Bone metabolism in rheumatoid arthritis

In active RA, bone resorption is increased and bone formation is normal or reduced in comparison to healthy controls. This uncoupling of bone formation and resorption with a negative remodelling balance leads to generalized bone loss. The pathogenesis of this altered bone metabolism is multifactorial, involving non-disease-specific factors (such as age, female sex and postmenopausal status) and disease-specific factors. Disease-specific factors are associated with disease activity (inflammatory cells and cytokines; hypogonadism), disease outcome (especially reduced mobility), and disease medication (e.g. corticosteroids). Introduction Local juxta-articular or periarticular osteoporosis is a well-recognized phenomenon in rheumatoid arthritis (RA) and is included in the 1987 American Rheumatism Association classification criteria. The hypothesis, based on the clinical observation that in active RA periarticular osteoporosis is more prominent than in inactive RA, is that inflammatory mediators and inflammatory cells cause local bone loss (1). Most studies on bone density in RA indicate that RA is also associated with a generalized bone loss and that this loss is more evident at the hip and radius than at the spine (2-6). The etiology of this bone loss seems to be different from local periarticular bone loss. Generalized bone loss in RA is multifactorial, involving not only general, non-disease-specific factors, such as age, female sex, and postmenopausal status, but also diseasespecific factors associated with disease activity, disease outcome and disease medication (corticosteroids, methotrexate ?, cyclosporine ?) (1, 7). The absolute and relative importance of these risk factors is not exactly known, but most authors agree that bone loss in RA is most pronounced in steroid-treated patients, in postmenopausal women, in elderly patients and in patients with more severe joint involvement. In addition to bone loss, patients with RA may have an increased risk of falls secondary to decreased general well-being (e.g. by anemia of chronic disease), functional impairment and muscle atrophy. In this paper the focus is on altered bone metabolism in RA associated with disease activity and disease outcome, causing generalized bone loss. The topic of RA medication and bone (metabolism) will be addressed elsewhere in this issue. Markers of bone metabolism in RA In general, there are two types of biochemical markers of bone metabolism: (a) markers measuring the (enzyme) activity of osteoblasts or osteoclasts, and (b) markers released at the assembly or breakdown of bone matrix which assess bone formation or resorption, respectively. After a description of markers of bone metabolism, data from the literature on bone markers in RA are given. Markers of bone formation Serum alkaline phosphatase (sAP) is an enzyme originating from the membranes of osteoblasts; it is a marker of the activity of osteoblasts and therefore of bone formation. The use of sAP as a marker of bone formation is hampered, however, by its low sensitivity to change (8, 9); because sAP has a long half-life, it is not suitable for demonstrating rapidly occurring changes in bone formation. Another disadvantage is that in patients with severe osteomalacia, sAP can exhibit falsepositive elevations without an increase in bone formation. Although alkaline phosphatase (AP) is also found in kidney, intestine and placenta, only the bone and liver isoenzymes are major contributors to serum levels in healthy adults. An ELISA has been developed for serum bone-specific alkaline phosphatase (sBAP) that is claimed to have low (5%) cross-reactivity with the liver isoenzyme; 1Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht; 2Department of Rheumatology, Free University Hospital Amsterdam, The Netherlands. J.W.G. Jacobs, MD and W.F. Lems, MD, Rheumatologists; R.N.J. de Nijs, MD; J.W.J. Bijlsma, Professor of Rheumatology. Please address correspondence and reprint requests to: Dr. J.W.G. Jacobs, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht,