There are three main cell types in bone: • Osteoclasts: multinucleated cells of haematopoietic origin, responsible for bone resorption. • Osteoblasts: mononuclear cells of mesenchymal origin, responsible for bone formation. • Osteocytes: these differentiate from osteoblasts during bone formation and become embedded in bone matrix. Osteocytes are responsible for sensing and responding to mechanical loading of the skeleton and play a critical role in regulating bone formation and bone resorption, by producing receptor activator of nuclear factor kappa B ligand (RANKL) and sclerostin (SOST). They also play a central role in regulating phosphate metabolism by producing the hormone fibroblast growth factor 23 (FGF23), which acts on the kidney to promote phosphate excretion (Fig. 25.2). The most abundant protein of bone is type I collagen, which is formed from two α1 peptide chains and one α2 chain wound together in a triple helix. Type I collagen is proteolytically processed inside the cell before being laid down in the extracellular space, releasing propeptide fragments that can be used as biochemical markers of bone formation (p. 1066). Subsequently, the collagen fibrils become ‘cross-linked’ to one another by pyridinium molecules, a process that enhances bone strength. When bone is broken down by osteoclasts, the cross-links are released, providing biochemical markers of bone resorption. Bone is normally laid down in an orderly fashion, but when bone turnover is high, as in Paget’s disease or severe hyperparathyroidism, it is laid down in a chaotic pattern, giving rise to ‘woven bone’, which is mechanically weak. Bone matrix also contains growth factors, other structural proteins and proteoglycans, thought to be involved in helping bone cells attach to bone matrix and in regulating bone cell activity. The other major component of bone is mineral, comprised of calcium and phosphate crystals deposited between the collagen fibrils in the form of hydroxyapatite [Ca10 (PO4)6 (OH)2]. Mineralisation is essential for bone’s rigidity and strength, but over-mineralisation can increase brittleness, which contributes to bone fragility in diseases like osteogenesis imperfecta (p. 1131). Bone remodelling is required for renewal and repair of the skeleton throughout life (see Fig. 25.2). It starts with the attraction of osteoclast precursors in peripheral blood to the target site, probably by local release of chemotactic factors from areas of microdamage. The osteoclast precursors differentiate into mature osteoclasts in response to RANKL, which is produced by osteocytes, activated T cells and bone marrow stromal cells. RANKL activates the RANK receptor, which is expressed on osteoclasts and precursors. This is blocked by osteoprotegerin (OPG), a decoy receptor for RANKL that inhibits osteoclast formation. Mature osteoclasts attach to the bone surface by a tight sealing zone, and secrete hydrochloric acid and proteolytic enzymes such as cathepsin K into the space underneath. The acid dissolves the mineral and cathepsin K degrades collagen. When resorption is complete, osteoclasts undergo programmed cell death, and bone formation begins with the attraction of osteoblast precursors to the resorption site. These differentiate into mature osteoblasts, which deposit new bone matrix in the resorption lacuna, until the hole is filled. Some osteoblasts become trapped in bone matrix and differentiate into osteocytes. These act as biomechanical sensors and produce several molecules that influence bone remodelling and phosphate metabolism. Bone formation is stimulated by Wnt proteins, which bind to and activate lipoprotein-related receptor protein 5 (LRP5), expressed on osteoblasts. This process is inhibited by SOST, which is produced by osteocytes (see Fig. 25.2). Initially, the newly formed bone matrix (osteoid) is uncalcified but subsequently becomes mineralised to form mature bone. Alkaline phosphatase (ALP), produced by osteoblasts, plays an important role in bone mineralisation by degrading pyrophosphate, an inhibitor of mineralisation. Bone remodelling is regulated by circulating hormones such as parathyroid hormone (PTH) and oestrogen, and locally produced factors such as cytokines (Box 25.2). Many systemic hormones exert effects on bone turnover by affecting local expression of RANK, RANKL, OPG, SOST and molecules in the Wnt/LRP5 pathway (Fig. 25.2, Box 25.2). Crystals can be identified by compensated polarised light microscopy of fresh SF (to avoid crystal dissolution and post-aspiration crystallisation). Urate crystals are long and needle-shaped, and show a strong light intensity and negative birefringence (Fig. 25.5A). Calcium pyrophosphate crystals are smaller, rhomboid in shape and usually less numerous than urate, and have weak intensity and positive birefringence (Fig. 25.5B). Radiographs are of diagnostic value in osteoarthritis (OA), where they demonstrate joint space narrowing that tends to be focal rather than widespread, as in inflammatory arthritis. Other features of OA detected on X-ray include osteophytes, subchondral sclerosis, bone cysts and calcified loose bodies within the synovium (see Fig. 25.20, p. 1084). Radiographs may show erosions and sclerosis of the sacroiliac joints and syndesmophytes in the spine in patients with seronegative spondyloarthritis (see Fig. 25.36, p. 1106). In peripheral joints, so-called proliferative erosions, associated with new bone formation and a periosteal reaction, may be observed. In tophaceous gout, well-defined punched-out erosions may occur (see Fig. 25.26, p. 1089). Calcification of cartilage, tendons and soft tissues or muscle may occur in chondrocalcinosis (see Fig. 25.27, p. 1090), calcific periarthritis and connective tissue diseases. Magnetic resonance imaging (MRI) gives detailed information on anatomy, allowing three-dimensional visualisation of bone and soft tissues that cannot be adequately assessed by plain X-rays. The technique is valuable in the assessment and diagnosis of many musculoskeletal diseases (Box 25.6). T1-weighted sequences are useful for defining anatomy, whereas T2-weighted sequences are useful for assessing tissue water content, which is often increased in synovitis and other inflammatory disorders (Fig. 25.6). Contrast agents, such as gadolinium, can be administered to increase sensitivity in detecting erosions and synovitis. Routine biochemistry is useful for assessing metabolic bone disease, muscle diseases and gout. Several bone diseases, including Paget’s disease, renal bone disease and osteomalacia, give a characteristic pattern that can be helpful diagnostically (Box 25.7). Serum levels of uric acid are usually raised in gout but a normal level does not exclude it, especially during an acute attack, when urate levels temporarily fall. Equally, an elevated serum uric acid does not confirm the diagnosis, since most hyperuricaemic people never develop gout. Levels of C-reactive protein (CRP) are a useful marker of infection and inflammation, and are more specific than the ESR. An exception is in connective tissue diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis, where CRP may be normal but ESR raised in active inflammatory disease. Accordingly, an elevated CRP in a patient with lupus or scleroderma suggests an intercurrent illness such as sepsis rather than active disease. More detail on the interpretation of CRP and ESR changes is given on page 84. Serum creatine kinase (CK) levels are useful in the diagnosis of myopathy or myositis, but specificity and sensitivity are poor and raised levels may occur in some conditions (Box 25.8). Biochemical monitoring of renal and hepatic function is important in ongoing care of patients on DMARD therapy.
Rheumatology and bone disease
Clinical examination of the musculoskeletal system
General Assessment of Locomotor System (GALS)
Functional anatomy and physiology
Bone
Bone is renewed and repaired during the bone remodelling cycle, in which old and damaged bone is removed by osteoclasts and replaced by osteoblasts. Osteocytes play a central role in bone remodelling by secreting RANKL, which promotes osteoclast differentiation and activity by binding to RANK. Osteocytes regulate bone formation by producing SOST, which binds to the LRP5 receptor and prevents its activation by members of the Wnt family. Osteocytes also regulate phosphate homeostasis by producing fibroblast growth factor 23 (FGF23), which is a circulating hormone that acts on the kidney to promote phosphate excretion. (CatK = cathepsin K; LRP5 = lipoprotein receptor protein 5; OPG = osteoprotegerin; RANK = receptor activator of nuclear factor kappa B; RANKL = RANK ligand; SOST = sclerostin)
Bone matrix and mineral
Bone remodelling
Joints
Investigation of musculoskeletal disease
Joint aspiration
A Monosodium urate crystals showing bright negative birefringence under polarised light and needle-shaped morphology. B Calcium pyrophosphate crystals showing weak positive birefringence under polarised light and are few in number. They are more difficult to detect than urate crystals.
Imaging
Plain radiography
Magnetic resonance imaging
Ultrasonography
Lateral image of a metacarpophalangeal joint in inflammatory arthritis. The periosteum (P) of the phalanx shows as a white line. The dark, hypo-echoic area indicates an effusion. The coloured areas demonstrated by power Doppler indicate increased vascularity. The inset shows a transverse image of the same joint.
Bone mineral density
A DEXA scan of the hip. B Bone mineral density (BMD) values plotted in g/cm2 (left axis) and as the T-score values (right axis). The solid line represents the population average plotted against age, and the interrupted lines are ± 2 standard deviations from the average. The patient shown, aged 72, has an osteoporotic T-score of −3.0 but a Z-score of −1.0, which is within the ‘normal range’ for that age, reflecting the fact that bone is lost with age.
Blood tests
Haematology
Biochemistry
Rheumatology and bone disease
25.1
25.2
25.3
25.4
25.5
25.6
25.7
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