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Skeletal disorders—general approach and clinical conditions 

Skeletal disorders—general approach and clinical conditions

Chapter:
Skeletal disorders—general approach and clinical conditions
Author(s):

R. Smith

and B.P. Wordsworth

DOI:
10.1093/med/9780199204854.003.2001_update_001

Update:

Chapter reviewed—minor updates throughout.

Updated on 29 May 2014. The previous version of this content can be found here.
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date: 28 April 2017

Bone is made up of (1) cells—osteoblasts, osteoclasts, and ostoecytes; and (2) extracellular mineralized matrix—roughly one-third organic (90% type I collagen) and two-thirds inorganic (mainly hydroxyapatite). Bone modelling occurs during growth and remodelling throughout life due to the constant processes of osteoclastic bone resorption and osteoblastic bone formation, which are closely linked and regulated within bone multicellular units. In the adult, the replacement of old bone with new occurs at an annual turnover rate of 25% in cancellous bone, and 2 to 3% in cortical bone.

Common presentations of bone disease include (1) deformity and short stature; (2) bone pain and fracture; (3) myopathy—in osteomalacia and rickets; (4) features of underlying disease—e.g. renal failure, myeloma. A full general medical history, carefully taken family history, and thorough physical examination—with particular emphasis on the musculoskeletal system—may be crucial in making the correct diagnosis. Many generalized disorders of the skeleton have entirely normal routine biochemical values, while in others changes are diagnostic. Radiographic imaging can be diagnostic in some cases, with MRI and CT imaging increasingly employed in addition to conventional (‘plain’) radiographs and bisphosphonate-labelled isotope scans. Bone biopsy is required for diagnosis in some circumstances.

An enormous variety of conditions can have skeletal manifestations: this chapter emphasizes those in which impact on the skeleton is a substantial feature.

Classic metabolic bone diseases

Osteomalacia and rickets—most frequently result from a lack of vitamin D or a disturbance of its metabolism, with the main histological feature of osteomalacia being defective mineralization of bone matrix. Causes are (1) nutritional—e.g. low dietary intake; (2) malabsorptive—e.g. coeliac disease; (3) renal—including renal tubular disorders, e.g. inherited hypophosphataemias, and chronic kidney disease; (4) miscellaneous—e.g. anticonvulsant drugs. Dominant symptoms are bone pain and tenderness, skeletal deformity, and proximal muscle weakness, often accompanied by the features of the underlying disorder and by those of hypocalcaemia. Biochemical changes depend on the cause, but in vitamin D deficiency or malabsorption there are low plasma calcium and phosphate, low urinary calcium excretion, and an increase in plasma alkaline phosphatase; a low plasma 25(OH)D level is a good indication of vitamin D deficiency. The radiological hallmark of active osteomalacia is the Looser’s zone, a ribbon-like area of defective mineralization that is most often seen in the long bones, pelvis, ribs, and around the scapulae. Typically vitamin D levels will be in the deficiency range (<30nm/litre) but where there is doubt about the diagnosis, a bone biopsy examined before and after decalcification will demonstrate failure of mineralization and wide osteoid seams. Rickets and osteomalacia should respond rapidly to vitamin D (or one of its metabolites) in appropriate doses, and the response may be a useful way of confirming the diagnosis.

Paget’s disease of bone—a common disorder (3–4% of people >40 years of age), characterized by excessive and disorganized resorption and formation of bone. Predominantly of genetic cause, with the most frequent mutation being in the gene coding for the ubiquitin-binding protein sequestosome. The condition is often asymptomatic, but symptoms of Paget’s include pain, deformity, fracture, deafness and nerve compression; bone sarcoma arises in 1% or less of symptomatic patients. There is a marked increase in the level of plasma alkaline phosphatase, and the most characteristic radiological appearance is an increase in size of the affected bone. Many patients do not require any treatment. Bone pain should initially be treated with simple analgesics. If these are ineffective, or there are pagetic complications, treatment with a bisphosphonate is indicated, which often induces almost complete and permanent suppression of disease without significant side effects.

Parathyroid bone disease—hyperparathyroidism—see Chapters 13.6 and 21.6; hypoparathyroidism—see Chapter 13.6.

Osteoporosis—see Chapter 20.4.

Synthetic defects in the major components of the organic bone matrix and connective tissue

Osteogenesis imperfecta—involves those tissues that contain the main fibrillar collagen, type I. Manifest as a spectrum of disease, including (1) type II—the most severe; commonly arises from single base changes in COL1A1 or COL1A2 genes; nearly always lethal; to (2) type III—causes severe and progressive disability; patients rarely walk and have very short stature; sclerae may be blue in infancy but may take on a normal colour in childhood; to (3) type I—the commonest and least serious form; appears to be caused by a null allele for collagen I, so that only 50% of collagen is produced, but this is of normal composition; fractures sometimes occur in the perinatal period but may be delayed until the menopause; other features can include hypermobility and dislocation of joints, dentinogenesis imperfecta, and cardiac valve disease (e.g. aortic incompetence); blueness of the sclerae is characteristic. In the first few years of life nonaccidental injury, ‘battered baby syndrome’, is the main differential diagnosis. Cyclic intravenous pamidronate may alleviate symptoms, increase bone density and reduce fracture rate in severe disease.

Skeletal dysplasias—a term used to cover a wide range of generalized disorders of the skeleton affecting both cartilage and bone. Can be classified into families on the basis of (1) clinical features—e.g. bodily proportions—achondroplasia is the prototype of the short-limbed, short-stature phenotype; spondyloepiphyseal dysplasias have prominent spinal involvement and short stature is partly due to shortness of the trunk; or (2) biochemical features/genetic analysis.

Inherited defects of connective tissue—see Chapter 20.2.

Skeletal disorders caused by enzyme defects

Homocystinuria—caused by cystathionine β‎-synthase deficiency; ocular, skeletal, central nervous, and vascular manifestations; skeletal features similar to Marfan’s syndrome and include long, thin body habitus, pectus excavatum, scoliosis, and genu valgum. See Chapter 12.2.

Alkaptonuria—caused by decreased activity of homogentisate 1,2-dioxygenase; should be suspected when there is premature disc degeneration and/or early degenerative arthritis; characteristic features include abnormal dark pigmentation of the cartilage of the ear and nose, the sclerae, and of the urine. See Chapter 12.2.

Hypophosphatasia—caused by reduction in tissue nonspecific alkaline phosphatase; varies from a lethal perinatal disorder to an asymptomatic disease in adults, but adults may present with progressive stiffness, pain in the bones, and apparent ‘stress’ fractures.

Lysosomal storage diseases—a large group of conditions due to various inborn errors that affect the function of specific lysosomal enzymes normally responsible for the breakdown of a variety of complex molecules. Can cause a wide range of musculoskeletal problems, including some with devastating consequences, e.g. odontoid hypoplasia can lead to atlantoaxial instability, compression of the long spinal tracts, and paraplegia in Morquio’s syndrome. See Chapter 12.8.

Intrinsic disorders of bone cells

Osteopetrosis (‘marble bone disease’)—a group of disorders with a range of severity characterized by increased bone density. (1) Severe osteopetrosis—widespread increased density of the bones without modelling or remodelling, producing Erlenmeyer-flask deformity of the metaphyses; other features include leucoerythroblastic anaemia and hepatosplenomegaly, nerve compression, blindness, and deafness. (2) Mild osteopetrosis—affected individuals may be asymptomatic or affected by increased number of fractures affecting both the long bones and the small bones of the hands and feet. (3) Carbonic anhydrase II deficiency—features include mental retardation, growth failure, dental malocclusion, osteopetrosis, renal tubular acidosis, and cerebral calcification.

Fibrous dysplasia—a postzygotic activating mutation in GNAS1, the gene for the α‎ subunit of the G-protein signalling system, leads to areas of immature fibrous tissue, either single or multiple, within the skeleton. Radiology reveals a smooth-walled translucent area within the bone, often with thinning of the cortex and sometimes with associated deformity. (1) Monostotic fibrous dysplasia—lesions may occur in any bone; the most frequent presenting symptom is bone pain; fracture may occur. (2) Polyostotic fibrous dysplasia—multiple bone lesions; frequently associated with pigmentation and sexual precocity, especially in females (McCune–Albright syndrome).

Ectopic ossification—this may be acquired at the site of injury, or in tumours and in a variety of other disorders. Inherited ectopic ossification is a major and disabling feature of two conditions: fibrodysplasia ossificans progressiva and progressive osseous heteroplasia.

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