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Recent Advances in the Pathogenesis and Treatment of Osteoporosis

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Recent Advances in the Pathogenesis and Treatment of Osteoporosis AGEING Clinical Medicine 2015 Vol 15, No 6: s92–s96 R e c e n t a d v a n c e s i n t h e p a t h o g e n e s i s a n d t r e a t m e n t of osteoporosis Authors: E l i z a b e t h M C u r t i s , A R e b e c c a J M o o n , B E l a i n e M D e n n i s o n , C N i c h o l a s C H a r v e y D a n d C y r u s C o o p e rE Over recent decades, the perception of osteoporosis has and propensity to fracture. Worldwide, there are nearly 9 changed from that of an inevitable consequence of ageing, to million osteoporotic fractures each year, and the US Surgeon that of a well characterised and treatable chronic non-commu- General's report of 2004, consistent with data from the UK, nicable disease, with major impacts on individuals, healthcare suggested that almost one in two women and one in five men systems and societies. Characterisation of its pathophysiol- will experience a fracture in their remaining lifetime from ABSTRACT ogy from the hierarchical structure of bone and the role of its the age of 50 years.1 The cost of osteoporotic fracture in the cell population, development of effective strategies for the UK approaches £3 billion annually and, across the EU, the identifi cation of those most appropriate for treatment, and estimated total economic cost of the approximately 3.5 million an increasing armamentarium of effi cacious pharmacologi- fragility fractures in 2010 was €37 billion. 2 In this article we cal therapies, have underpinned this evolution. Despite this review the pathogenesis of osteoporosis and approaches to marked progress, individuals who experience a fragility fracture improving bone strength, aimed at reducing the immense remain under-treated in many areas of the world, and there is burden of osteoporotic fracture. substantial need for investment both in secondary and primary prevention globally. In this brief article, we give an overview of P a t h o g e n e s i s the pathogenesis of osteoporosis, and summarise current and future approaches to its assessment and treatment. Hierarchical structure Fractures occur when the force applied to a bone exceeds its K E Y W O R D S : osteoporosis, epidemiology, pathophysiology, strength. A bone needs to be both stiff and flexible to resist treatment, risk assessment, dxa fracture, which is achieved through a hierarchical structure. Collagen type-1 fibrils are wound in a triple helical structure, Introduction linked together with non-collagenous proteins, which help to prevent shearing. Hydroxyapatite crystals deposited on the Osteoporosis is characterised by deterioration of bone mass collagen structure add strength, particularly in compression. and microarchitecture, resulting in increased bone fragility Cross-linkage between collagen fibrils with non-collagenous proteins is reduced in osteoporotic bone, leading to reduced tensile strength. 3 In addition, larger hydroxyapatite crystals are found in osteoporosis, making bone more brittle and prone to A Authors: academic clinical fellow, MRC Lifecourse Epidemiology fracture. 4 Unit, University of Southampton, Southampton, UK ; B clinical research fellow, MRC Lifecourse Epidemiology Unit, University of B o n e c e l l s Southampton, Southampton, UK, and Paediatric Endocrinology, Southampton University Hospitals NHS Foundation Trust, Osteoblasts, osteocytes and osteoclasts are the three main S o u t h a m p t o n , U K ; C professor of musculoskeletal epidemiology, types of bone cells. Osteoblasts are bone forming and MRC Lifecourse Epidemiology Unit, University of Southampton, may become embedded within bone mineral as mature S o u t h a m p t o n , U K ; D professor of rheumatology and clinical osteocytes (comprising 90–95% of the cells within bone) epidemiology, MRC Lifecourse Epidemiology Unit, University or remain on the surface as bone-lining cells. Osteoclasts of Southampton, Southampton, UK, and NIHR Southampton are multinucleated cells responsible for bone resorption. Biomedical Research Centre, University of Southampton and Osteoblasts and osteoclasts work together in a coordinated University Hospital Southampton NHS Foundation Trust, fashion at specific sites on the surface of trabecular or S o u t h a m p t o n , U K ; E director and professor of rheumatology, cortical bone, forming ‘bone multicellular units’. During MRC Lifecourse Epidemiology Unit, University of Southampton, bone formation, osteoblasts lay down new osteoid collagen Southampton, UK, NIHR Southampton Biomedical Research Centre, matrix and over a period of weeks to months, crystals of University of Southampton and University Hospital Southampton calcium hydroxyapatite form on the collagen fibrils. Bone is NHS Foundation Trust, Southampton, UK, and NIHR Musculoskeletal laid down during growth and repair and through adaptation Biomedical Research Unit, University of Oxford, Oxford, UK to mechanical loading in a process known as modelling. s92 © Royal College of Physicians 2015. All rights reserved. CCMJv15n6S-Cooper.inddMJv15n6S-Cooper.indd ss9292 009/11/159/11/15 99:25:25 PPMM Pathogenesis and treatment of osteoporosis Remodelling, in contrast, involves a cycle of resorption Table 2. The spectrum of antifracture efficacy of and formation of existing bone. Osteocytes play a key role in the regulation of modelling and remodelling. The pharmacological interventions for osteoporosis. arrangement of the osteocytes around Haversian canals acts Intervention Vertebral Non-vertebral Hip as a mechanosensory system and allows communication Alendronate + + + both directly between neighbouring osteocytes and through the release of endocrine, paracrine and autocrine signalling Risedronate + + + factors to other bone cells. The various pathways important Zoledronic acid + + + to the regulation of osteoblast and osteoclast activity, such Etidronate + – – as receptor activator of nuclear factor kappa B–receptor activator of nuclear factor kappa B ligand (RANK–RANKL) Ibandronate + +* – and Wnt signalling, are increasingly recognised as targets for Raloxifene + – – anti-osteoporosis agents. Strontium ranelate + + +* Teriparatide + + – Changes in bone structure across the life course Denosumab + + + The balance of formation and resorption has a critical influence *post hoc analysis in a subset of patients. on bone mass and strength throughout life. There is a positive balance during childhood until achievement of peak bone mass in early adulthood, 5 with a subsequent period of stability and then a negative balance in older age, with osteoclast activity Clinical risk factors greater than osteoblast activity, leading to bone loss. In women, There are many factors that influence fracture risk, either this process is accelerated after the menopause. At the level of the through bone mineral density (BMD) or through independent whole bone, the cellular mechanisms and associated influences mechanisms. These include age, glucocorticoid therapy, a result in differences in structure between males and females, previous personal history of fracture, a family history of hip and alterations with advancing age. Males typically have a fracture, current smoking practice, alcohol abuse and certain larger bone cross-sectional area than females, and in addition diseases associated with osteoporosis eg rheumatoid arthritis, there is a significant reduction in cortical thickness in females diabetes, osteogenesis imperfecta in adults, untreated long- following the menopause, contributing to the well established standing hyperthyroidism, hypogonadism or premature sex differences in fracture risk. The structure of the trabeculae menopause (<45 years), chronic malnutrition, malabsorption differs between the sexes, with young women having fewer and and chronic liver disease. These are summarised in Table 1 , thinner trabeculae than young men, and a greater reduction in 6 and have, in terms of risk assessment, been incorporated into trabecular number in women as they age. In addition, cortical 8 7 the FRAX® tool, a WHO supported initiative which uses risk porosity increases at a faster rate in female ageing. factors, with or without BMD measurement, to estimate a 10-year probability of either hip fracture or major osteoporotic Table 1. Risk factors for osteoporosis . fracture. FRAX® is by far the most commonly used such tool Risk factors independent Risk factors dependent globally, covering 75% of the world's population, and may, as in of BMD on BMD the UK, be linked to assessment algorithms to define thresholds for intervention with treatment.9 Age Untreated hypogonadism, premature menopause Treatment of osteoporosis Previous personal history of Malabsorption fragility fracture Vitamin D and calcium supplementation Maternal history of hip fracture Endocrine disease eg The role of vitamin D and calcium supplementation has been – heritable influences hyperthyroidism much debated in recent years with numerous meta-analyses Glucocorticoid therapy Chronic renal disease suggesting conflicting findings. A large UK randomised controlled trial demonstrated that supplementation with either Smoking Chronic liver disease calcium, vitamin D or both for secondary fracture prevention ≥ Alcohol intake 3 units/day Chronic obstructive pulmonary at the population level appeared ineffective,10 a l t h o u g h disease supplementation in high-risk settings where deficiencies are 11 Rheumatoid arthritis Immobility expected, for example in nursing homes, may be beneficial. 2 A recent individual patient data meta-analysis demonstrated Body mass index ≤19 kg/m Drugs eg androgen deprivation that overall, there appeared to be a modest benefit for combined therapy, aromatase inhibitors vitamin D and calcium supplementation for hip fractures, Falls total fractures and probably vertebral fractures, but that there 12 Caucasian was no benefit for vitamin D alone. Although there has been discussion from one research group that excess calcium intake Geography – latitudes furthest may be associated with increased cardiovascular risk,13 t h i s from equator has not been substantiated across many other studies. Indeed, = BMD bone mineral density. it is reassuring to note that a recent individual-patient-data © Royal College of Physicians 2015.
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