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Thesis Rests with Its Author University of Bath DOCTOR OF MEDICINE The pathophysiology of osteoporosis in ankylosing spondylitis Mitra, Devashis Award date: 1995 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 09. Oct. 2021 THE PATHOPHYSIOLOGY OF OSTEOPOROSIS IN ANKYLOSING SPONDYLITIS Submitted by Devashis Mitra For the degree of Doctor of Medicine of the University of Bath 1995 Copyright Attention is drawn to the feet that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that the copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. Restrictions on use This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation. Signature UMI Number: U601966 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U601966 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 2 3 AUG 1996 DEDICATION To Neelam for all her love and support, and To Akul for bringing so much joy into our lives STATEMENT OF ORIGINALITY The work contained herein is my own. I personally carried out the following: 1. Screening and selection of patients and controls. 2. All clinical assessments including metrology. 3. Setting up and running the following biochemical markers of bone turnover for patients with ankylosing spondylitis: Serum osteocalcin, Total alkaline phosphatase, Bone alkaline phosphatase, and, Urinary pyridinoline and deoxypyridinoline. 4. Establishing normal ranges for the for the following markers of bone turnover: Osteocalcin, Bone alkaline phosphatase, and, Urinary pyridinoline and deoxypyridinoline. 5. Vertebral morphometry for all patients with ankylosing spondylitis and normal controls. Bone sialoprotein was performed in collaboration with Tore Saxne, Department of Rheumatology, Lund University, Lund, Sweden. Signature TABLE OF CONTENTS Summary List of abbreviations Chapter 1. Introduction 1 Ankylosing spondylitis 2 Cellular basis of bone turnover 15 Biochemical markers of bone turnover 33 Osteoporosis in men 41 Osteoporosis in inflammatory arthritides 46 Osteoporosis in ankylosing spondylitis 48 Vertebral fractures and their relevance in ankylosing spondylitis 54 Radiographic diagnosis of osteoporosis 57 Bisphosphonates in osteoporosis 63 Aims and objectives 67 Chapter 2. Methodology 68 Consent 69 Selection of patients 70 Selection of controls 71 Clinical assessments 73 Vertebral deformity definition by morphometry 77 Biochemical markers of bone metabolism 83 Bone mineral density measurements by DXA 93 Statistical analysis 100 i Chapter 3. Prevalence of vertebral deformities in early ankylosing spondylitis and its relationship to bone mineral density Summary 101 Introduction 103 Methods 104 Results 106 Discussion 116 Chapter 4. Biochemical markers of bone turnover in early ankylosing spondylitis and their relationship with bone mineral density and vertebral deformities Summary 121 Introduction 123 Methods 124 Results 126 Discussion 137 Chapter 5. The efficacy of etidronate in males with early ankylosing spondylitis and osteoporosis: a double blind placebo controlled study Summary 141 Introduction 143 Methods 144 Results 147 Discussion 156 ii Chapter 6. Conclusions 159 Chapter 7. Further studies 169 Acknowledgements 172 References 174 Appendices Appendix 1 Ankylosing spondylitis data sheet 203 Appendix 2 Reference values for vertebral deformities 2. a. UK reference values 208 2. b. AS reference values 210 2. c. Control reference values 212 Abstracts and presentations arising from this work 214 iii SUMMARY Ankylosing spondylitis (AS) is often complicated by axial osteoporosis and vertebral deformities although their relationship is not well established. The aims of this study were to determine the bone mineral density (BMD), biochemical markers of bone turnover and the prevalence of vertebral deformities in men with early AS, to establish the relationship between the markers of bone turnover, BMD and vertebral deformities, and, to assess the efficacy of etidronate on patients with AS and osteoporosis. A detailed clinical assessment was performed to establish disease activity. Sex hormones, calciotropic hormones and biochemical markers of bone formation and resorption were measured in all patients in comparison with controls of similar age range. BMD of the lumbar spine and femoral neck was measured by dual energy x-ray absorptiometry and vertebral deformities were defined by two methods. A double blind placebo controlled study with etidronate was performed in a group of patients with AS and osteoporosis. BMD of the lumbar spine and femoral neck was significantly reduced in the patients with AS. The prevalence of vertebral deformities in AS was 16.7% (McCloskey method) and 24.2% (Eastell-grade 1) and 7.6% (Eastell-grade 2). Compared to controls the AS patients had an increased risk for deformities. No relationship between BMD and vertebral deformities was observed. Patients with AS had significantly low osteocalcin compared with controls of similar age. No relationship was observed between markers of bone turnover and BMD or vertebral deformties. In the double blind study, patients in the etidronate group showed a significant improvement in lumbar spine BMD and disease activity compared with the placebo group. Axial osteoporosis and vertebral deformities are features of early AS. The lack of relationship between BMD and deformity suggests that other factors in addition to low BMD may be implicated in the pathogenesis of vertebral deformities. Markers of bone turnover are not good predictors of either low bone mass or vertebral deformity. AS patients with active disease and osteoporosis may benefit from etidronate therapy. LIST OF ABBREVIATIONS AS Ankylosing spondylitis BMD Bone mineral density DXA Dual energy x-ray absoiptiometry Def Vertebral deformity UKR UK reference values for definition of vertebral deformity ASR AS reference values CR Control reference values ALP Alkaline phosphatase (total) BALP Bone alkaline phosphatase BSP Bone sialoprotein Pyr Pyridinoline Dpyr Deoxypyridinoline 25(OH)VitD 25 hydroxy vitamin D PTH Parathyroid hormone FSH Follicle stimulating hormone LH Luteinizing hormone SHBG Sex hormone binding globulin TFI Testosterone free index CRP C-reactive protein IL-1 Interleukin 1 TNF Tumour necrosis factor Chapter 1. INTRODUCTION 1.1. Ankylosing spondylitis 1. 2. Cellular basis of bone turnover 1. 3. Biochemical markers of bone turnover 1. 4. Osteoporosis in men 1. 5. Osteoporosis in inflammatory arthritides 1. 6. Osteoporosis in ankylosing spondylitis 1. 7. Vertebral fractures and their relevance in ankylosing spondylitis 1. 8. Radiographic diagnosis of osteoporosis 1. 9. Bisphosphonates in osteoporosis 1.10. Aims and objectives 1 1.1. ANKYLOSING SPONDYLITIS I. I. 1. Historical Review In 1982, Dastugue described a skeleton (3500 BC) in a neolithic grave in Calvados. Bony bridging of the vertebral bodies in the specimen was clearly present, but the presence of sacroiliitis was difficult to comment on, as these joints were not well preserved. The paleopathologist Sir Mark Ruffer in 1912 described a Nefermaat (2900 BC). The remains demonstrated a rigid block of bone from the mid cervical region to the sacrum Short (1974) described 18 examples of ankylosing spondylitis (AS) derived from Egyptian sources extending from 2900 BC to 200 AD. The general recognition of AS was promoted following the descriptions by von Bechterew in 1893 (St. Petersburg), Strumpell in 1897 (Berlin) and Marie in 1898 (Paris) [Spencer et al 1980]. 1. 1, 2. Nomenclature The term ankylosing spondylitis is derived from the Greek words ankylos (bent) and spondylos (vertebra). Various other terms have been used in the past to describe AS, including spondylitis ankylopoietica, spondylitis deformans, atrophic spondylitis, spondylitis atrophica ligamentosa, pelvospondylitis ossificans, spondylitis rhizomelica,
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