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Bone densitometry measurements in early inflammatory disease A . K. B H A L L A B. S H E N S T O N E

Bone remodelling occurs continuously throughout the skeleton, taking place in discrete units involving initial bone resorption by osteoclasts with subsequent bone formation by osteoblasts. These cellular activities are regulated by local factors produced by bone or bone-related cells and are modulated by systemic hormones. Numerous local factors have been identified that influence bone resorption and formation in vitro, including cytokines, prostaglandins and mast cell products (Table 1). Various local factors which stimulate bone formation may act as 'coupling factors' generated in response to or as a result of the resorption process and resulting in tight co-ordination of bone resorption and formation. Hormones influence bone turnover by either promoting or inhibiting osteoclas~ic and osteoblastic differentiation and activity (Canalis et al, 1988; Raisz, 1988; Raisz and Rodan, 1990; Russell, 1990) (Table 2). Table 1. Local factors affecting bone cells. Osteoblasts Tumour necrosis factor 13 and a Insulin-like growth factor I and II Platelet-derived growth factor Fibroblast growth factor Interleukin 1 (low dose) Lymphotoxin Interferon y

Osteoclasts Interleukin l Tumour necrosis factor a Lymphotoxin Interleukin 6 Interferon y Tumour necrosis factor a and 13 Platelet-derived growth factor Heparin Bradykinin

Table 2. Hormones affecting bone cells. Osteoblasts Parathyroid hormone 1,25-dihydroxyvitamin D Cortisol Growth hormone Insulin

Baillidre' s Clinical Rheumatology-Vol. 6, No. 2, June 1992 ISBN 0-7020-1636-5

Osteoclasts Parathyroid hormone 1,25-dihydroxyvitamin D Calcitonin Oestrogen Cortisol Thyroxine

405 Copyright 9 1992, by Bailli6re Tindall All rights of reproduction in any form reserved

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Osteoporosis results from an imbalance between bone resorption and formation, with either increased resorption, decreased formation or a combination of both. The imbalance may arise from alterations in the production and action of local factors or a disturbance in the regulation of hormones. Inflammatory arthritis is associated with osteoporosis which may be localized or generalized. Periarticular osteoporosis has long been recognized as one of the earliest radiological signs of diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and septic arthritis. Its aetiology is unclear, with several proposed mechanisms including local tissue hyperaemia, joint immobilization and the effects of inflammatory mediators released from the synovium (Reid, 1989). At present it is thought that the release of inflammatory mediators, particularly cytokines, from the various inflammatory cells is the most likely cause. Almost every known cytokine has been detected in the synovial fluid of patients with RA or other inflammatory synovitis (Lipsky et al, 1989; Feldman et al, 1990). The most abundant cytokines in synovial fluid are derived from macrophages and include interleukin (IL)-I and tumour necrosis factor (TNF) (Feldman et al, 1990). Both of these cytokines have potent bone resorbing effects, both by direct action on osteoclast differentiation and function and by stimulating prostaglandin (PG) E2 production (Gowen et al, 1983; Dayer et al, 1986). The effect of these mediators on local bone loss may also be potentiated by co-existent factors causing bone loss, including an alteration in circulatory calcitropic hormone levels, corticosteroid use and changes in physical activity.

BONE LOSS IN RA

Establishing whether generalized osteoporosis occurs in RA has been controversial, primarily due to the insensitivity of early measurement techniques and the variety of methods used. With the advent of dual photon absorptiometry (DPA), quantitative computed tomography (QCT) and dual energy X-ray absorptiometry (DEXA) precise measurements of the bone density of the axial skeleton and proximal long bones has become possible, and it is now clear that generalized osteoporosis does occur in RA patients. Decreased bone mineral content (BMC) has been demonstrated using neutron activation analysis (Reid et al, 1982), QCT (Compston et al, 1988) and DPA (Sambrook et al, 1986, 1987; Peretz et al, 1989). Histological studies have demonstrated decreased trabecular bone volume, with variable changes in bone resorption and formation (Duncan et al, 1965; Ng et al, 1984; Mellish et al, 1987; Compston et al, 1989). Current controversies include whether all or only some RA patients are affected by generalized osteoporosis, the contribution of various aetiological factors and its clinical significance. Not unexpectedly, patients with long-standing destructive and disabling disease have low bone mass (Verstraeten and Dequeker, 1984; Als et al, 1985). Population-based epidemiological studies reveal an increased fracture risk in RA patients which is related to age, impaired ambulation,

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body mass and corticosteroid use (Hooyman et al, 1984; Cooper and Wockham, 1990). Potential factors causing generalized osteoporosis in inflammatory arthritis include: 1. 2. 3. 4. 5.

Systemic actions of inflammatory products associated with disease activity. Alterations in circulating hormones. Altered calcium metabolism. Changes in load bearing of the skeleton. Effect of drugs used in the treatment of arthritis.

Usually local factors such as cytokines exert their effect within the local microenvironment. Some cytokines such as IL-1 and IL-6 may have systemic actions such as the induction of fever and the acute phase response during inflammation (Eastgate et al, 1988; Hourrian et al, 1988). In inflammatory arthritis large amounts of these local factors are produced within the joint and have the potential for systemic absorption affecting bone turnover at distant sites. Elevated serum levels of IL-1 have been demonstrated in RA patients which correlate with disease activity (Eastgate et al, 1988). However, various inhibitors have also been found in both serum and synovial fluid which may antagonize cytokine actions (Arend and Dayer, 1990) and the net systemic effect of cytokine produced during joint inflammation on bone turnover in vivo is unclear. Some studies have demonstrated an association between disease activity and decreased BMC (Sambrook et al, 1985a; Laan et al, 1991), whilst others have not (Rosenspire et al, ,1980; Hall et al, 1991). Difficulty in identifying a correlation between disease activity and BMC is not surprising as almost all the studies involve crosssectional measurements of BMC, a reflection of long-term accumulation of acute changes in bone turnover, with measurements of disease activity, which varies relatively rapidly and may be associated with short-term changes in bone turnover best measured by serological and urinary markers of bone metabolism. Studies which involve a longitudinal evaluation of disease activity with BMC have demonstrated a correlation between the two (Reid et al, 1982; Sambrook et al, 1985c; Laan et al, 1991). During inflammatory diseases, alterations in circulating levels of hormone have the potential for directly affecting bone turnover or modulating the effects of local factors. Various hormonal disturbances have been described in RA patients. Circulating sex hormone levels may be altered in RA, but their significance in terms of disease activity and bone turnover is unclear. Cutolo et al (1986) reported increased levels of testosterone and dihydroepiandrosterone sulphate (DHEAS) in postmenopausal RA patients, while Sambrook et al (1988) found decreased levels of oestrone, DHEAS and testosterone and suggested that the reduction in oestrone and testosterone, but not DHEAS, were secondary to prednisolone use. They also noted that reduced D H E A S levels in postmenopausal women with RA correlated with reduced femoral neck bone mineral density (BMD), suggesting that the disease itself may somehow reduce adrenal androgen production.

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B H A L L A A N D B. S H E N S T O N E

Decreased free and total testosterone levels have been found in males with RA (Gordon et al, 1986; Spector et al, 1989). There are conflicting results regarding the effects of RA on calcitropic hormones. In most studies, the circulating levels of 25-hydroxyvitamin D, calcitonin and parathyroid hormones are reported to be normal (Bird et al, 1980; Sambrook et al, 1985b; Peretz et al, 1989), but others have shown low levels of 25-hydroxyvitamin D (Van Soesbergen et al, 1986). Alterations in calcium metabolism may also lead to osteoporosis. Although calcium malabsorption has been described in RA patients (Sambrook et al, 1985a), the majority of workers have reported normal serum calcium and phosphate levels. Urinary calcium excretion has been reported to be normal (D'Angelo et al, 1985) or elevated (Perlik and Katova, 1983), but the significance of the latter finding is unclear. Decreased physical activity leads to decreased functional loading of the skeleton, resulting in increased bone resorption. Decreased BMC is significantly correlated with the functional activity of RA patients in the majority of studies, both at the femoral neck and the lumbar spine (Hancock et al, 1978; Sambrook et al, 1986, 1987; Hall et al, 1991), and this is probably one Of the major factors in the bone loss associated with RA. Drugs used in the treatment of arthritis may affect bone turnover directly by affecting bone cells and the action of inflammatory mediators, or indirectly by reducing inflammation and improving functional impairment. Corticosteroid in high doses results in generalized bone loss and an increased rate of fracture (Reid et al, 1982; Hooyman et al, 1984; Verstraeten and Dequeker, 1986; Sambrook et al, 1987; Peretz et al, 1989; Cooper and Wockham, 1990). This effect is not as obvious at lower doses and there is conflicting evidence as to whether bone loss occurs with corticosteroid doses less than 7.5 mg of prednisone per day (Bulter et al, 1991; Hall et al, 1991). The effect of intermittent intravenous pulse corticosteroids is unclear, although it is likely to result in acute suppression of bone metabolism, which may be cumulative with frequent treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro affect osteoblast and osteoclast function and prostaglandin and cytokine production (Khokher and Dandona, 1988; Li et al, 1989; Hopkins, 1990; Bulter et al, 1991). No significant independent effect in vivo has been demonstrated. The effect of disease-modifying antirheumatic drugs (DMARDs) on generalized BMC has not been extensively studied. The rate of generalized bone loss in RA patients taking DMARDS was not different from those not taking DMARDs in one study (Reid et al, 1986), but other workers have shown that DMARDs prevent bone loss or increase BMC (Shorn, 1983; Kalla et al, 1991), probably by suppressing disease activity and by improving mobility. The measurement of BMD in patients with inflammatory arthritis helps evaluate the risk of osteoporotic fractures, monitor preventative therapy and possibly alter or modify treatment options. For example, patients about to start oral corticosteroid therapy should have their BMD measured and the potential effects on their BMD weighed against other therapeutic options. It has been proposed that, since periarticular osteoporosis probably directly reflects inflammatory disease within the joint and correlates with

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other methods of radiographic grading of disease activity, it may have a role as an objective measure of response to disease treatment. B O N E LOSS IN OTHER RHEUMATIC DISORDERS

Ankylosing spondylitis (AS) is characterized by inflammation of the entheses in the spine and peripheral skeleton. This leads to local bony erosion or juxta-insertional osteoporosis in early disease, but subsequently new bone formation and ankylosis of the spine occurs. Spinal osteoporosis has been attributed to immobility, and increased spinal fractures are observed (Ralston et al, 1990). Recently Will et al (1989) have observed significant osteopenia of the lumbar spine and femoral reck in male patients with early AS who maintained normal spinal mobility and were physically fit and active. Bone turnover, assessed by measuring urinary calcium excretion, was not elevated. Assessment of the BMD of the femoral neck and carpus of patients with more advanced disease demonstrated continuing bone loss and indicates that bone loss in early AS is predominantly trabecular but later also involves cortical bone. Femoral neck BMD in AS patients was also significantly reduced compared with normal same-sex siblings with similar activity levels, suggesting that bone loss in AS is a consequence of the disease and not due to a lower peak bone mass or a more rapid rate of bone loss in AS families (Will et al, 1990). In SLE bone loss may be due to steroid therapy or hyperparathyroidism secondary to renal failure. A recent preliminary study, however, showed no significant bone loss in SLE irrespective of whether or not the patients,were taking oral corticosteroids (Dhillon et al, 1990). Further studies are needed with large numbers of patients to assess the effects of SLE alone on bone mass and turnover and whether there are further complications when corticosteroids are used. M E A S U R E M E N T OF BMD AND BONE T U R N O V E R

IN SYNOVITIS Currently there are a wide range of techniques available to quantify BMD (Table 3). Because of varying precision, cost, availability or stage of development, the most commonly reported techniques currently include Table 3. Methodsof measuringBMD. Radiogrammetry Radiodensitometry Singlephoton absorptiometry Dual energyX-ray absorptiometry Quantitativecomputedtomography Magneticresonanceimaging Neutron activationanalysis Compton scattering Ultrasonic transmission

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single photon absorptiometry (SPA), DPA, DEXA and QCT. SPA is used to measure predominantly cortical bone at peripheral sites. A radioisotopic source (iodine-125) is used with a scintillation detector. With the advent of rectilinear scanning and improved computing methods the precision is about 1%, the scanning time is short (15min) and the radiation dose is low (10mrem). DPA uses gadolinium-153 as the radioisotopic source which, being a multi-energy isotope, emits two different photon energies which are used to correct for fat and other soft tissues, allowing bone density to be measured in the lumbar spine and hip. The precision is 2-3% and the radiation dose is low (10 mrem), but it is relatively slow to scan (40 rain). DEXA is a further development from DPA using the same principles but involving a dual energy X-ray source and a modified detector. It can scan the whole body as well as the lumbar spine and hip with a precision of 1%, and is associated with less radiation exposure than either DPA or QCT. QCT uses computed tomography in a quantitative mode and has the advantage of being able to separate trabecular from cortical bone. Measurements can be made on the spine, hip and peripheral bones. The precision is 1-3% for single energy and 3-5% for dual energy techniques, but the radiation dose delivered is higher (200-700 mrem) (Cohn, 1990). Serial BMD measurements are required to determine rates of bone turnover. These need to be done at least 6 to 12 months apart to detect a significant change due to the relative insensitivity of available techniques. Thus any BMD measurement is a reflection of the accumulation of acute change in bone turnover over the preceding months. Acute changes in bone turnover cannot be measured by estimating serial BMDs, but can be assessed by estimating in the serum or urine products released during formation and resorption (Kraenzlin et al, 1989; Linghall and Lind, 1989). Markers of bone formation are derived from osteoblasts and of bone resorption from osteoclasts and breakdown products of bone collagen (Table 4). Markers which have been used to study bone turnover in RA include serum total alkaline phosphatase (tALP), bone alkaline phosphatase isoenzymes (bALP), osteocalcin, the urinary calcium/creatinine ratio (Ca/Cr), the hydroxyproline/creatinineratio (HP/Cr) and the lysylpyridinoline/creatinine ratio (LP/Cr). The serum tALP level is comprised of a number of different isoenzymes from different tissues (Moss, 1982). In conditions characterized Table 4. Markersof acute bone turnover. FORMATION

RESORPTION

Serum

Serum

Total alkalinephosphatase Bone alkalinephosphatase Osteocalcin Procollagen I and III propeptides

Tartrate-resistant acidphosphatase

Ur/ne Hydroxyproline Calcium/creatinineratio Lysylpyridinoline/creatinineratio Glycosylatedhydroxylysine

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by high bone turnover where the bALP percentage is high, tALP is a useful indicator of bone formation. In other conditions, such as RA, tALP is less useful as increased levels are often due to increases in liver isoenzymes and in these situations bALP measurement is required for accurate assessment of bone formation. Osteocalcin comprises 20% of the non-collagenous protein of bone and is synthesized and secreted by osteoblasts. During secretion a small percentage escapes into the circulation where it can be measured (Lian and Gundberg, 1988). In patients with RA, low, normal and high levels have been found (Gevers et al, 1986; Weisman et al, 1986; Magaro et al, 1989; Peretz et al, 1989), possibly reflecting methodological problems, differing assay specificities and possibly impaired carboxylation of osteocalcin resulting in poor incorporation into bone (Fairney et al, 1990). Urinary hydroxyproline levels have been used as markers "of bone resorption. However, hydroxyproline is found in all collagens and is not specific to bone; it is also derived from the breakdown of the Clq component of complement, which is elevated in inflammatory conditions. Lysylpyridinoline is derived from collagen crosslinks specific to bone and dentin and is excreted in the urine (Black et al, 1988; Uebelhart et al, 1990); urinary LP/Cr ratios are elevated in patients with RA (Seibel et al, 1989). Markers of acute bone turnover provide complementary information to B M D measurement, enhancing its significance by providing information as to whether there is an associated high turnover state. They are sensitive enough to detect short-term changes in bone turnover such as may occur with changes in disease activity or drug treatment in R A (see Chapter 7). The influence of potential aetiological factors on bone turnover in inflammatory disease is likely to be most clearly defined in patienfs with early disease, as it is at this time that bone mass is highest and potential changes likely to be greatest and most easily detected. The influence of complicating additive factors such as immobility and corticosteroids can also be avoided if studies are undertaken in patients with recent onset of disease. There have been only two studies where patients with early RA have been studied as a distinct subgroup (Sambrook et al, 1985c; Laan et al, 1991). The first (Sambrook et al, 1985c) was a prospective and longitudinal study of 17 postmenopausal female patients with a mean disease duration of 15 months (range 5 to 31 months). Accelerated bone loss, compared with a control group, was found in trabecular bone from the distal radius but not from the radial midshaft or lumbar spine, suggesting that bone loss in early disease is predominantly mediated by local factors. Joint count and C-reactive protein levels correlated with the rate of lumbar spine bone loss but not with bone loss at the radius, indicating that global measures of disease activity reflect poorly what is occurring in individual joints. The second (Laan et al, 1991) was a prospective study which followed 147 RA patients with a disease duration of less than i year and compared parameters of disease activity and functional capacity with lumbar spine and hip BMDs. Preliminary analysis indicates that BMD of the spine and hip may be correlated with diseasedependent mechanisms such as the erythrocyte sedimentation rate, functional capacity and disease duration. Further prospective longitudinal studies in early arthritis comparing

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c h a n g e s in a c u t e b o n e t u r n o v e r a n d B M D w i t h d i s e a s e a c t i v i t y , f u n c t i o n a l status and different treatment regimens are required to elucidate the s i t u a t i o n a n d to i n d i c a t e p r e v e n t a t i v e s t r a t e g i e s to i m p r o v e b o t h l o c a l i z e d a n d g e n e r a l i z e d o s t e o p o r o s i s in e a r l y i n f l a m m a t o r y a r t h r i t i s .

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Ralston SM, Urquhart GD, Brezeski M & Sturrock RD (-t990) Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis. British Medical Journal 300: 563-565. Reid D (1989) Osteoporosis in rheumatoid arthritis. Bone 6: 22-23. Reid DM, Kennedy NSJ, Smith MA, Tothill P & Nuki G (1982) Total body calcium in rheumatoid arthritis; effects of disease activity and corticosteroid treatment. British Medical Journal 285: 330-332. Reid DM, Kennedy NSJ, Smith MA et al (1986) Bone loss in rheumatoid arthritis and primary generalised osteoarthritis. Effects of corticosteroids, suppressive antirheumatic drugs and calcium supplements. British Journal of Rheumatology 25: 253-259. Rosenspire KC, Kennedy AC, Steinbeck J, Blau M & Green FA (1980) Investigation of the metabolic activity of bone in rheumatoid arthritis. Journal o f Rheumatology 7: 469-473. Russell RGG (1990) Bone cell biology: the role of cytokines and other mediators. In Smith R (ed.) Osteoporosis, pp 9-34. London: Royal College of Physicians. Sambrook PN, Abeyesekera G, Ansell B et al (1985a) Calcium absorption in rheumatoid arthritis. Annals o f the Rheumatic Diseases 44: 485-488. Sambrook PN, Ansell BM, Foster Set al (1985b) Bone turnover in early rheumatoid arthritis 1. Biochemical and kinetic indexes. Annals of the Rheumatic Diseases 44: 575-579. Sambrook PN, Ansell BM, Foster S, Gumpell JM, Hesp R & Reeve J (1985c) Bone turnover in early rheumatoid arthritis 2. Longitudinal bone density studies. Annals o f the Rheumatic Diseases 44: 580-589. Sambrook PN, Eisman JA, Yeates MG, Pocock NA, Eberl S & Champion GD (1986) Osteoporosis in rheumatoid arthritis, safety of low dose corticosteroids. Annals o f the Rheumatic Diseases 45: 950-953. Sambrook PN, Eisman JA, Champion GD, Yeates MG, Pocock NA & Eberl S (1987) Determinants of axial bone loss in rheumatoid arthritis. Arthritis and Rheumatism 30: 721-728. Sambrook PN, Eisman JA, Champion GD & Pocock NA (1988) Sex hormone status and osteoporosis in postmenopausal women with rheumatoid arthritis. Arthritis and Rheumatism 31: 973-978. Seibel MJ, Duncan A & Robins SP (1989) Urinary hydroxypyridinium crosslinks provide indices of cartilage and bone involvement in arthritic disease. Journal of Rheumatology 16: 964-970. Shorn D (1983) Osteoporosis in the rheumatoid hand--the effects of treatment with D-penicillamine and oral gold salts. South African Medical Journal 63: 121-123. Spector TD, Oilier W, Perry LA, Silman AL, Thompson PW & Edwards A (1989) Free and serum testosterone in 276 males. A comparison of rheumatoid arthritis, ankylosing spondylitis and healthy controls. Clinical Rheumatology 8: 37-41. Uebelhart.D, Gineyts E, Chapuy MC & Delmas PD (1990) Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone and Mineral 8: 87-96. Van Soesenberg RM, Lips P, Van Den Ende A & Van der Korst JK (1986) Bone metabolism in rheumatoid arthritis compared with post-menopausal osteoporosis. Annals of the Rheumatic Diseases 45: 149-155. Verstraeten A & Dequeker J (1984) Vertebral and peripheral bone mineral content and fracture incidence in post-menopausal patients with rheumatoid arthritis. Annals o f the Rheumatic Diseases 27" 1353-1361. Verstraeten A & Dequeker J (t986) Vertebral and peripheral bone mineral content and fracture incidence in post menopausal patients with rheumatoid arthritis. Annals o f the Rheumatic Diseases 45: 852-857. Weisman MH, Orth RW, Catherwood BD, Manolagas SC & Deftos LJ (1986) Measures of bone loss in rheumatoid arthritis. Archives of Internal Medicine 146: 701-704. Will R, Palmer R, Bhalla AK, Ring F & Calin A (1989) Osteoporosis in early ankylosing spondylitis: a primary pathological event? Lancet ii: 1483-1485. Will R, Palmer R, Elvins D, Ring F & Bhalla AK (1990) A lower femoral neck BMD occurs in patients with ankylosing spondylitis (AS) compared with their normal same sex siblings. In Christiansen C & Overgaard K (eds) Osteoporosis 1990, pp 1672-1674. Denmark: Handelstrykkeriet Aalborg.

Bone densitometry measurements in early inflammatory disease.

10 Bone densitometry measurements in early inflammatory disease A . K. B H A L L A B. S H E N S T O N E Bone remodelling occurs continuously through...
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