone tumor staging IIIB.

Novel Role of Y1 Receptors in the Coordinated Regulation of Bone and Energy Homeostasis

The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1(-/-) mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1(-/-) mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.

Can classic metaphyseal lesions follow uncomplicated caesarean section?

Classic metaphyseal lesion (CML) is the term given to a fracture that most often occurs in the posteromedial aspect of the distal femur, proximal tibia, distal tibia, and proximal humerus in infants; this finding is strongly associated with non-accidental injury. To demonstrate that the CML may occur following simple lower segment caesarean section (LSCS). A review of 22 years of an obstetric practice that delivers 8,500 babies per year. We identified three neonates born by elective LSCS, each with distal femoral metaphyseal fractures on postpartum radiographs. All caesarean sections were elective and uncomplicated. External cephalic version was not employed preoperatively. Postpartum radiographs demonstrated a fracture of the distal femoral metaphysis in each neonate, typical of a CML. We propose that a CML can occur in the setting of a simple, elective and uncomplicated LSCS where no external cephalic version is employed.

Osteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice

The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative microCT at 6, 12, and 32 weeks of age (n=8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. microCT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p<0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p<0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p<0.01) and an increase in trabecular separation (p<0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. These findings show that inactivation of the DNA binding-dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding-dependent actions of the AR in mature osteoblasts.

Soy isoflavones avert chronic inflammation-induced bone loss and vascular disease

BackgroundEvidence from epidemiological, clinical and animal studies suggests a link may exist between low bone density and cardiovascular disease, with inflammatory mediators implicated in the pathophysiology of both conditions. This project examined whether supplementation with soy isoflavones (IF), shown to have anti-inflammatory properties, could prevent tissue expression of TNF-α and the development of skeletal pathology in an animal model of chronic inflammation.MethodsEight-week old, intact, female C57BL/6J mice were used. In Phase 1, a lipopolysaccharide (LPS)-dose response study (0, 0.133, 1.33 and 13.3 μg/d) was conducted to determine the LPS dose to use in Phase 2. The results indicated the 1.33 μg LPS/d dose produced the greatest decrease in lymphocytes and increase in neutrophils. Subsequently, in Phase 2, mice were randomly assigned to one of six groups (n = 12–13 per group): 0 or 1.33 μg LPS/d (placebo or LPS) in combination with 0, 126 or 504 mg aglycone equivalents of soy IF/kg diet (Control, Low or High dose IF). Mice were fed IF beginning 2 wks prior to the 30-d LPS study period.ResultsAt the end of the study, no differences were detected in final body weights or uterine weights. In terms of trabecular bone microarchitecture, μCT analyses of the distal femur metaphysis indicated that LPS significantly decreased trabecular bone volume (BV/TV) and number (TbN), and increased separation (TbSp). Trabecular bone strength (i.e. total force) and stiffness were also compromised in response to LPS. The High IF dose provided protection against these detrimental effects on microarchitecture, but not biomechanical properties. No alterations in trabecular thickness (TbTh), or cortical bone parameters were observed in response to the LPS or IF. Immunohistomchemical staining showed that tumor necrosis factor (TNF)-α was up-regulated by LPS in the endothelium of small myocardial arteries and arterioles as well as the tibial metaphysis and down-regulated by IF.ConclusionThese results suggest IF may attenuate the negative effects of chronic inflammation on bone and cardiovascular health. Additional research is warranted to examine the anti-inflammatory properties of the soy isoflavones and the mechanisms underlying their prevention of chronic inflammation-induced bone loss.

Depression induces bone loss through stimulation of the sympathetic nervous system.

Major depression is associated with low bone mass and increased incidence of osteoporotic fractures. However, causality between depression and bone loss has not been established. Here, we show that mice subjected to chronic mild stress (CMS), an established model of depression in rodents, display behavioral depression accompanied by impaired bone mass and structure, as portrayed by decreases in trabecular bone volume density, trabecular number, and trabecular connectivity density assessed in the distal femoral metaphysis and L3 vertebral body. Bone remodeling analysis revealed that the CMS-induced skeletal deficiency is accompanied by restrained bone formation resulting from reduced osteoblast number. Antidepressant therapy, which prevents the behavioral responses to CMS, completely inhibits the decrease in bone formation and markedly attenuates the CMS-induced bone loss. The depression-triggered bone loss is associated with a substantial increase in bone norepinephrine levels and can be blocked by the beta-adrenergic antagonist propranolol, suggesting that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. These results define a linkage among depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating an interaction among behavioral responses, the brain, and the skeleton, which leads to impaired bone structure. Together with the common occurrence of depression and bone loss in the aging population, the present data implicate depression as a potential major risk factor for osteoporosis and the associated increase in fracture incidence.

Dried plum prevents bone loss in a male osteoporosis model via IGF-I and the RANK pathway

Previously, dietary supplementation with dried plums, a rich source of polyphenolic compounds with antioxidant and anti-inflammatory properties, has been shown to improve bone density, microstructure and biomechanics in female animal models of osteopenia. We designed this study to determine the extent to which dried plum prevents skeletal deterioration in gonadal hormone deficient male animals and to begin to understand its mechanism of action. Sixty 6-month-old male Sprague–Dawley rats were either sham-operated (Sham=1 group) or orchidectomized (ORX=4 groups) and randomly assigned to dietary treatments: standard semi-purified diet (Control) with either LD=5%, MD=15%, or HD=25% (w/w) dried plum for 90 days. At the end of the treatment period, both the MD and HD dried plum completely prevented the ORX-induced decrease in whole body, femur, and lumbar vertebra bone mineral density (BMD). Biomechanical testing indicated that the MD and HD of dried plum prevented the ORX-induced decrease in ultimate load of the cortical bone as well as the compressive force and stiffness of trabecular bone within the vertebrae. Analyses of trabecular microarchitecture of the distal femur metaphysis and vertebral body revealed that HD dried plum protected against the decrease in trabecular bone volume (BV/TV) induced by ORX. In the distal femur, all doses of dried plum improved trabecular number (TbN) and separation (TbSp) compared to the ORX-control group, while MD and HD dried plum prevented the ORX-induced changes in vertebral TbN and TbSp. At the end of the 90-day treatment, no remarkable changes in serum osteocalcin or alkaline phosphatase in any of the treatment groups were observed, while serum insulin-like growth factor (IGF)-I was increased by dried plum. The ORX-induced increase in urinary deoxypyridinoline (DPD) excretion was completely prevented by all doses of dried plum coinciding with down-regulation of gene expression for receptor activator of NFκ-B ligand (RANKL) and osteoprotegerin (OPG) in the bone. We conclude that dried plum prevents osteopenia in androgen deficient male rats, and these beneficial effects may be attributed in part to a decrease in osteoclastogenesis via down-regulation of RANKL and stimulation of bone formation mediated by IGF-I.

A single intravenous administration of zoledronic acid prevents the bone loss and mechanical compromise induced by aromatase inhibition in rats

Recent evidence has demonstrated that long-term estrogen deprivation using aromatase inhibitor therapy in postmenopausal women with breast cancer results in bone loss and increased fracture risk. Bisphosphonates are potent inhibitors of bone resorption and have demonstrated efficacy in preventing bone loss in postmenopausal women with low bone mineral density (BMD) and in patients with breast cancer receiving estrogen deprivation therapy. Therefore, this study investigated the effects of the bisphosphonate zoledronic acid on BMD and bone strength in rats treated with the aromatase inhibitor, letrozole. Peripheral quantitative computed tomography demonstrated that treatment of rats with daily oral letrozole (1 mg/kg) induced significant bone loss and cortical thinning compared with control animals ( P < 0.01). A single prior intravenous dose of zoledronic acid dose dependently protected against letrozole-induced bone loss and cortical thinning, with the highest evaluated dose (20 μg/kg) resulting in BMD values that were not significantly different from controls over the 24 weeks of letrozole treatment. Furthermore, biomechanical testing of the distal femoral metaphysis demonstrated that zoledronic acid (20 μg/kg) significantly prevented the decrease in stiffness and elastic modulus induced by letrozole treatment. Taken together, these data support the use of zoledronic acid for the prevention of bone loss in women with breast cancer receiving aromatase inhibitor therapy.

The Effect of Varying Magnitudes of Whole-Body Vibration on Several Skeletal Sites in Mice

It has been reported that whole-body vibration (WBV) is anabolic to trabecular bone in animal models and humans. It is likely that this anabolic response does not occur uniformly throughout the entire body. Two factors that may affect the observed anabolic response are vibration magnitude and skeletal site of interest. In this study, mice were loaded with WBV of varying magnitudes. After five weeks of loading, bone marrow was flushed from tibias in order to quantify osteoprogenitor cells. Staining with alizarin red (an indicator of mineralization) showed a significant decrease in percent stained area in the 0.3 g loaded group compared to the control group and the 1.0 g group. MicroCT analysis was performed at five skeletal sites: the proximal tibial metaphysis, femoral condyles, distal femoral metaphysis, proximal femur, and L5 vertebral body. Increasing magnitudes of WBV were associated with a non-dose-dependent increase in trabecular bone volume (BV/TV) at the proximal tibial metaphysis, although other sites were unresponsive. There were statistically significant increases in BV/TV in the 0.1 g group (32% increase) and 1.0 g group (43% increase) compared to control (p < 0.05). The 0.1 g and 1.0 g groups also had higher BV/TV than the 0.3 g loaded group. If this non-dose-dependent phenomenon is verified by future studies, it suggests that a range of magnitudes should be examined for each application of WBV.

Alteration of femoral bone morphology and density in COX-2−/− mice

A role of COX-2 in pathological bone destruction and fracture repair has been established; however, few studies have been conducted to examine the involvement of COX-2 in maintaining bone mineral density and bone micro-architecture. In this study, we examined bone morphology in multiple trabecular and cortical regions within the distal and diaphyseal femur of 4-month-old wild-type and COX-2−/− mice using micro-computed tomography. Our results demonstrated that while COX-2−/− female mice had normal bone geometry and trabecular microarchitecture at 4 months of age, the male knockout mice displayed reduced bone volume fraction within the distal femoral metaphysis. Furthermore, male COX-2−/− mice had a significant reduction in cortical bone mineral density within the central cortical diaphysis and distal epiphysis and metaphysis. Consistent with the observed reduction in cortical mineral density, biomechanical testing via 4-point-bending showed that male COX-2−/− mice had a significant increase in postyield deformation, indicating a ductile bone phenotype in male COX-2−/− mice. In conclusion, our study suggests that genetic ablation of COX-2 may have a sex-related effect on cortical bone homeostasis and COX-2 plays a role in maintaining normal bone micro-architecture and density in mice.

Pamidronate Treatment and Posttreatment Bone Density in Children With Spastic Quadriplegic Cerebral Palsy

Little is known about the long-term effects of a course of pamidronate treatment on bone mineral density (BMD) of children with spastic quadriplegic cerebral palsy (SQCP). Nine patients with SQCP who had low bone density and/or history of previous fracture(s) were studied during treatment and more than 1 yr after cyclic pamidronate treatment ended. Over the 12 mo of treatment, spine BMD increases raised average Z-score from -4.0 to -2.8. In the distal femoral metaphysis, BMD increase raised average Z-score from -3.6 to -1.7. Observations posttreatment ranged from 12 to 49 mo. Changes in BMD were variable among individuals. Group spine Z-score an average of 34 mo posttreatment approached pretreatment value. Six of eight patients had final distal femur posttreatment Z-scores the same or better than pretreatment baseline an average of 27.1 mo later. While most but not all gains in BMD were lost over the first 2 yr after treatment, no patient sustained fracture during or after treatment for a cumulative follow-up of more than 27 patient-yr.

Cyclical Intravenous Pamidronate Treatment Affects Metaphyseal Modeling in Growing Patients With Osteogenesis Imperfecta

This analysis of 50 growing patients with osteogenesis imperfecta revealed that 2-4 years of pamidronate treatment lead to abnormalities in the shape of the distal femoral metaphyses. Cyclical intravenous pamidronate therapy is of clinical benefit in children and adolescents with moderate to severe osteogenesis imperfecta (OI) but might interfere with the shaping of long bone metaphyses during growth. We evaluated the distal femur in 50 growing children with moderate to severe OI (mean age, 6.7 +/- 3.4 years; 26 girls) who had received 2-4 years of pamidronate therapy (annual dose, 9 mg/kg body weight). The mediolateral width of the distal femoral growth plate and of the metaphysis, as well as the ratio between these two measures (called metaphyseal index), were determined on lower limb radiographs. Compared with untreated OI patients who were matched for OI type and age, pamidronate-treated patients had similar growth plate width but wider metaphyses, resulting in a 26% higher metaphyseal index (p < 0.001). Apart from the effect on bone shape, each pamidronate cycle induces a transverse line in metaphyses that are adjacent to active growth plates. Analyses of these transverse lines revealed that they persist for an average time of approximately 4 years, with a range from 2 to 8 years. Pamidronate interferes with the process of periosteal resorption that is normally responsible for shaping the distal femoral metaphysis. Pamidronate-induced transverse lines disappear with time, supporting the view that these lines represent horizontal trabeculae that undergo remodeling. There is no evidence at present that these treatment induced morphological changes have any clinical implications.

Avulsive Cortical Irregularity and F-18 FDG PET

Abstract:F-18 FDG PET showed marked uptake in the posteromedial left distal femoral metaphysis of a 9-year-old boy whose history of trilateral retinoblastoma indicated a high risk of additional malignancies, including osteosarcoma. Evaluation with radiographs and MRI revealed that an avulsive cortic