Osteoporosis

Diagnosis and Management

Dale W. Stovall

• Publisher: Wiley-Blackwell
• Year: 2013
• Print ISBN: 9781119968917
• eBook ISBN: 9781118316313
• Edition: 1
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

You can reduce the risk of your patients suffering an
osteoporosis-related fracture.

Osteoporosis is a highly prevalent, treatable disease, but it is currently
incurable. Successful early diagnosis can lead to effective treatment
strategies that reduce the risk of a patient's life being compromised by
serious fracture injury.

In Osteoporosis, Dr Dale Stovall has assembled world-leading experts who
guide you through modern best-practice approaches to:

• Diagnosis of osteoporosis
• Risk assessment for fractures
• Use of calcium and vitamin D
• Medical therapy and follow up
• Future approaches to treatment

Osteoporosis empowers you to identify and treat your patients with
osteoporosis and low bone mass, preventing subsequent fractures and
improving their quality of life.

CHAPTER 1

Epidemiology and Genetics of Postmenopausal Osteoporosis

Mark Edwards1, Rebecca Moon1, Nick Harvey1 & Cyrus Cooper1,2

1University of Southampton, University Hospital Southampton, Southampton, UK

2University of Oxford, Oxford, UK

Introduction

Osteoporosis is a skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture [1]. The term osteoporosis literally means “porous bone” and refers to a condition in which bone is normally mineralized but reduced in quantity. In 1994, a working group of the World Health Organization (WHO) provided a practical definition of osteoporosis as a bone mineral density (BMD) of greater than 2.5 SD below the young normal mean [2]. Earlier definitions had incorporated fracture and so to provide comparability, the subset of women with osteoporosis who had also suffered one or more fragility fractures were deemed to have severe “established” osteoporosis.

The etiology of osteoporotic fractures is complex. Low bone density is not the only risk factor for fracture and there has been a move towards making an assessment of individualized 10-year absolute fracture risk using the WHO FRAX based on multiple clinical risk factors [3]. Family history, and in particular parental hip fracture, is included in the FRAX tool reflecting the hereditary component of the condition. There is growing recognition of a complex interaction between genetic and environmental factors. Only a small number of specific genes contributing to osteoporosis risk have been consistently identified; however, the investigation of gene-environment interactions with developmental plasticity has yielded promising results, raising the possibility of intervening during fetal development or early life to reduce individual fracture risk and the global burden of this disease. It is estimated that around 200 million women worldwide have osteoporosis with an osteoporotic fracture occurring every 3 seconds [4]. This equates to 1 in 3 women over 50 years of age suffering an osteoporotic fracture [5,6]. Fragility fractures make up 0.83% of the worldwide burden of noncommunicable disease. This figure rises to 1.75% in Europe, where fragility fractures also account for more disability adjusted life years (DALYs) than many other chronic diseases [7]. At present the annual cost of all osteoporotic fractures worldwide is in excess of $17 billion and is expected to rise to $25 billion by 2025 [8]. The cost of treating osteoporotic fractures is also increasing in the UK and expected to rise to over £2 billion by 2020 [9]. This chapter will review the genetic and early environmental factors associated with osteoporosis and describe the demographic, global and secular trends in its epidemiology.

Genetics

Heritability estimates in osteoporosis

Peak bone mass is an important factor in determining BMD in later life. It has been suggested by twin and family studies that between 50% and 85% of the variance in BMD is determined by heritable factors [10–12], including both genetics and shared environmental exposures. These estimates do, however, vary depending on the skeletal site, with lumbar spine BMD demonstrating a greater heritable component than the distal forearm BMD [10, 12, 13]. Several studies have suggested that increasing age also influences the extent to which bone outcomes are determined by heritable factors. It has been shown that the heritable component of BMD is lower in postmenopausal compared with premenopausal women [10, 12], probably reflecting the greater role of additional lifestyle, dietary and disease-related factors occurring in postmenopausal women. Similarly, the heritable component of the rate of change in BMD in postmenopausal women is lower than that for peak bone mass, which occurs much earlier in life [14].

In terms of osteoporotic fractures, it is known that the risk is greater in those with a parent who has suffered a hip fracture. There is, however, less evidence for a significant genetic component to this association. A heritable component has also been found in the determination of femoral neck geometry [15], markers of bone turnover [16], age at menopause [17], and muscle strength [18], all of which confer some susceptibility to osteoporotic fracture. These factors, in addition to the associations with BMD, suggest that there is likely to be a role in fracture prediction; however, due to the size of the effect, it has been difficult to demonstrate in epidemiological studies.

Genetic studies in osteoporosis

Having determined that there is a small, but significant, genetic component to the risk of osteoporosis, different types of genetic investigations have been used to attempt to identify specific genetic loci. Linkage studies are useful in identifying genetic mutations in monogenic disorders and the genes responsible for a number of rare diseases associated with severe osteoporosis, fragility fractures or high bone mass, which result from single gene mutations inherited in classical Mendelian fashion, have been identified through this technique. Osteogenesis imperfecta, for example, is most commonly caused by mutations in the COL1A1 and COL1A2 genes resulting in abnormal type 1 collagen formation. Loss of function mutations in the LRP5 gene, encoding LDL receptor-related protein 5, a key regulator in osteoblastic bone formation, have been implicated in osteoporosis-pseudoglioma syndrome. Conversely gain-of-function mutations in the same gene are associated with familial high bone mass syndrome.

However, postmenopausal osteoporosis has been associated with a large number of common genetic variants each of which imparts only a minor effect. Linkage studies have therefore been of limited success in identifying contributory genes due to the low power to detect these common variants.

Candidate gene association studies (CGAS) and genome wide association studies (GWAS) have successfully identified a number of susceptibility loci. In CGAS, candidate genes are chosen for analysis based on a known role in the regulation of calcium metabolism or bone cell function. Many of the causative genes in monogenic disorders of bone fragility have been investigated. Single nucleotide polymorphisms (SNPs) are common variants which occur in at least 1% of the population. The frequency of these SNPs in candidate genes are compared in unrelated subjects in either a case-control study for categorical outcomes, for example history of an osteoporotic fracture, or as a population study for a quantitative outcome, for example BMD. A number of susceptibility variants have been identified using this method. However, false negative results are not uncommon due to limited power of the studies, and the results of studies in different populations are often conflicting.

With increasing acceptability to undertake genetic studies that are not hypothesis driven, GWAS have been able to clearly and reproducibly identify susceptibility loci for BMD variation. Large numbers (100 000–1 000 000) of common SNPs spread at close intervals across the genome are analyzed rather than focusing on a single candidate gene. A significant observation in the variant site is interpreted to indicate that the corresponding region of the genome contains functional DNA-sequence variants for the disease or trait being studied. These can include sequence variants leading to amino acid alterations in proteins, changes to gene promoter regions or alterations to mRNA degradation. However, a number of potential loci have also been identified, for which the function remains unknown. This might additionally offer the possibility of identifying novel pathways and mechanisms involved in bone formation and the development of osteoporosis.

Due to the large number of tests, GWAS are subject to stringent statistical thresholds. As with CGAS, false negatives are likely. Meta-analysis has been increasingly used to determine the true effects of genetic polymorphisms. The GENOMOS consortium (Genetic Markers of Osteoporosis; www.genomos.eu) was initially formed to undertake prospective meta-analysis of CGAS, and has identified SNP variants in COL1A1 and LRP5 associated with femoral and lumbar spine BMD. It has subsequently developed into the GEFOS (Genetic Factors for Osteoporosis; www.gefos.org) consortium which is undertaking meta-analysis of ongoing GWAS, and has identified or confirmed a number of loci associated with lumbar spine or femoral neck BMD [19].

Genes involved in osteoporosis

A number of genes have been identified through CGAS and GWAS as possible candidates for the regulation of bone mass and osteoporotic fracture susceptibility. A substantial number of these can be classified as influencing three biological pathways: the estrogen pathway, the Wnt-ß-catenin signaling pathway and the RANKL-RANK-OPG pathway. These are briefly summarized below.

The estrogen pathway

Estrogen is a well-recognized regulator of skeletal growth, bone mass and bone geometry. Estrogen receptor deficiency and aromatase deficiency are monogenic disorders associated with osteoporosis. Genetic variation at a number of SNPs in the estrogen receptor type 1 gene (ESR1) have been associated with many osteoporotic traits and risk factors including BMD [19], age at menopause [20] and postmenopausal bone loss [21].

Wnt-ß-catenin signaling pathway

The Wnt signaling pathway has a key role in many developmental processes. In bone, the activation of this pathway by Wnt binding to LRP5 or LRP6 transmembrane receptors leads to osteoblast differentiation and proliferation, bone mineralization and reduction in apoptosis. Loss of function mutations of LRP5 result in osteoporosis-pseudoglioma syndrome, but more subtle polymorphisms have been associated with variance in BMD or fracture risk in the normal population. Some of these variants have been confirmed by meta-analysis [19, 22...

Table of contents

• Cover
• Title Page
• Copyright
• List of Contributors
• Preface
• Chapter 1: Epidemiology and Genetics of Postmenopausal Osteoporosis
• Chapter 2: Osteoporosis in Men
• Chapter 3: Mechanisms of Bone Remodeling
• Chapter 4: Fracture Risk Assessment
• Chapter 5: Secondary Causes of Osteoporosis: Bone Diseases
• Chapter 6: Glucocorticoid-induced Osteoporosis
• Chapter 7: Secondary Causes of Osteoporosis: Other Medications
• Chapter 8: Hormone Therapy for Osteoporosis
• Chapter 9: Bisphosphonates
• Chapter 10: Denosumab
• Chapter 11: Parathyroid Hormone: Anabolic Treatment of Osteoporosis
• Chapter 12: Optimum Calcium and Vitamin D for the Prevention and Treatment of Osteoporosis
• Chapter 13: The Use of Combination Therapy in the Treatment of Postmenopausal Osteoporosis
• Chapter 14: Emerging Therapies
• Chapter 15: Monitoring Therapy for Osteoporosis
• Chapter 16: Persistence and Compliance with Medications to Prevent Fractures: Epidemiology, Etiology, and Management Issues
• Appendix: A Clinician's Approach to the Patient
• Index