Current Topics in Osteoporosis

The following sections are included:

• FOREWORD

• TABLE OF CONTENTS

The following sections are included:

• Research agenda
• Summary
• Introduction
• Definition
• Predicting fracture risk
• Fracture epidemiology
  • Hip fracture
    • Geographical pattern
    • Secular trends
    • Incidence by sex and age
  • Vertebral fracture
    • Geographical pattern
    • Temporal trends
  • Distal forearm fracture
• Socio-economic impact of osteoporosis
  • Mortality
  • Morbidity and quality of life
• Costs of osteoporosis
• REFERENCES

A brief discussion into the nature of the condition, its prevalence, incidence and its target population was required before the social and financial costs could be stated. Indeed it was crucial to establish the condition as an important financial stress to health services worldwide. Estimations were then made concerning the costs, both economically and socially, with subsequent research to determine the most viable method for reduction of such costs. The possibility of reducing hospitalization periods via the introduction of community care projects, the concept of screening for the condition and an increased awareness of the preventive mechanisms were all considered. It became apparent that, due to limited knowledge concerning the disease and its treatment, it was best to focus attention on preventing the condition.

Fragility fractures of the spine and hip are a public health problem in both Asian and Caucasian women. Epidemiological studies have suggested that the vertebral fracture prevalence or incidence is similar or higher, while the hip fracture rate is lower in Asian women than Caucasian women. Most of the comparative studies have been focused on racial differences in areal BMD (aBMD), in which the lower aBMD in Asians than Caucasians is largely due to Asians having smaller bone size. Both growth- and age-related factors may contribute to the pathogenesis of bone fragility at each group and to the racial differences in fractures rates between the two groups. However, the structural basis and the pathophysiologic mechanisms responsible for the purported racial differences in fracture rates are largely unknown. There is very limited data in Asian women regarding the structural basis of bone modelling and remodelling on the periosteal and endosteal surfaces of bone during growth and aging, nor hypothesisdriven studies comparing the racial differences of growth and agerelated surface specific changes. Comparative studies between the two groups are needed in almost every aspect of skeletal biology. However, these studies require careful design and attention to methodological issues. The results of these comparative studies will provide important insights into the structural basis and pathophysiology of bone fragility in both groups.

The following sections are included:

• Introduction: The Causes of Osteoporotic Fragility
  • Decreased Intrinsic Bone Strength
  • Increased Propensity for Injury

• Calcium
  • The Skeleton as the Calcium Nutrient Reserve
  • The Calcium Requirement and the Consequences of Suboptimal Calcium Intake
  • Nutrient-Nutrient Interactions: Factors that Influence the Calcium Requirement
  • Calcium Requirement and Body Size
  • Calcium Sources

• Vitamin D
  • The Functioning of Vitamin D in the Calcium Economy
  • Sources of Vitamin D

• Protein

• Phosphorus

• Minerals and Trace Nutrients
  • Trace Minerals
  • Other Vitamins

• Conclusion

• REFERENCES

The strength of a bone is directly related to its ability to resist fracture in a given loading environment. Bone strength is dependent on a number of factors that can be grouped broadly into three categories: material properties (i.e. mean levels of mineralization, organic properties), bone architecture (i.e. cortical thickness, distribution, porosity; trabecular thickness, connectivity, perforations) and bone mass (i.e. more massive bone is stronger).

Estrogen deprivation reduces bone mass, accelerates bone remodeling, and weakens bone structure. Under current guidelines, the diagnosis of osteoporosis rests heavily upon bone mass, measured as BMD. This approach can be questioned, however, by the facts that fracture resistance is more dependent on age than BMD, and treatment agents with antifracture efficacy have little effect on bone mass. We outline a comprehensive set of considerations to exclude other possibilities and support a diagnosis of osteoporosis.

The following sections are included:

• Introduction

• Biochemical markers of bone formation
  • Enzymes
  • Bone matrix protein

• Biochemical markers of bone resorption
  • Ezymes
  • Collagen degradation products
  • Non collagen bone matrix degradation product

• Variability – a consideration when using biochemical markers

• Clinical application of biochemical markers in osteoporosis
  • Monitoring response to antiresorptive drugs
  • Other potential clinical applications

• Conclusion

• REFERENCE

Bone marrow adipogenesis is a postnatal event during bone and marrow development. In the adult bone, marrow adipocytes occupy the largest space of the marrow cavity, and serve as a source of energy, autocrine and paracrine factors. Marrow adipocyte share a common multipotential mesenchymal stem cell with other marrow stomal lineages, and functional overlap exists among them. In the marrow stroma microenvironment, adipogenesis is closely associated with osteogenesis, hematopoiesis and osteoclastogenesis. With ageing, increased marrow adipocytes accompany with decreased trabecular bone volume. Marrow adipogenesis may be an important complication of osteoporosis. Many regulators including hormones, growth factors, proinflammatory cytokines and their receptors such as nuclear hormone receptors, trans-memberane kinase receptors and G-protein coupled receptors are involved in the signaling pathway of adipogenesis, and may present potential molecular targets for the manipulation of adipocyte differentiation. Marrow adipocyte may be considered as an important target cell for the therapeutic intervention in osteoporosis. The inhibition of marrow adipogenesis and concomitant enhancement in osteogenesis may provide a potential approach to increase bone formation and therefore provide more efficacious prevention or treatment of osteoporosis.

The chapter briefly introduces some statistical methods used to develop osteoporosis diagnosis techniques, to assess fracture risk, to evaluate and compare diagnostic markers, quality control, clinical trials, and cost-effectiveness analysis. It focuses on statistical concepts and gives references for their applications in osteoporosis without mathematical details.

Osteoporosis is a growing health problem affecting many postmenopausal women. The overall goal of postmenopausal osteoporosis (PMO) management is the prevention of fracture. The prevention strategy includes increased calcium and vitamin D intake, exercise, and fall prevention. For patients with a high-risk of osteoporosis, the Food and Drug Administration (FDA) approved pharmacological agents including estrogen may be considered. Drugs approved by the FDA for the treatment of PMO include calcitonin, raloxifene, alendronate, risedronate, and teriparatide. This chapter reviews current understanding of PMO prevention and treatment.

Osteoclasts are bone resorbing cells. The increased formation and activation of osteoclasts underlies many common bone lytic disorders such as osteoporosis, Paget's disease, bone metastatic diseases, arthritis, and aseptic bone loosening. Currently, drugs used in management of osteoporosis are limited to bisphosphonates, calcium and vitamin D. Although there is evidence that hormone replacement therapy prevents bone loss in postmenopausal women, its beneficial effect on bone is overshadowed by its association with increased risks in breast cancer and cardiovascular disease. Unravelling the genetic regulation of osteoclastogenesis and osteoclast activation and discovering therapeutic agents to control these processes are critical for the development of effective treatment for osteoporosis. This chapter reviews novel potential targets for anti-resorptive drugs and determines the viability of these targets, giving special consideration to specificity to bone and any side effects. Several groups of targets have been identified as being promising: including the RANKL/RANK/OPG axis; intracellular signalling molecules, such as c-Src; integrins, especially the α_vβ₃ integrin, and enzymes, such as cathepsins and vacuolar H+ATPase. A significant amount of in vitro data concerning many of these targets have been generated, yet there is still little research investigating the capacity for drugs to manipulate these targets and to provide beneficial and non-toxic therapy in a clinical setting. It is clear that some targets are more promising than others, namely RANKL/RANK/OPG axis, cathepsin K and c-Src tyrosine kinase. However, additional research is required before any one target or therapy can be pursued clinically.

Male osteoporosis is becoming increasingly recognized as a significant medical issue affecting the older male population. Pande recognized that 25-30% of all hip fractures occur in men.¹ By the age of 90 years, one of every six men will have a hip fracture. Although there is an increase in morbidity and mortality in both male and female after hip fracture, the mortality rate in men is higher.^2,3 This article highlights current understanding of the epidemiology and causes of male osteoporosis, diagnosis, and treatment options.

Osteoarthritis is one of the most common joint disorders in the elderly in China (1, 2) and throughout the world (3). Among adults 60 years of age and older in Beijing, China, prevalence of radiographic osteoarthritis was 34.1% in knee (1) and 46.0% in hand (2), whereas the prevalence of symptomatic osteoarthritis was 11.1% for knee (1) and 4.7% for hand (2). Prevalence of hip and hand osteoarthritis in the United States population is even higher than that observed in Beijing, China (2, 4). Numerous risk factors for osteoarthritis have been studied, and one that has been extensively evaluated is bone mineral density or osteoporosis.

The rarity of co-existence between osteoarthritis and osteoporosis was reported by clinicians four decades ago (5, 6). Two cases series reports indicated a general absence of osteoarthritis in excised femoral head in subjects with femoral fracture (7) or in post mortem skeleton (8). These clinical observations have led numerous investigators to examine the relationship between osteoporosis and osteoarthritis, and to explore the potential role of bone mineral density in the development of osteoarthritis.

The following sections are included:

• Introduction

• Primary osteoporosis in pediatrics
  • Nutritional Rickets
  • Vitamin D pseudodeficiency (PDDR)
  • Hereditary 1,25-dihydroxy vitamin D resistant rickets (HVDRR)
  • Osteogenesis imperfecta (brittle bones disease)
    • Mild OI with normal stature
    • Moderate OI with short stature
    • Severe OI with triangular face
    • Lethal OI
    • Congenital brittle bones with dense areas in bones
  • Syndromes resembling osteogenesis imperfecta (SROI) [139]
    • Congenital brittle bones with hyperplastic callus formation
    • Osteoporosis pseudoglioma syndrome [149, 150]
    • Other ocular forms of SROI
    • Congenital brittle bones with craniosynostosis (Cole-Carpenter syndrome)
    • Congenital brittle bones with congenital joint contractures
    • Congenital brittle bones with mineralization defect
    • Congenital brittle bones with rhizomelia
  • Idiopathic Juvenile Osteoporosis
  • Hypophosphatasia
  • Hyperphosphatasia
  • Primary hypomagnesemia

• Secondary osteoporosis in pediatrics
  • Immobilization
  • Neuromuscular diseases
  • Type I diabetes mellitus
  • Renal causes
  • Hypogonadism
  • Malabsorption
  • Inborn errors of metabolism
  • Malignancy and steroid induced osteoporosis
  • Prematurity
  • Juvenile rheumatoid arthritis
  • Drugs and toxics

• Work-up

• Treatment

• REFERENCES

The following sections are included:

• Introduction

• Evidence for Genetic Basis of Osteoporosis and Associated Traits

• Searching for Osteoporosis Genes
  • Candidate Gene Association Studies
    • Functional candidate genes
    • Gene-by-gene and gene-by-non-genetic factor interactions
  • Linkage Studies
    • Linkage approach
    • Linkage studies in humans
    • Replications
  • Gene Expression Studies
    • Comparative gene expression studies of healthy and diseased tissues
    • Effects of various inherent regulators on gene expression profiles of bone-related tissues

• Acknowledgment

• REFERENCES

Osteoporosis, a common complex disease determined by multiple genetic, environmental and lifestyle factors, is mainly characterized by low bone density, leading to increased risk of low trauma fracture. Current genetics studies have shown that genetic factors play an important role not only in the etiopathogenesis but also in the treatment of osteoporosis. This fact has great implication in terms of antiosteoporosis clinical therapeutics. Several potential ways to use genetic information for the prevention and treatment of osteoporosis are reviewed and discussed in this article. The first application is identification of novel genes or genetic variants of candidate genes that are associated with osteoporosis, which could be used either as drug targets or as reagents for drug development. Second, genetic approaches could furnish genetic profiling for drug efficacy or toxicity assessment. Finally, the knowledge gained through genetic studies can be applied to anti-osteoporosis gene therapy and personalized treatment. Genomics is also fostering new strategies in osteoporosis research and prevention. Pharmacogenomics, functional genomics, proteomics and modern bioinformatics will greatly contribute to optimizing osteoporosis drug development and therapeutics.

The following sections are included:

• Introduction

• Whole-Genome Linkage and Association Studies
  • Whole-Genome Linkage Scan
  • Fine Mapping
  • Whole-Genome Association Mapping

• High-Throughput Methods for Analysis of Differential Gene Expression
  • Limitations of the Traditional Gene Expression Studies of Osteoporosis
  • EST Sequencing
  • Subtractive Cloning
  • Differential Display
  • Serial Analysis of Gene Expression (SAGE)
  • cDNA Microarrays
  • What to Use: Cell Cultures or Fresh Tissue Samples?
  • The High-Throughput Methods of Differential Gene Expression Analysis in Study of Osteoporosis: the Prospects

• Proteomics

• Conclusions

• Acknowledgments

• REFERENCES

The following sections are included:

• Introduction

• The Ovariectomized (OVX) Rat Model

• Study Design Using Young Adult OVX Rat Model

• The OVX Mouse Model

• The OVX Dog Model

• The OVX Nonhuman Primate

• Other OVX Animal Models

• The Knockout/Transgenic Models

• Summary

• REFERENCES

‘Kidney tonifying’ herbal medicine has been traditionally using in treatment of fractures, joint diseases, and gonadal dysfunctions in Asia for thousands of years. In the last 2 decades, many such herbal formulae have also been developed and evaluated clinically in smallscale trials for prevention and treatment of osteoporosis. In order to explore the potential underlying mechanisms as to how these herbs or herbal formulae work on their target cells, tissues or organs, both in vitro and in vivo experimental studies have been conduced. The related English literature is however lacking and majority of such studies are published in local journals, such as in China. Up to date, no single herb or herbal component has been found to be effective since osteoporosis is a multifactorial deteriorating skeletal condition. Phytoestrogen, found in many herbs or plants, shows structural similarities to estrogen and binds to estrogen receptors, suggesting an important pathway for maintaining bone mineral homeostasis and as a bioactive component in quality assurance. This paper provides a brief overview of the herbal preparations developed for the prevention and treatment of estrogen deficiency induced bone loss in rodent animals and postmenopausal women. The outcomes of the majority of the previous investigations are encouraging. This warrants further studies, including identification and purification of active components for development of new herbal formulae and evidence-based clinical trials in prevention and treatment of osteoporosis and its related medical conditions. The potential beneficial effects on non-skeletal elements associated with prevention of fragility fractures are also briefly mentioned. In order to enhance the quality of the research, “General Guidelines for Research & Development of Herbal Medicine and Evaluation of Its Efficacy in the Prevention and Treatment of Osteoporosis and Fragility Fractures” have therefore been proposed.

The following sections are included:

• APPENDIX: AN INTRODUCTION TO HOLOGIC TECHNOLOGY

• SUBJECT INDEX