Bone metabolic and hormonal characteristics of Australian Antarctic expeditioners

Summary: Serum 25(OH)D levels decline without sunlight exposure. We studied 120 expeditioners to Antarctica to determine the skeletal and hormonal responses to sunlight deprivation. With emerging vitamin D insufficiency, serum calcium decreased, PTH increased, and bone loss at the proximal femur was observed. Baseline serum 25(OH)D levels >100 nmol/L prevented vitamin D insufficiency. Introduction: Vitamin D stores deplete without adequate sunlight exposure unless supplementation is provided. We studied 120 healthy adults who spent a year in Antarctica as a model for sunlight deprivation to define the timing and magnitude of the skeletal and hormonal responses to emerging vitamin D insufficiency. Methods: Fasting blood samples were assessed at baseline, 6 and 12 months for serum 25-hydroxyvitamin D (25(OH)D), osteocalcin (OC), bone formation (P1NP) and resorption (CTx), PTH and calcium. Lumbar spine and proximal femur BMD was measured using DXA. Differences over time were determined using repeated measures ANOVA. Percent changes were expressed as (Delta value/(value A +value B)/2)x100. Relationships between outcome measures were determined using Spearman's correlations. Results: Vitamin D insufficiency (<50 nmol/L) was observed in 85% of expeditioners by 6 months when serum calcium decreased and PTH increased (p<0.01). By 12 months, OC increased by 7.4±3.0% (p<0.05), and BMD decreased by 1.0±2.0% at the total proximal femur (p<0.05). For those with vitamin D sufficiency at baseline (>50 nmol/L), sunlight deprivation produced vitamin D insufficiency within 4 months unless baseline values were >100 nmol/L. Conclusion: Supplementation may be necessary for expeditioners with limited access to UV light.

Análisis de micromovilidad en vástagos femorales mediante ensayo dinámico de oscilaciones libres

La artroplastia de cadera se considera uno de los mayores avances quirúrgicos de la Medicina. La aplicación de esta técnica de Traumatología se ha incrementado notablemente en los últimos anos, a causa principalmente del progresivo incremento de la esperanza de vida. En efecto, con la edad aumentan los problemas de artrosis y osteoporosis, enfermedades típicas de las articulaciones y de los huesos que requieren en muchos casos la sustitución protésica total o parcial de la articulación. El buen comportamiento funcional de una prótesis depende en gran medida de la estabilidad primaria, es decir, el correcto anclaje de la prótesis en el momento de su implantación. Las prótesis no cementadas basan su éxito a largo plazo en la osteointegración que tiene lugar entre el material protésico y el tejido óseo, y para lograrla es imprescindible conseguir unas buenas condiciones de estabilidad primaria. El aflojamiento aséptico es la principal causa de fallo de artroplastia total de cadera. Este es un fenómeno en el que, debido a complejas interacciones de factores mecánicos y biológicos, se producen movimientos relativos que comprometen la funcionalidad del implante. La minimización de los correspondientes danos depende en gran medida de la detección precoz del aflojamiento. Para lograr la detección temprana del aflojamiento aséptico del vástago femoral se han ensayado diferentes técnicas, tanto in vivo como in vitro: análisis numéricos y técnicas experimentales basadas en sensores de movimientos provocados por cargas transmitidas natural o artificialmente, tales como impactos o vibraciones de distintas frecuencias. Los montajes y procedimientos aplicados son heterogéneos y, en muchas ocasiones, complejos y costosos, no existiendo acuerdo sobre una técnica simple y eficaz de aplicación general. Asimismo, en la normativa vigente que regula las condiciones que debe cumplir una prótesis previamente a su comercialización, no hay ningún apartado referido específicamente a la evaluación de la bondad del diseño del vástago femoral con respecto a la estabilidad primaria. El objetivo de esta tesis es desarrollar una metodología para el análisis, in vitro, de la estabilidad de un vástago femoral implantado, a fin de poder evaluar las técnicas de implantación y los diferentes diseños de prótesis previamente a su oferta en el mercado. Además se plantea como requisito fundamental que el método desarrollado sea sencillo, reversible, repetible, no destructivo, con control riguroso de parámetros (condiciones de contorno de cargas y desplazamientos) y con un sistema de registro e interpretación de resultados rápido, fiable y asequible. Como paso previo, se ha realizado un análisis cualitativo del problema de contacto en la interfaz hueso-vástago aplicando una técnica optomecánica del campo continuo (fotoelasticidad). Para ello se han fabricado tres modelos en 2D del conjunto hueso-vástago, simulando tres tipos de contactos en la interfaz: contacto sin adherencia y con holgura, contacto sin adherencia y sin holgura, y contacto con adherencia y homogéneo. Aplicando la misma carga a cada modelo, y empleando la técnica de congelación de tensiones, se han visualizado los correspondientes estados tensionales, siendo estos más severos en el modelo de unión sin adherencia, como cabía esperar. En todo caso, los resultados son ilustrativos de la complejidad del problema de contacto y confirman la conveniencia y necesidad de la vía experimental para el estudio del problema. Seguidamente se ha planteado un ensayo dinámico de oscilaciones libres con instrumentación de sensores resistivos tipo galga extensométrica. Las muestras de ensayo han sido huesos fémur en todas sus posibles variantes: modelos simplificados, hueso sintético normalizado y hueso de cadáver, seco y fresco. Se ha diseñado un sistema de empotramiento del extremo distal de la muestra (fémur) con control riguroso de las condiciones de anclaje. La oscilación libre de la muestra se ha obtenido mediante la liberación instantánea de una carga estética determinada y aplicada previamente, bien con una maquina de ensayo o bien por gravedad. Cada muestra se ha instrumentado con galgas extensométricas convencionales cuya señal se ha registrado con un equipo dinámico comercial. Se ha aplicado un procedimiento de tratamiento de señal para acotar, filtrar y presentar las respuestas de los sensores en el dominio del tiempo y de la frecuencia. La interpretación de resultados es de tipo comparativo: se aplica el ensayo a una muestra de fémur Intacto que se toma de referencia, y a continuación se repite el ensayo sobre la misma muestra con una prótesis implantada; la comparación de resultados permite establecer conclusiones inmediatas sobre los efectos de la implantación de la prótesis. La implantación ha sido realizada por un cirujano traumatólogo utilizando las mismas técnicas e instrumental empleadas en el quirófano durante la práctica clínica real, y se ha trabajado con tres vástagos femorales comerciales. Con los resultados en el dominio del tiempo y de la frecuencia de las distintas aplicaciones se han establecido conclusiones sobre los siguientes aspectos: Viabilidad de los distintos tipos de muestras sintéticas: modelos simplificados y fémur sintético normalizado. Repetibilidad, linealidad y reversibilidad del ensayo. Congruencia de resultados con los valores teóricos deducidos de la teoría de oscilaciones libres de barras. Efectos de la implantación de tallos femorales en la amplitud de las oscilaciones, amortiguamiento y frecuencias de oscilación. Detección de armónicos asociados a la micromovilidad. La metodología se ha demostrado apta para ser incorporada a la normativa de prótesis, es de aplicación universal y abre vías para el análisis de la detección y caracterización de la micromovilidad de una prótesis frente a las cargas de servicio. ABSTRACT Total hip arthroplasty is considered as one of the greatest surgical advances in medicine. The application of this technique on Traumatology has increased significantly in recent years, mainly due to the progressive increase in life expectancy. In fact, advanced age increases osteoarthritis and osteoporosis problems, which are typical diseases of joints and bones, and in many cases require full or partial prosthetic replacement on the joint. Right functional behavior of prosthesis is highly dependent on the primary stability; this means it depends on the correct anchoring of the prosthesis at the time of implantation. Uncemented prosthesis base their long-term success on the quality of osseointegration that takes place between the prosthetic material and bone tissue, and to achieve this good primary stability conditions is mandatory. Aseptic loosening is the main cause of failure in total hip arthroplasty. This is a phenomenon in which relative movements occur, due to complex interactions of mechanical and biological factors, and these micromovements put the implant functionality at risk. To minimize possible damage, it greatly depends on the early detection of loosening. For this purpose, various techniques have been tested both in vivo and in vitro: numerical analysis and experimental techniques based on sensors for movements caused by naturally or artificially transmitted loads, such as impacts or vibrations at different frequencies. The assemblies and methods applied are heterogeneous and, in many cases, they are complex and expensive, with no agreement on the use of a simple and effective technique for general purposes. Likewise, in current regulations for governing the conditions to be fulfilled by the prosthesis before going to market, there is no specific section related to the evaluation of the femoral stem design in relation to primary stability. The aim of this thesis is to develop a in vitro methodology for analyzing the stability of an implanted femoral stem, in order to assess the implantation techniques and the different prosthesis designs prior to its offer in the market. We also propose as a fundamental requirement that the developed testing method should be simple, reversible, repeatable, non-destructive, with close monitoring of parameters (boundary conditions of loads and displacements) and with the availability of a register system to record and interpret results in a fast, reliable and affordable manner. As a preliminary step, we have performed a qualitative analysis of the contact problems in the bone-stem interface, through the application of a continuous field optomechanical technique (photoelasticity). For this proposal three 2D models of bone–stem set, has been built simulating three interface contact types: loosened an unbounded contact, unbounded and fixed contact, and bounded homogeneous contact. By means of applying the same load to each model, and using the stress freezing technique, it has displayed the corresponding stress states, being more severe as expected, in the unbounded union model. In any case, the results clearly show the complexity of the interface contact problem, and they confirm the need for experimental studies about this problem. Afterward a free oscillation dynamic test has been done using resistive strain gauge sensors. Test samples have been femur bones in all possible variants: simplified models, standardized synthetic bone, and dry and cool cadaveric bones. An embedding system at the distal end of the sample with strong control of the anchoring conditions has been designed. The free oscillation of the sample has been obtained by the instantaneous release of a static load, which was previously determined and applied to the sample through a testing machine or using the gravity force. Each sample was equipped with conventional strain gauges whose signal is registered with a marketed dynamic equipment. Then, it has applied a signal processing procedure to delimit, filter and present the time and frequency response signals from the sensors. Results are interpreted by comparing different trials: the test is applied to an intact femur sample which is taken as a reference, and then this test is repeated over the same sample with an implanted prosthesis. From comparison between results, immediate conclusions about the effects of the implantation of the prosthesis can be obtained. It must be said that the implementation has been made by an expert orthopedic surgeon using the same techniques and instruments as those used in clinical surgery. He has worked with three commercial femoral stems. From the results obtained in the time and frequency domains for the different applications the following conclusions have been established: Feasibility of the different types of synthetic samples: simplified models and standardized synthetic femur. Repeatability, linearity and reversibility of the testing method. Consistency of results with theoretical values deduced from the bars free oscillations theory. Effects of introduction of femoral stems in the amplitude, damping and frequencies of oscillations Detection of micromobility associated harmonics. This methodology has been proved suitable to be included in the standardization process of arthroplasty prosthesis, it is universally applicable and it allows establishing new methods for the analysis, detection and characterization of prosthesis micromobility due to functional loads.

Serum procalcitonin, interleukin-6, soluble intercellular adhesin molecule-1 and IgG to short-chain exocellular lipoteichoic acid as predictors of infection in total joint prosthesis revision

The diagnosis of prosthetic joint infection and its differentiation from aseptic loosening remains problematic. The definitive laboratory diagnostic test is the recovery of identical infectious agents from multiple intraoperative tissue samples; however, interpretation of positive cultures is often complex as infection is frequently associated with low numbers of commensal microorganisms, in particular the coagulase-negative staphylococci (CNS). In this investigation, the value of serum procalcitonin (PCT), interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) as predictors of infection in revision hip replacement surgery is assessed. Furthermore, the diagnostic value of serum IgG to short-chain exocellular lipoteichoic acid (sce-LTA) is assessed in patients with infection due to CNS. Presurgical levels of conventional serum markers of infection including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell count (WBC) is also established. Forty-six patients undergoing revision hip surgery were recruited with a presumptive clinical diagnosis of either septic (16 patients) or aseptic loosening (30 patients). The diagnosis was confirmed microbiologically and levels of serum markers were determined. Serum levels of IL-6 and sICAM-1 were significantly raised in patients with septic loosening (P=0.001 and P=0.0002, respectively). Serum IgG to sce-LTA was elevated in three out of four patients with infection due to CNS. In contrast, PCT was not found to be of value in differentiating septic and aseptic loosening. Furthermore, CRP, ESR and WBC were significantly higher (P=0.0001, P=0.0001 and P=0.003, respectively) in patients with septic loosening. Serum levels of IL-6, sICAM-1 and IgG to sce-LTA may provide additional information to facilitate the diagnosis of prosthetic joint infection.

EVIDENCE FOR MECHANICAL STRAINS INFLUENCE IN OSTEOPHYTE DEVELOPMENT

Purpose: Osteophytes are osteo-cartilaginous metaplastic tissue outgrowths of bone capped by cartilage usually found in degenerative and inflammatory joint disease. The presence and degree of maturity of osteophytes, along with joint space narrowing, are the main radiographic criteria for diagnosis and grading osteoarthritis (OA). Although osteophytes are known for being anatomic signs of advanced OA, they can occur in non-symptomatic joints, in joints with no other observable alterations, and in early stage OA. It remains unclear if they develop from molecular, physiological and/or mechanical stimuli. We hypothesized that mechanical strains play a role in osteophyte development. The overall objective of this thesis was to find evidence that osteophytes are influenced by mechanical strains. Methods: The first project was to develop a mechanically-induced osteophyte animal model. One single impact load that was reported to induce moderate joint damage was applied to the periosteum of the rat knee. Animals were sacrificed at four time points to characterize the evolution of damaged tissue and the joint by histology. A second study using human mature hip osteophytes was conducted to evaluate if mature osteophyte presented histological signs of proliferating and developmental processes. The histological characterization of mature osteophyte was used to compare findings of the mechanically-induced osteophyte in the animal model to validate the use of this rodent model in studying some aspect of osteophyte development of human. Lastly, a detailed three-dimensional (3D) radiological morphometric analysis was performed on microscopic computed tomography (µCT) scanned femoral heads collected from total hip arthroplasty patients presenting mature hip osteophytes. Quantitative morphometric measures of osteophytes internal structure was compared to three regions of the femoral head of known quality of organisation and mechanical constraint. Results and Conclusion: Osteophyte can be mechanically induced by a single load impact to the joint periosteum, indicating that a moderate trauma to the periosteal layer of the joint may play a role in osteophyte development. Mature osteophytes have proliferation, developing and remodelling zones and have trabecular structures. Mechanically-induced osteophytes and mature osteophytes presented similar histological composition. Mature osteophytes have organized internal structure. These results provide evidence that mechanical strain can influence osteophyte development.

Impact on hip fracture mortality after the establishment of an orthogeriatric care program in a colombian hospital

El objetivo del estudio es evaluar la mortalidad a un año en pacientes con fractura de cadera, mayores de 65 años tratados en un programa establecido de orto-geriatría. 298 se trataron de acuerdo al protocolo de orto-geriatría, se calculo la mortalidad a un año, se establecieron los predictores de mortalidad orto-geriátrico. La sobrevida anual se incremento de 80% a 89% (p = .039) durante los cuatro años de seguimiento del programa y disminuyo el riesgo de mortalidad anual postoperatorio (Hazard Ratio = 0.54, p = .049). La enfermedad cardiaca y la edad maor a 85 años fueron predictores positivos para mortalidad.

Resorbable composite scaffolds for craniofacial bone tissue engineering

Aim: Bone loss associated with trauma, osteo-degenerative diseases and tumors has tremendous socioeconomic impact related to personal and occupation disability and health care costs. In the present climate of increasing life expectancy with an ensuing increase in bone-related injuries, orthopaedic surgery is undergoing a paradigm shift from bone-grafting to bone engineering, where a scaffold is implanted to provide adequate load bearing and enhance tissue regeneration. We aim to develop composite scaffolds for bone tissue engineering applications to replace the current gold standard of autografting. ---------- Methods: Medical grade polycaprolactone-tricalcium phosphate (mPCL/TCP) scaffolds (80/20 wt%) were custom made using fused deposition modelling to produce 1x1.5x2 cm sized implants for critical-sized pig cranial implantations, empty defects were used as a control. Autologous bone marrow stromal cells (BMSCs) were extracted and precultured for 2 weeks, dispersed within fibrin glue and injected during scaffold implantation. After 2 years, microcomputed tomography and histology were used to assess bone regenerative capabilities of cell versus cell-free scaffolds. ---------- Results: Extensive bone regeneration was evident throughout the entire scaffold. Clear osteocytes embedded within mineralised matrix and active osteoblasts present around scaffold struts were observed. Cell groups performed better than cell-free scaffolds. ---------- Conclusions: Bone regeneration within defects which cannot heal unassisted can be achieved using mPCL/TCP scaffolds. This is improved by the inclusion of autogenous BMSCs. Further work will include the inclusion of growth factors including BMP-2, VEGF and PDGF to provide multifunctional scaffolds, where the three-dimensional (3D) template itself acts as a biomimetic, programmable and multi-drug delivery device.

Resorbable composite scaffolds for bone tissue engineering

Bone loss associated with trauma osteo-degenerative diseases and tumors has tremendous socioeconomic impact related to personal and occupation disability and health care costs. Bone grafting is often critical to surgical therapies. Autogenous bone is presently the preferred grafting material; however, this holds several disadvantages such as donor site morbidity. In the present climate of increasing life expectancy with an ensuing increase in bone-related injuries, orthopaedic surgery is undergoing a paradigm shift from bone-grafting to bone engineering, where a scaffold is implanted to provide adequate load bearing and enhance tissue regeneration. Our group at Queensland University of Technology (QUT) have developed, characterised and tested polycaprolactone/ tricalcium phosphate (PCL/TCP) composite scaffolds for low load-bearing bone defects. These scaffolds are being further developed for application in higher load bearing sites. Our approach emphasizes the importance of the biomaterials’ structural design, the scaffold architecture and structural and nutritional requirements for cell culture. These first-generation scaffolds made from medical grade PCL (mPCL) have been studied for more than 5 years within a clinical setting 1. This paper describes the application of second-generation scaffolds in small and large animal bone defect models and the ensuing bone regeneration as shown by histology and µCT.

Can the contra-lateral limb be used as a control with respect to analyses of bone remodelling?

Bone loss may result from remodelling initiated by implant stress protection. Quantifying remodelling requires bone density distributions which can be obtained from computed tomography scans. Pre-operative scans of large animals however are rarely possible. This study aimed to determine if the contra-lateral bone is a suitable control for the purpose of quantifying bone remodelling. CT scans of 8 pairs of ovine tibia were used to determine the likeness of left and right bones. The deviation between the outer surfaces of the bone pairs was used to quantify geometric similarity. The density differences were determined by dividing the bones into discrete volumes along the shaft of the tibia. Density differences were also determined for fractured and contra-lateral bone pairs to determine the magnitude of implant related remodelling. Left and right ovine tibiae were found to have a high degree of similarity with differences of less than 1.0 mm in the outer surface deviation and density difference of less than 5% in over 90% of the shaft region. The density differences (10–40%) as a result of implant related bone remodelling were greater than left-right differences. Therefore, for the purpose of quantifying bone remodelling in sheep, the contra-lateral tibia may be considered an alternative to a pre-operative control.

An evidence-informed strategy to prevent osteoporosis in Australia

Osteoporosis imposes a tremendous burden on Australia : 1.2 million Australians have osteoporosis and 6.3 million have Osteopenia. In the 2007-08 financial year, 82000 Australians suffered fragility fractures, of Which >17000 were hip fractures. In the 2000-01 financial year, direct costs were estimated at $1.9 billion per year and an additional $5.6 billion on indirect costs. Osteoporosis was designated a National Health Priority Area in 2002; however, implementation of national plans has not yet matched the rhetoric in terms of urgency. Building healthy bones throughout life, the Osteoporosis Australia strategy to prevent osteoporosis throughout the life cycle, presents an evidence-informed set of recommendations for consumers, health care professionals and policymakers. The strategy was adopted by consensus at the Osteoporosis Australia Summit in Sydney, 20 October 2011. Primary objectives throughout the life cycle are: to maximise peak bone mass during childhood and adolescence to prevent premature bone loss and improve or maintain muscle mass, strength and functional capacity in healthy adults to prevent and treat osteoporosis in order to minimise the risk of suffering fragility fractures, and reduce falls risk, in older people. The recommendations focus on three affordable and important interventions to ensure people have adequate calcium intake, vitamin D levels and appropriate, physical activity throughout their lives. Recommendations relevant to all stages of life include: daily dietary calcium intakes should be consistent with Australian and New Zealand guidelines serum levels of vitamin D in the general population should be above 50 nmol/L in winter or early spring for optimal bone health regular weight-bearing physical activity, Muscle strengthening exercises and challenging balance/ mobility activities should be conducted in a safe environment.

Breast cancer cells induce osteolytic bone lesions in vivo through a reduction in osteoblast activity in mice

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

Mice lacking β-Adrenergic receptors have increased bone mass but are not protected from deleterious skeletal effects of ovariectomy

Activation of β2-adrenergic receptors inhibits osteoblastic bone formation and enhances osteoclastic bone resorption. Whether β-blockers inhibit ovariectomy-induced bone loss and decrease fracture risk remains controversial. To further explore the role of β-adrenergic signaling in skeletal acquisition and response to estrogen deficiency, we evaluated mice lacking the three known β-adrenergic receptors (β-less). Body weight, percent fat, and bone mineral density were significantly higher in male β-less than wild-type (WT) mice, more so with increasing age. Consistent with their greater fat mass, serum leptin was significantly higher in β-less than WT mice. Mid-femoral cross-sectional area and cortical thickness were significantly higher in adult β-less than WT mice, as were femoral biomechanical properties (+28 to +49%, P < 0.01). Young male β-less had higher vertebral (1.3-fold) and distal femoral (3.5-fold) trabecular bone volume than WT (P < 0.001 for both) and lower osteoclast surface. With aging, these differences lessened, with histological evidence of increased osteoclast surface and decreased bone formation rate at the distal femur in β-less vs. WT mice. Serum tartrate-resistance alkaline phosphatase-5B was elevated in β-less compared with WT mice from 8–16 wk of age (P < 0.01). Ovariectomy inhibited bone mass gain and decreased trabecular bone volume/total volume similarly in β-less and WT mice. Altogether, these data indicate that absence of β-adrenergic signaling results in obesity and increased cortical bone mass in males but does not prevent deleterious effects of estrogen deficiency on trabecular bone microarchitecture. Our findings also suggest direct positive effects of weight and/or leptin on bone turnover and cortical bone structure, independent of adrenergic signaling.

A soluble activin Type IIA receptor induces bone formation and improves skeletal integrity

Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF-superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF-� signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we demonstrate that pharmacological blockade of ligand signaling through the high affinity receptor for activin, type II activin receptor (ActRIIA), by administration of the soluble extracellular domain of ActRIIA fused to a murine IgG2a-Fc, increases bone formation, bone mass, and bone strength in normal mice and in ovariectomized mice with established bone loss. These observations support the development of this pharmacological strategy for the treatment of diseases with skeletal fragility.

A prospective model of care for breast cancer rehabilitation : bone health and arthralgias

Musculoskeletal health can be compromised by breast cancer treatment. In particular, bone loss and arthralgias are prevalent side effects experienced by women treated with chemotherapy and/or adjuvant endocrine therapy. Bone loss leads to osteoporosis and related fractures, while arthralgias threaten quality of life and compliance to treatment. Because the processes that lead to these musculoskeletal problems are initiated when treatment begins, early identification of women who may be at higher risk of developing problems, routine monitoring of bone density and pain at certain stages of treatment, and prudent application of therapeutic interventions are key to preventing and/or minimizing musculoskeletal sequelae. Exercise may be a particularly suitable intervention strategy because of its potential to address a number of impairments; it may slow bone loss, appears to reduce joint pain in noncancer conditions, and improves other breast cancer outcomes. Research efforts continue in the areas of etiology, measurement, and treatment of bone loss and arthralgias. The purpose of this review is to provide an overview of the current knowledge on the management and treatment of bone loss and arthralgias in breast cancer survivors and to present a framework for rehabilitation care to preserve musculoskeletal health in women treated for breast cancer.

A comparative study of Sr-incorporated mesoporous bioactive glass scaffolds for regeneration of osteopenic bone defects

SUMMARY: Recently, the use of the pharmacological agent strontium ranelate has come to prominence for the treatment of osteoporosis. While much investigation is focused on preventing disease progression, here we fabricate strontium-containing scaffolds and show that they enhance bone defect healing in the femurs of rats induced by ovariectomy. INTRODUCTION: Recently, the use of the pharmacological agent strontium ranelate has come to prominence for the treatment of osteoporosis due to its ability to prevent bone loss in osteoporotic patients. Although much emphasis has been placed on using pharmacological agents for the prevention of disease, much less attention has been placed on the construction of biomaterials following osteoporotic-related fracture. The aim of the present study was to incorporate bioactive strontium (Sr) trace element into mesoporous bioactive glass (MBG) scaffolds and to investigate their in vivo efficacy for bone defect healing in the femurs of rats induced by ovariectomy. METHODS: In total, 30 animals were divided into five groups as follows: (1) empty defect (control), (2) empty defects with estrogen replacement therapy, (3) defects filled with MBG scaffolds alone, (4) defects filled with MBG + estrogen replacement therapy, and (5) defects filled with strontium-incorporated mesopore-bioglass (Sr-MBG) scaffolds. RESULTS: The two groups demonstrating the highest levels of new bone formation were the defects treated with MBG + estrogen replacement therapy and the defects receiving Sr-MBG scaffolds as assessed by μ-CT and histological analysis. Furthermore, Sr scaffolds had a reduced number of tartrate-resistant acid phosphatase-positive cells when compared to other modalities. CONCLUSION: The results from the present study demonstrate that the local release of Sr from bone scaffolds may improve fracture repair. Future large animal models are necessary to investigate the future relationship of Sr incorporation into biomaterials.

PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton

We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z< -2.0) and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (785 unrelated individuals, mean age 118 months), were genotyped for the five most informative SNPs (minor allele frequency >5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021-0.047). This association was restricted to the youngest tertile of the population (age 16-39 years, P = 0.013-0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.