The locomotor and nervous systems

Chapter 15 The locomotor and nervous systems




Metabolic Bone Diseases


Bone has three important functions: it provides structural support to the body, it houses the haemopoietic bone marrow, and it is metabolically active, being essential for calcium and phosphate homoeostasis (see Chapter 12). Bone consists of a proteinaceous matrix, 90% of which is formed by type I collagen fibres, the remainder being glycoprotein and proteoglycan ground substance. This provides the support for the mineral component, which consists of spindle-shaped crystals of hydroxyapatite, a complex hydrated calcium phosphate. Bone has two structurally distinct components: dense, cortical bone (the major form) and spongy trabecular bone, which supports the bone marrow.


Mature bone undergoes constant remodelling, a process that involves up to approximately 10% of the skeleton at any one time. This process involves the resorption of small volumes of bone by osteoclasts (which subsequently undergo apoptosis) and their replacement by osteoid generated by osteoblasts (Fig. 15.1), which rapidly becomes mineralized to form mature bone. Some of the osteoblasts become trapped in the new bone and are transformed into osteocytes. The whole process is coordinated by numerous hormones, growth factors and cytokines, such that under normal circumstances the rates of resorption and bone formation are matched.



Metabolic bone diseases are a result of a disruption of this normally orderly process. The corresponding changes in plasma calcium and phosphate concentrations and alkaline phosphatase activity (a marker of osteoblastic activity) are summarized in Figure 15.2. Alkaline phosphatase promotes bone mineralization by breaking down pyrophosphate (an inhibitor of mineralization) to phosphate (which is required for the process).




Rickets and osteomalacia


These conditions are characterized by defective mineralization of osteoid. Rickets occurs in infancy and childhood (while bones are growing); osteomalacia is its adult equivalent. Defective mineralization is most frequently due to an inadequate supply of calcium, usually because of deficiency or malabsorption of vitamin D. Such ‘calciopenic’ rickets and osteomalacia can also be due to impaired production of calcitriol or resistance to its actions. These are respectively features of two rare, inherited conditions: in vitamin-D-dependent rickets type I, there is deficiency of renal 1α-hydroxylase; in type II, there is resistance to the actions of calcitriol secondary to a receptor defect. Inheritance in both cases is autosomal recessive. Impaired production of calcitriol also occurs in chronic kidney disease and contributes to the pathogenesis of renal osteodystrophy, in which features of osteomalacia are usually present. Osteomalacia has also been reported in individuals living in institutions who are being treated with anticonvulsants, probably as a combined result of vitamin D deficiency and altered hepatic metabolism of the vitamin, and as a complication of certain tumours (oncogenic osteomalacia).


Defective bone mineralization can also be due to an inadequate supply of phosphate. The cause is usually a renal tubular phosphate leak, such as occurs in the Fanconi syndrome, renal tubular acidosis type 1 and, as an isolated phenomenon, in hypophosphataemic (‘vitamin D-resistant’) rickets (X-linked dominant (the commonest form), X-linked recessive, and autosomal dominant). Hypophosphatasia is a rare, inherited cause of rickets in which there is a deficiency of alkaline phosphatase.


The clinical features of rickets and osteomalacia include bone pain and tenderness, and (particularly in rickets) skeletal deformities. Proximal muscle weakness is frequently present; hypocalcaemia is occasionally symptomatic, but in about 50% of patients with privational disease, calcium concentration is maintained just within the reference range by secondary hyperparathyroidism (increased secretion of parathyroid hormone (PTH) as a result of hypocalcaemia). Osteomalacia can coexist with osteoporosis.


Both rickets and osteomalacia give rise to characteristic radiological appearances, although these may not always be apparent in osteomalacia, and bone biopsy is sometimes required to confirm the diagnosis. Treatment is with vitamin D or one of its hydroxylated derivatives, together with supplements of calcium or phosphate as appropriate. Biochemical monitoring is through measurement of calcium, phosphate and alkaline phosphatase, all of which should normalize, and, if appropriate, 25-hydroxycholecalciferol or calcitriol. Twenty four hour urinary calcium excretion is also valuable: hypocalciuria is usual in most forms of rickets and osteomalacia, and rising excretion during treatment suggests that bone is becoming replete with calcium.



Osteoporosis


Osteoporosis is characterized by reduced bone mass and abnormalities of bone micro-architecture, which render it more fragile and susceptible to fracture. It is defined as a bone mineral density >2.5 standard deviations below the mean for young people or by the occurrence of a typical fracture. The lifetime risk of fracture due to osteoporosis is about 40% in women and 15% in men; such fractures are a considerable source of morbidity and mortality.


The two most frequent causes of osteoporosis are ageing and postmenopausal oestrogen deficiency. Peak bone mass plateaus at about age 30 years and begins to decline from age 40 at a rate of about 1% of mass per year. This is a result of loss of bone because of the decrease in osteoblastic activity in relation to osteoclastic activity that occurs in the remodelling process with ageing. It involves both trabecular and cortical bone, is particularly associated with femoral neck fractures, and affects men and women. Postmenopausal osteoporosis results from accelerated bone loss in the first five years after the menopause and primarily affects trabecular bone. It typically leads to compression fractures of the vertebral bodies (leading to deformity and loss of height). The other type of fracture particularly associated with osteoporosis is Colles’ fracture (of the distal radius), also more common in women.


These types of osteoporosis are classified as primary. Osteoporosis can also occur secondarily to a variety of conditions (Fig. 15.3), often in younger people. These conditions can also exacerbate primary osteoporosis.



The diagnosis of osteoporosis is based on measurements of bone density, for example by dual-energy X-ray absorptiometry (DEXA). Quantitative ultrasonography appears a promising, although not yet established, technique. Plasma calcium and phosphate concentrations are normal in uncomplicated osteoporosis; so too is alkaline phosphatase activity (unless a fracture has occurred or osteomalacia is also present).


There has been considerable interest in the development of markers of bone turnover that could be used to identify patients at risk of developing osteoporosis (fast bone-losers) and to monitor the effects of treatment. Several markers are available for the assessment of both bone resorption and bone formation. Markers of bone resorption include various substances derived from collagen, for example pyridinium cross-links of collagen (deoxypyridinoline and pyridinoline, both measured in urine) and cross-linking telopeptides of type I collagen (measured in serum). Markers of bone formation include plasma osteocalcin, bone-specific alkaline phosphatase and procollagen type I terminal peptides (N-terminal and C-terminal). These all show promise but no one substance in either class has yet been shown conclusively to be superior to any other. Their value in guiding clinical practice has yet to be fully established, but suppression of markers of resorption during treatment, for example with bisphosphonates, becomes maximal sooner (approximately three months) than changes in bone density can reliably be detected (up to two years); furthermore, a failure to respond is suggestive of non-compliance with treatment. There is also evidence that changes in the concentrations of these markers correlate more closely with the reduction in risk of fracture than changes in bone mineral density.


Osteoporosis is associated with high morbidity and mortality. Valuable preventive measures include moderate regular weight-bearing exercise and an adequate dietary calcium intake, particularly during growth, to optimize peak bone mass, and continuation of these measures, reduction of alcohol intake and cessation of smoking to reduce the rate of bone loss. In women with premature menopause, hormone replacement treatment (HRT) is the most effective preventive measure. Bisphosphonates (drugs that reduce osteoclastic activity) are regarded as the treatment of choice, but they can be poorly tolerated as a result of complex dosing regimens designed to avoid gastrointestinal side-effects (although this is less of a problem with newer agents that do not need to be taken daily); strontium ranelate may be an effective alternative. HRT is also effective, even in elderly women, but the benefits have to be balanced against the increased risks of certain malignancies (particularly of the breast), stroke and ischaemic heart disease, and HRT is no longer advised for this indication alone. Raloxifene (a selective oestrogen receptor modulator) reduces the risk of vertebral (but not other) fractures and appears to reduce the risk of breast cancer. Calcium and vitamin D supplements, calcitonin and calcitriol may be valuable in particular circumstances. Testosterone is effective in hypogonadal men but should not be used in men with normal testicular function because it increases the risk of prostatic cancer. Treatment with a recombinant fragment of PTH (teriparatide) or intact PTH increases bone density and reduces the fracture risk, but both entail daily subcutaneous injections. In patients with established osteoporosis, it is important to identify and manage appropriately risk factors for falls (e.g. postural hypotension).



Paget’s disease of bone


This is a condition of unknown aetiology (although there is some evidence that paramyxovirus infection in genetically predisposed individuals is responsible), characterized by increased osteoclastic activity, which engenders increased osteoblastic activity and thus new bone formation. The new bone that is formed is abnormal and laid down in a disorganized fashion. As a result, bones become thickened, deformed and painful. The most frequently affected bones are those of the pelvis, spine and skull, and the femora.


Paget’s disease is a disease of the elderly. It is frequently asymptomatic: only about 5% of patients have symptoms, of which the most frequent (80%) is pain. Others features include deformity, pathological fracture, compression of adjacent tissues (e.g. the auditory nerves, causing deafness) and a steal syndrome in which the increased vascularity of the abnormal bone diverts blood flow away from adjacent tissues, causing ischaemia. Osteosarcoma is a feared, but rare (<1%), complication.



Plasma alkaline phosphatase activity is increased and reflects disease activity; plasma calcium and phosphate concentrations are usually normal, although hypercalcaemia may develop if a patient with Paget’s disease is immobilized. It is relatively common to find an unexpectedly increased serum alkaline phosphatase activity in elderly subjects; if serum calcium and phosphate concentrations, and liver function tests are normal, Paget’s disease is the most frequent cause.


The treatment of Paget’s disease involves the use of analgesics and, in more severe cases, bisphosphonates to reduce osteoclastic activity.






Articular Disease


Joints can be affected by a wide variety of diseases, both specifically and as part of multi-system disease. Osteoarthritis, rheumatoid arthritis and other inflammatory arthritides are a major source of pain and disability. For most, the role of the biochemical laboratory in management is limited: one example is the measurement of C-reactive protein (see p. 227) to monitor inflammatory conditions. For one group, however, biochemical tests are important in both diagnosis and management: these are the crystalline arthritides, in particular, gout.


Many biochemistry laboratories also provide a service for the measurement of autoantibodies. Plasma concentrations of rheumatoid factor (RhF) are raised in the majority of patients with rheumatoid disease. RhF is an antibody (usually immunoglobulin M (IgM), the type detected by most assays for RhF), directed against the Fc portion of the IgG molecule). Anti-cyclic citrullinated peptide (CCP) antibodies are also frequently present in the plasma. Their detection appears to be more sensitive for diagnosis, and high titres are associated with a greater risk of developing joint damage. Anti-CCP antibodies may be detectable several years before rheumatoid disease becomes apparent clinically. The relative diagnostic or prognostic value of measurement of a related antibody, anti-mutated citrullinated vimentin (anti-MCV), is at present uncertain. Approximately 30% of patients with rheumatoid arthritis are also positive for antinuclear antibodies, but these are particularly associated with systemic lupus erythematosus (SLE). Both these conditions (particularly SLE) can affect many tissues other than joints.



Gout and hyperuricaemia




Uric acid metabolism


Purine nucleotides are essential components of nucleic acids: they are intimately involved in energy transformation and phosphorylation reactions and act as intracellular messengers. There are three sources of purines in humans: the diet, degradation of endogenous nucleotides and de novo synthesis (Fig. 15.5). As purines are metabolized to uric acid, the body urate pool (and hence plasma concentration) depends on the relative rates of both urate formation from these sources and urate excretion. Urate is excreted by both the kidneys and the gut, renal excretion accounting for approximately two-thirds of the total. Urate secreted into the gut is metabolized to carbon dioxide and ammonia by bacterial action (uricolysis).



Urate handling by the kidney is complex (Fig. 15.6). It is filtered at the glomeruli and almost totally reabsorbed in the proximal convoluted tubules; distally, both secretion and reabsorption occur. Normal urate clearance is about 10% of the filtered load. In normal subjects, urate excretion increases if the filtered load is increased. In chronic kidney disease, the plasma concentration rises only when the glomerular filtration rate falls below about 20 mL/min.



Dietary purines account for about 30% of excreted urate. The introduction of a purine-free diet typically reduces plasma urate concentrations by only 10–20%.


The metabolic pathways involved in uric acid synthesis are shown in outline in Figure 15.7. De novo synthesis leads to the formation of inosine monophosphate (IMP), which can be converted to the nucleotides adenosine monophosphate (AMP) and guanosine monophosphate (GMP). Nucleotide degradation involves the formation of the corresponding nucleosides (inosine, adenosine and guanosine); these are then metabolized to purines. The purine derived from IMP is hypoxanthine, which is converted by the enzyme xanthine oxidase first to xanthine and then to uric acid. Guanine can be metabolized to xanthine (and so to uric acid) directly, but adenine cannot. However, AMP can be converted to IMP by the enzyme AMP deaminase and, at the nucleoside level, adenosine can be converted to inosine. Thus, surplus GMP and AMP can be converted to uric acid and excreted.



However, the excretion of uric acid represents the waste of a metabolic investment, because purine synthesis requires considerable energy expenditure. Pathways exist whereby purines can be salvaged and converted back to their parent nucleotides. For guanine and hypoxanthine, this is accomplished by the enzyme hypoxanthine–guanine phosphoribosyl transferase (HGPRT), and for adenine by adenine phosphoribosyl transferase (APRT).


Plasma urate concentrations are, in general, higher in men than in women. Marked increases occur at puberty in males (there is a lesser increase in females at this time) and perimenopausally in women (Fig. 15.8). Urate concentrations tend to be higher in people in the higher socio-economic groups and in the obese. There is considerable, genetically determined, variation in plasma urate concentrations between different ethnic groups, with particularly high concentrations, for example, in Polynesian and Maori people.


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Apr 3, 2019 | Posted by in BIOCHEMISTRY | Comments Off on The locomotor and nervous systems

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