Osteoporosis
Associated Pathogenesis ByIan Joffe
With Rheumatoid and Management and Solomon Epstein
Rheumatoid arthritis is associated with both localized and generalized osteoporosis. Localized osteoporosis can be considered to be caused by local disease mechanisms, including the generation of factors from activation of the cytokine pathway. The etiology of generalized osteoporosis has been difficult to elucidate, particularly because of the lack of sensitive techniques to measure bone mineral density. The introduction of single- and dual-photon absorptiometry and quantitative computed tomography has allowed more accurate assessment of bone mineral density. In general, bone mineral density loss at appendicular sites does not correlate well with axial bone density loss. Corticosteroid treatment exaggerates the development of osteoporosis in up to 40% of patients with rheumatoid arthritis. Sex hormone status, physical activity, disease duration, and functional class are all significant predictors for the development of osteoporosis. Current therapy for prevention and treatment is based largely on theoretical considerations. Physical activity should be encouraged once acute joint inflammation has settled. Postmenopausal women and amenorrheic premenopausal women will benefit from cyclical estrogen replacement. Patients with low serum Itbdihydroxy vitamin D, levels, and males with
R
HEUMATOID arthritis (RA) has protean clinical manifestations. Independent of its systemic and articular involvement, the disease
Abbreviations: APD, (3-amino-l-hydroxypropylidene)-l,lbisphosphonate; BGP, bone Gla protein; CAMP, cyclic adenosine monophosphate; CsA, cyclosporin A, DPA, dualphoton absorptiometry; DXA, dual-energy X-ray absorptiometry; ELISA, enzyme-linked immunosorbent assay; EGF, epidermal growth factor; FSH, follicle-stimulating hormone; IM, intramuscular; IGF-1, insulin-like growth factor 1; IFN, interferon; IL, interleukin; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; mRNA, messenger ribonucleic acid; NSAIDs, nonsteroidal antiinflammatory drugs; OCT, 22-oxa-la, 25-dihydroxyvitamin D,; PTH, parathyroid hormone; PGE,, prostaglandin E,; QCT, quantitative computed tomography; RA, rheumatoid arthritis; SPA, single-photon absorptiometry; SC, subcutaneous; TGF, transforming growth factor; TNF, tumor necrosis factor; 1,25-(OH),D,, 1,25dihydroxyvitamin D,; la-(OH)D,, la-hydroxyvitamin D,; 2%(OH)D,, 25-hydroxyvitamin D,. 256
Arthritis:
low serum testosterone levels, are candidates for replacement therapy with the appropriate hormones. In patients who are receiving corticosteroids the dose should be limited, and oral calcium supplements are of benefit. The use of the newer corticosteroid deflazacort, and disease-modifying immunosuppressive drugs, are discussed. Other therapeutic options which should be considered, although published trials are scarce, are calcitonin and the diphosphonates. Further studies are awaited concerning the optimum prevention and treatment of osteoporosis associated with rheumatoid arthritis. For the present, management should be based on theoretical considerations. The introduction of dual-energy X-ray absorptiometry for measuring bone mineral density represents a significant improvement over the older techniques, and will assist in future clinical trials. Inhibitors of the cytokine pathway, or the products stemming from activation of this pathway, need to be evaluated in the treatment of osteoporosis associated with rheumatoid arthritis. Copyright 0 199 1 by W. B. Saunders Company INDEX WORDS: rheumatoid arthritis; osteoporosis; bone mineral density; corticosteroids.
is also characterized by both a localized Cjuxtaartitular) and a generalized osteoporosis. Although the exact cause of the osteopenic process has not yet been identified, numerous studies suggest that the bone loss results from multifactorial processes.
From the Division of Endocrinology and Metabolism, Albert Einstein Medical Center, and the Department of Medicine, Temple University School of Medicine, Philadelphia, PA. Supported in part by Rorer Pharmaceutical, Ft Washington, PA. Ian Joffe, MD: Research Fellow, Division of Endocrinology and Metabolism, Albert Einstein Medical Center; Solomon Epstein, MD: Head, Division of Endocrinology and Metabolism, Albert Einstein Medical Center; Professor of Medicine, Temple University School of Medicine. Address reprint requests to Solomon Epstein, MD, Head, Division of Endocrinology and Metabolism, Albert Einstein Medical Center, 5401 Old York Rd, Philadelphia, PA 19141. Copyright 8 1991 by WB. Saunders Company 0049-0172/91/2004-0005$5.00/0
Seminars in Arthritis andRheumatism, Vol20, No 4 (February), 1991:
pp256-272
OSTEOPOROSIS
AND RHEUMATOID
LOCALIZED
ARTHRITIS
(JUXTAARTICULAR)
OSTEOPOROSIS
Osteoporosis of juxtaarticular bone is one of the cardinal diagnostic criteria for RA.’ It is important to understand the pathobiology of RA and how it relates to the localized osteoporosis. The sequence of events may be summarized as follows: in an immunogenetically susceptible host, the presentation of a relevant antigen by antigen-presenting cells (macrophages or dendritic cells in the synovial membrane), is thought to trigger RA.’ The antigen-presenting cells interact with T lymphocytes, which in turn initiate both a cellular and humoral immune response. Each step of the immune response is tightly regulated by a variety of cytokines that interact in a complex manner with each other, including interleukins (IL) 1, 2, 4, 5, and 6, tumor necrosis factor OLand p (TNFa, TNFP), cx and y interferon (y-IFN), and transforming growth factor p (TGF p).“” The cytokines are secreted by a wide variety of cells, including T and B lymphocytes and monocytes/macrophages. The immune response becomes organized in the perivascular areas in the synovial membrane.’ Coupled with this immune response is the development of angiogenesis and synovialcell proliferation. Neutrophils are attracted in large numbers to the synovial fluid. Histological studies on juxaarticular bone from patients with RA show increased turnover of bone, with increases in osteoid surface, percentage resorptive surface, and number of osteoclasts.sX6Mononuclear cell infiltrates, primarily macrophages and lymphocytes, have also been observed in osteopenic bone near affected joints.6 Research has focused primarily on the products (local factors) of these various cell types in the inflamed rheumatoid synovium as being responsible for the increased bone turnover and localized osteoporosis. In particular, cytokines, released from activated lymphocytes and macrophages, are thought to be the major mediators of the localized osteoporosis. Local Factors An early study showed that media produced by synovial tissue, maintained in organ culture from patients with active RA, can resorb bone from mouse calvaria.’ The bone resorption was
257
largely accounted for by prostaglandin E, (PGE,) production, as addition of a prostaglandininhibitor markedly reduced PGE, levels and the bone resorption. Approximately 10 times more PGE, was produced by the synovium from patients with RA than normal synovia; however, the number of normal synovia examined was statistically small, and the results should be interpreted with caution. IL-l has been shown to have potent bone-resorbing activity in vitro.8 IL-l produced by a murine macrophage cell line can stimulate prostaglandin and collagenase production by nonlymphoid rheumatoid synovial cells in vitro.’ IL-l appears to exert its effect by activating phospholipase A, in human synovial cells, thereby resulting in the production of inflammatory arachidonic acid metabolites, including PGE,.” IL-l receptors are present on many different cell types. IL-l receptor number on neonatal mouse osteoblastlike cells can be influenced by various osteotropic agents, including IL-l, TGFP, epidermal growth factor (EGF), corticosteroids, and parathyroid hormone (PTH).” The regulation of bone cell IL-1 receptors may be an important mechanism in controlling bone remodeling. The cytokine, TNFa, has been shown to be the dominant inducer of IL-l production in rheumatoid joints.” In an elegant experiment, TNFa antibodies significantly reduced synovial cell IL-1 production in tissue culture from patients with RA. The TNFa antibodies inhibited IL-l mRNA production, indicating that the effect of TNFol on IL-l synthesis may be at the level of induction rather than on secretion or processing. TNFa levels, measured by an enzyme-linked imrnunosorbent assay (ELISA), have been found to be elevated in the synovial fluid of 6 of 12 patients with RA, and in the sera of 7 of these patients.13 Those patients with detectable TNFa had significantly higher erythrocyte sedimentation rates and synovial fluid leukocyte counts. IL-l activity released by cultured synovia from patients with RA, measured by a thymocyte proliferation assay, correlates positively with the findings of inflammation on arthroscopy and joint changes detected on roentgenograms, including bony destruction.‘4 These findings add
258
further strength to the role of IL-l and TNFol in inducing localized osteoporosis in RA. y-IFN levels are elevated in the serum and synovial fluid of approximately 40% of patients with RA, but there is no correlation with disease activity.‘3,1Sr-IFN activates macrophages, and augments their production of IL-l and TNFa,3 thus suggesting a synergistic or permissive role for this cytokine in localized osteoporosis. The presence of TNFa, and y-IFN in RA synovial fluid may suggest synergistic interactions between these cytokines that could contribute to the localized osteoporosis.13 TNFol and y-IFN also have direct effects on the proliferation and function of human trabecular osteoblastic cells in vitro.16 TNFa stimulates bone cell proliferation and prostaglandin production while inhibiting 1,25_dihydroxyvitamin D, (1,25-(OH),D,)-stimulated alkaline phosphatase activity and bone Gla protein (BGP) release. BGP is a specific marker of osteoblastic activity. In contrast, y-IFN inhibits proliferation and stimulated alkaline phosphatase activity of the cells, while inhibiting 1,2.5-(OH),D,-stimulated BGP production. IL-2 and IL-6 levels are elevated in the synovial fluid and serum of patients with RA.“-19 The significance of elevated serum levels of the various cytokines and their relation to the localized osteoporosis has not been determined. It is not known whether the elevated serum levels represent “spill over” from the synovial fluid or originate from cytokines produced in the circulation. The finding of enhanced IL-2 production by peripheral blood lymphocytes from patients with active RA, as compared with inactive disease, suggests a systemic contribution to the localized osteoporosis.*’
JOFFE AND EPSTEIN
numbers in the synovium and synovial fluid in active RA,23,24and systemic mastocytosis is associated with osteopenia.Z In conclusion, the available evidence suggests that the pathogenesis of the localized osteoporosis is the result of the production of local factors, including PGE,, interleukins, TNFa, y-IFN, and mast cell products by inflammatory cells from the adjacent synovium (Table 1). A contribution to the localized osteoporosis from systemically produced cytokines cannot be excluded. GENERALIZED
OSTEOPOROSIS
Generalized osteoporosis has long been recognized as a complication of RA, affecting both cortical and trabecular bone.26”0 However, the number of patients with RA affected by osteoporosis has been difficult to assess, largely because the use of standard radiography to evaluate the degree of generalized osteoporosis is a relatively insensitive method of determining bone mineral density 10~s.~~Conflicting results have been found in studies directed to ascertain Table 1: Factors Involved in Localized Osteoporosis Factor PGE,
Effect Secreted by rheumatoid synovium, and neutro-
Reference 7
9,12
phils; causes bone resorption, Blocked by NSAlDs in vitro. Secretion increased by IL-l, TNFu. IL-l
Secreted by macroph-
9,lO
ages and lymphocytes, activates phospholipase A, resulting in
Neutrophils and Mast Cells
Neutrophils are potent mediators of tissue destructioq’l and are present in large numbers in the synovial fluid of patients with active RA. Activation of neutrophils results in degranulation, with the release of proteinases, products of arachidonic acid metabolism, and reactive oxidants. Some of these products of neutrophil degranulation, such as PGE,, can cause bone resorption. Mast cell products can stimulate PGE, production by rheumatoid synovial cells in culture.= Mast cells are present in increased
PGE, production and bone resorption. TNFu
Induces IL-l mRNA pro-
12
duction, blocked by
16
TNFa antibodies. Stimulates osteoblastic cell proliferation. y-IFN
Activates macrophages,
3
increasing IL-l and TNFo production. Mast cell products
Stimulates PGE, production by rheumatoid synovial cells.
22
OSTEOPOROSIS
AND RHEUMATOID
259
ARTHRITIS
etiological factors associated with the development of generalized osteoporosis.26-30 Specifically, the influence of disease duration and severity, immobility, age, sex, menopausal status, and corticosteroid treatment on osteoporosis was assessed. Inconclusive findings were reached as a result of a lack of precision, accuracy, and reproducibility of the techniques used to measure bone mineral density, and the heterogeneity of the patient population. Bone Mass Measurements
More precise and accurate techniques for bone mass measurement are now available. These include single- and dual-photon absorptiometry (SPA, DPA), dual-energy X-ray absorptiometry (DXA), and quantitative computed tomography (QCT). SPA is performed at a peripheral skeletal site, usually the radius. DPA, QCT, and DXA have the advantage of being able to measure both peripheral and axial bone density. The essential issue involved in using these newer techniques is to what extent peripheral skeletal bone mass correlates with axial bone mass. Several studies have addressed this issue.32-42 The general consensus is that peripheral (cortical) bone density measurement is a poor indicator of axial (trabecular) bone loss. Bone mineral density measured at the radius by SPA, is a poor predictor of bone loss and subsequent fracture rate at a vertebral site, measured by DPA or QCT. In addition, by choosing a peripheral bone such as the radius to assess bone mass, localized juxtaarticular osteoporosis may be measured inadvertently, thus influencing the results. It is therefore important not to rely solely on peripheral bone density measurements in assessing the overall degree of bone loss induced by various etiological factors. Instruments of high precision and stability are needed to measure axial bone loss of 2% to 3% per year. Many conditions can affect lumbar spine bone mineral density measurements, including compression fractures and aortic calcification (see Wahner4” for a comprehensive review).
the spine, is predominantly juxtaarticular early in the disease.44 Few studies have examined the rate of generalized bone mineral density loss, currently estimated at - 1.9% and - 1% a year in the femoral neck (measured by DPA) of untreated patients with RA, and control patients, respectively.4s Total bone mass, reflected by total body calcium as measured by neutron activation analysis, correlates significantly with disease duration and parameters of disease activity, including articular index, functional state, erythrocyte sedimentation rate, and rheumatoid factor titre.46 CORTICOSTEROIDS
AND OSTEOPOROSIS
Corticosteroid-induced osteoporosis has been recognized since 1932 when Cushing first described skeletal decalcification occurring secondarily to excess corticosteroid secretion. The pathogenesis of corticosteroid-induced osteoporosis has recently been reviewed in detail by Lukert et a1,47and is due to a number of adverse effects on calcium homeostasis. The abnormalities in calcium homeostasis induced by corticosteroids include effects on gonadal hormone secretion, calcium absorption, renal handling of calcium, and direct effects on bone. Corticosteroids and Gonadal Hormone Secretion
Corticosteroids blunt secretion of luteinizing hormone (LH) in response to luteinizing hormone-releasing hormone (LHRH) in both men and women.4s,49 Corticosteroids also suppress serum testosterone secreted by the testes,49-5’ mediated by suppression of follicle-stimulating hormone (FSH) and LH. FSH-induced estrogen production in cultured rat granulosa cells is inhibited by corticosteroids.” This state of “hypogonadism” induced by corticosteroids may play an important role in the development of osteopenia. Acute estrogen deficiency results in increased bone turnover, as evidenced by bone histomorphometry and elevated serum BGP levels.53-“5In the rat, estrogen deficiency and corticosteroids were additive in increasing the rate of bone 10~s.~~
Disease Duration and Severity
Corticosteroids and Intestinal Calcium Absorption
In untreated patients with RA, bone loss, as measured by CT at the distal radius and DPA at
Corticosteroids decrease intestinal calcium absorption but the precise mechanism(s) have
JOFFE AND EPSTEIN
not been clarified. Suppression of serum 1,25(OH),D, levels have been implicated,57.58 although this has been disputed by Findling et a1.59
Urinary excretion of calcium and phosphorus is increased in patients receiving corticosteroid therapy.s9’60 This results in secondary hyperparathyroidism59‘61 that can be improved by thiazide or lo-hydroxyvitamin D, (lc+(OH)D,) therapy.61 Some of the bone changes seen with corticosteroid treatment may thus be due to secondary hyperparathyroidism.
It is now clear that corticosteroids only accentuate the propensity towards the development of osteoporosis in RA, occurring in up to 40% of patients with RA receiving corticosteroids.46’75-77 However, it has been difficult to identify which patients are susceptible, as well as the effect of different corticosteroid regimes on the development of osteoporosis. The reasons for these discrepancies include differences in the methods used to assess osteoporosis and differences in the patient groups studied, particularly with respect to severity of RA, menopausal status and corticosteroid dosage.” Most studies have been cross-sectional, a further drawback when considering a longitudinal effect on bone loss.
Corticosteroids and Direct Effects on Bone
Low Versus High Dose Corticosteroids
A number of direct effects of corticosteroids on bone have been observed. In the presence of corticosteroids, the ability of macrophages to bind to bone is enhanced-this binding of macrophages may be one of the initial events in the bone degradative process.“’ In cultured neonatal rat calvaria, Hahn et al showed that physiological concentrations of cortisol produce an enhancement of osteoblast metabolism and increased osteoblast sensitivity to PTH.63 Physiological doses of corticosteroids appear to suppress osteoclastic activity, with no further suppression at pharmacological dosesF4 Chuyn et aY5 showed that in fetal rat calvaria, cortisol inhibited the proliferation of precursor cells for osteoblasts. Corticosteroids have other complex effects on bone, including an increase in receptor number for 1,25-(OH),D,,” and an augmentation in CAMP levels in an osteoblastlike cell line.67 Corticosteroids reduce serum insulin-like growth factor 1 (IGF-1),68 and increase IGF-1 receptor concentrations in cultured fetal rat osteoblastlike cells.69 High-dose cortisone acetate treatment in the rat suppresses bone formation as reflected histomorphometrically and by low serum BGP levels.” In humans, steroid-induced bone loss occurs primarily in trabecular bone.‘l Histologically, there is a reduction of trabecular bone volume.72,73Trabecular osteoclastic resorption surfaces are increased73 with a tendency towards a nonsignificant increase in osteoclastic number,74 suggesting increased bone resorption.
A number of studies have addressed the important issue of the influence of corticosteroid dose on the development of osteoporosis in RA (Table 2). Sambrook et al measured bone mineral density by DPA in the lumbar spine and femoral neck in predominantly postmenopausal women with RA.” Patients receiving low-dose prednisolone (mean dose 8.0 -r- 0.5 mg/d) and nonsteroid receivers all significantly lost bone mineral density compared with normal controls. The loss of bone mineral density was similar in both steroid and nonsteroid receivers, thus suggesting no deleterious effect of low-dose corticosteroids on bone mineral metabolism. All patient groups had similar disease duration, but the group receiving steroids had greater disease severity. Premenopausal and postmenopausal women receiving corticosteroids all lost comparable values of bone mineral density. There was no significant difference in the vertebral fracture incidence between corticosteroid and noncorticosteroid users. In a longitudinal study over 2 years, there was no difference in bone mineral density at the lumbar spine or femoral neck (measured by DPA), in women with RA receiving low-dose prednisolone (mean dose 6.6 mg/d) when compared with age and sex-matched controls with RA not receiving corticosteroids.45 All groups with F&Ahad significantly lower initial bone mineral densities when compared with control patients. The mean change in bone density was 0.2, 0.1, and -0.1% a year in the spine, and -2.0, -1.9, and -1.0% a year in the
Corticosteroids and Renal Excretion of Calcium and Phosphorus
OSTEOPOROSIS
AND RHEUMATOID
261
ARTHRITIS
Table 2: Effect of Low-Dose Corticosteroids
on Osteoporosis
In RA
Number
Reference
Method
of
Dose
Patients
of
of
Study
on
Steroid
Bone
Design
Steroids
(mg/dl*
Difference from Control
Measurement
45
Lt
15
6.6
DPA of L, F
NS
46
CS
31
4.6-9.5
NAA
S
76
CS
54
Associated Pathogenesis ByIan Joffe
With Rheumatoid and Management and Solomon Epstein
Rheumatoid arthritis is associated with both localized and generalized osteoporosis. Localized osteoporosis can be considered to be caused by local disease mechanisms, including the generation of factors from activation of the cytokine pathway. The etiology of generalized osteoporosis has been difficult to elucidate, particularly because of the lack of sensitive techniques to measure bone mineral density. The introduction of single- and dual-photon absorptiometry and quantitative computed tomography has allowed more accurate assessment of bone mineral density. In general, bone mineral density loss at appendicular sites does not correlate well with axial bone density loss. Corticosteroid treatment exaggerates the development of osteoporosis in up to 40% of patients with rheumatoid arthritis. Sex hormone status, physical activity, disease duration, and functional class are all significant predictors for the development of osteoporosis. Current therapy for prevention and treatment is based largely on theoretical considerations. Physical activity should be encouraged once acute joint inflammation has settled. Postmenopausal women and amenorrheic premenopausal women will benefit from cyclical estrogen replacement. Patients with low serum Itbdihydroxy vitamin D, levels, and males with
R
HEUMATOID arthritis (RA) has protean clinical manifestations. Independent of its systemic and articular involvement, the disease
Abbreviations: APD, (3-amino-l-hydroxypropylidene)-l,lbisphosphonate; BGP, bone Gla protein; CAMP, cyclic adenosine monophosphate; CsA, cyclosporin A, DPA, dualphoton absorptiometry; DXA, dual-energy X-ray absorptiometry; ELISA, enzyme-linked immunosorbent assay; EGF, epidermal growth factor; FSH, follicle-stimulating hormone; IM, intramuscular; IGF-1, insulin-like growth factor 1; IFN, interferon; IL, interleukin; LH, luteinizing hormone; LHRH, luteinizing hormone-releasing hormone; mRNA, messenger ribonucleic acid; NSAIDs, nonsteroidal antiinflammatory drugs; OCT, 22-oxa-la, 25-dihydroxyvitamin D,; PTH, parathyroid hormone; PGE,, prostaglandin E,; QCT, quantitative computed tomography; RA, rheumatoid arthritis; SPA, single-photon absorptiometry; SC, subcutaneous; TGF, transforming growth factor; TNF, tumor necrosis factor; 1,25-(OH),D,, 1,25dihydroxyvitamin D,; la-(OH)D,, la-hydroxyvitamin D,; 2%(OH)D,, 25-hydroxyvitamin D,. 256
Arthritis:
low serum testosterone levels, are candidates for replacement therapy with the appropriate hormones. In patients who are receiving corticosteroids the dose should be limited, and oral calcium supplements are of benefit. The use of the newer corticosteroid deflazacort, and disease-modifying immunosuppressive drugs, are discussed. Other therapeutic options which should be considered, although published trials are scarce, are calcitonin and the diphosphonates. Further studies are awaited concerning the optimum prevention and treatment of osteoporosis associated with rheumatoid arthritis. For the present, management should be based on theoretical considerations. The introduction of dual-energy X-ray absorptiometry for measuring bone mineral density represents a significant improvement over the older techniques, and will assist in future clinical trials. Inhibitors of the cytokine pathway, or the products stemming from activation of this pathway, need to be evaluated in the treatment of osteoporosis associated with rheumatoid arthritis. Copyright 0 199 1 by W. B. Saunders Company INDEX WORDS: rheumatoid arthritis; osteoporosis; bone mineral density; corticosteroids.
is also characterized by both a localized Cjuxtaartitular) and a generalized osteoporosis. Although the exact cause of the osteopenic process has not yet been identified, numerous studies suggest that the bone loss results from multifactorial processes.
From the Division of Endocrinology and Metabolism, Albert Einstein Medical Center, and the Department of Medicine, Temple University School of Medicine, Philadelphia, PA. Supported in part by Rorer Pharmaceutical, Ft Washington, PA. Ian Joffe, MD: Research Fellow, Division of Endocrinology and Metabolism, Albert Einstein Medical Center; Solomon Epstein, MD: Head, Division of Endocrinology and Metabolism, Albert Einstein Medical Center; Professor of Medicine, Temple University School of Medicine. Address reprint requests to Solomon Epstein, MD, Head, Division of Endocrinology and Metabolism, Albert Einstein Medical Center, 5401 Old York Rd, Philadelphia, PA 19141. Copyright 8 1991 by WB. Saunders Company 0049-0172/91/2004-0005$5.00/0
Seminars in Arthritis andRheumatism, Vol20, No 4 (February), 1991:
pp256-272
OSTEOPOROSIS
AND RHEUMATOID
LOCALIZED
ARTHRITIS
(JUXTAARTICULAR)
OSTEOPOROSIS
Osteoporosis of juxtaarticular bone is one of the cardinal diagnostic criteria for RA.’ It is important to understand the pathobiology of RA and how it relates to the localized osteoporosis. The sequence of events may be summarized as follows: in an immunogenetically susceptible host, the presentation of a relevant antigen by antigen-presenting cells (macrophages or dendritic cells in the synovial membrane), is thought to trigger RA.’ The antigen-presenting cells interact with T lymphocytes, which in turn initiate both a cellular and humoral immune response. Each step of the immune response is tightly regulated by a variety of cytokines that interact in a complex manner with each other, including interleukins (IL) 1, 2, 4, 5, and 6, tumor necrosis factor OLand p (TNFa, TNFP), cx and y interferon (y-IFN), and transforming growth factor p (TGF p).“” The cytokines are secreted by a wide variety of cells, including T and B lymphocytes and monocytes/macrophages. The immune response becomes organized in the perivascular areas in the synovial membrane.’ Coupled with this immune response is the development of angiogenesis and synovialcell proliferation. Neutrophils are attracted in large numbers to the synovial fluid. Histological studies on juxaarticular bone from patients with RA show increased turnover of bone, with increases in osteoid surface, percentage resorptive surface, and number of osteoclasts.sX6Mononuclear cell infiltrates, primarily macrophages and lymphocytes, have also been observed in osteopenic bone near affected joints.6 Research has focused primarily on the products (local factors) of these various cell types in the inflamed rheumatoid synovium as being responsible for the increased bone turnover and localized osteoporosis. In particular, cytokines, released from activated lymphocytes and macrophages, are thought to be the major mediators of the localized osteoporosis. Local Factors An early study showed that media produced by synovial tissue, maintained in organ culture from patients with active RA, can resorb bone from mouse calvaria.’ The bone resorption was
257
largely accounted for by prostaglandin E, (PGE,) production, as addition of a prostaglandininhibitor markedly reduced PGE, levels and the bone resorption. Approximately 10 times more PGE, was produced by the synovium from patients with RA than normal synovia; however, the number of normal synovia examined was statistically small, and the results should be interpreted with caution. IL-l has been shown to have potent bone-resorbing activity in vitro.8 IL-l produced by a murine macrophage cell line can stimulate prostaglandin and collagenase production by nonlymphoid rheumatoid synovial cells in vitro.’ IL-l appears to exert its effect by activating phospholipase A, in human synovial cells, thereby resulting in the production of inflammatory arachidonic acid metabolites, including PGE,.” IL-l receptors are present on many different cell types. IL-l receptor number on neonatal mouse osteoblastlike cells can be influenced by various osteotropic agents, including IL-l, TGFP, epidermal growth factor (EGF), corticosteroids, and parathyroid hormone (PTH).” The regulation of bone cell IL-1 receptors may be an important mechanism in controlling bone remodeling. The cytokine, TNFa, has been shown to be the dominant inducer of IL-l production in rheumatoid joints.” In an elegant experiment, TNFa antibodies significantly reduced synovial cell IL-1 production in tissue culture from patients with RA. The TNFa antibodies inhibited IL-l mRNA production, indicating that the effect of TNFol on IL-l synthesis may be at the level of induction rather than on secretion or processing. TNFa levels, measured by an enzyme-linked imrnunosorbent assay (ELISA), have been found to be elevated in the synovial fluid of 6 of 12 patients with RA, and in the sera of 7 of these patients.13 Those patients with detectable TNFa had significantly higher erythrocyte sedimentation rates and synovial fluid leukocyte counts. IL-l activity released by cultured synovia from patients with RA, measured by a thymocyte proliferation assay, correlates positively with the findings of inflammation on arthroscopy and joint changes detected on roentgenograms, including bony destruction.‘4 These findings add
258
further strength to the role of IL-l and TNFol in inducing localized osteoporosis in RA. y-IFN levels are elevated in the serum and synovial fluid of approximately 40% of patients with RA, but there is no correlation with disease activity.‘3,1Sr-IFN activates macrophages, and augments their production of IL-l and TNFa,3 thus suggesting a synergistic or permissive role for this cytokine in localized osteoporosis. The presence of TNFa, and y-IFN in RA synovial fluid may suggest synergistic interactions between these cytokines that could contribute to the localized osteoporosis.13 TNFol and y-IFN also have direct effects on the proliferation and function of human trabecular osteoblastic cells in vitro.16 TNFa stimulates bone cell proliferation and prostaglandin production while inhibiting 1,25_dihydroxyvitamin D, (1,25-(OH),D,)-stimulated alkaline phosphatase activity and bone Gla protein (BGP) release. BGP is a specific marker of osteoblastic activity. In contrast, y-IFN inhibits proliferation and stimulated alkaline phosphatase activity of the cells, while inhibiting 1,2.5-(OH),D,-stimulated BGP production. IL-2 and IL-6 levels are elevated in the synovial fluid and serum of patients with RA.“-19 The significance of elevated serum levels of the various cytokines and their relation to the localized osteoporosis has not been determined. It is not known whether the elevated serum levels represent “spill over” from the synovial fluid or originate from cytokines produced in the circulation. The finding of enhanced IL-2 production by peripheral blood lymphocytes from patients with active RA, as compared with inactive disease, suggests a systemic contribution to the localized osteoporosis.*’
JOFFE AND EPSTEIN
numbers in the synovium and synovial fluid in active RA,23,24and systemic mastocytosis is associated with osteopenia.Z In conclusion, the available evidence suggests that the pathogenesis of the localized osteoporosis is the result of the production of local factors, including PGE,, interleukins, TNFa, y-IFN, and mast cell products by inflammatory cells from the adjacent synovium (Table 1). A contribution to the localized osteoporosis from systemically produced cytokines cannot be excluded. GENERALIZED
OSTEOPOROSIS
Generalized osteoporosis has long been recognized as a complication of RA, affecting both cortical and trabecular bone.26”0 However, the number of patients with RA affected by osteoporosis has been difficult to assess, largely because the use of standard radiography to evaluate the degree of generalized osteoporosis is a relatively insensitive method of determining bone mineral density 10~s.~~Conflicting results have been found in studies directed to ascertain Table 1: Factors Involved in Localized Osteoporosis Factor PGE,
Effect Secreted by rheumatoid synovium, and neutro-
Reference 7
9,12
phils; causes bone resorption, Blocked by NSAlDs in vitro. Secretion increased by IL-l, TNFu. IL-l
Secreted by macroph-
9,lO
ages and lymphocytes, activates phospholipase A, resulting in
Neutrophils and Mast Cells
Neutrophils are potent mediators of tissue destructioq’l and are present in large numbers in the synovial fluid of patients with active RA. Activation of neutrophils results in degranulation, with the release of proteinases, products of arachidonic acid metabolism, and reactive oxidants. Some of these products of neutrophil degranulation, such as PGE,, can cause bone resorption. Mast cell products can stimulate PGE, production by rheumatoid synovial cells in culture.= Mast cells are present in increased
PGE, production and bone resorption. TNFu
Induces IL-l mRNA pro-
12
duction, blocked by
16
TNFa antibodies. Stimulates osteoblastic cell proliferation. y-IFN
Activates macrophages,
3
increasing IL-l and TNFo production. Mast cell products
Stimulates PGE, production by rheumatoid synovial cells.
22
OSTEOPOROSIS
AND RHEUMATOID
259
ARTHRITIS
etiological factors associated with the development of generalized osteoporosis.26-30 Specifically, the influence of disease duration and severity, immobility, age, sex, menopausal status, and corticosteroid treatment on osteoporosis was assessed. Inconclusive findings were reached as a result of a lack of precision, accuracy, and reproducibility of the techniques used to measure bone mineral density, and the heterogeneity of the patient population. Bone Mass Measurements
More precise and accurate techniques for bone mass measurement are now available. These include single- and dual-photon absorptiometry (SPA, DPA), dual-energy X-ray absorptiometry (DXA), and quantitative computed tomography (QCT). SPA is performed at a peripheral skeletal site, usually the radius. DPA, QCT, and DXA have the advantage of being able to measure both peripheral and axial bone density. The essential issue involved in using these newer techniques is to what extent peripheral skeletal bone mass correlates with axial bone mass. Several studies have addressed this issue.32-42 The general consensus is that peripheral (cortical) bone density measurement is a poor indicator of axial (trabecular) bone loss. Bone mineral density measured at the radius by SPA, is a poor predictor of bone loss and subsequent fracture rate at a vertebral site, measured by DPA or QCT. In addition, by choosing a peripheral bone such as the radius to assess bone mass, localized juxtaarticular osteoporosis may be measured inadvertently, thus influencing the results. It is therefore important not to rely solely on peripheral bone density measurements in assessing the overall degree of bone loss induced by various etiological factors. Instruments of high precision and stability are needed to measure axial bone loss of 2% to 3% per year. Many conditions can affect lumbar spine bone mineral density measurements, including compression fractures and aortic calcification (see Wahner4” for a comprehensive review).
the spine, is predominantly juxtaarticular early in the disease.44 Few studies have examined the rate of generalized bone mineral density loss, currently estimated at - 1.9% and - 1% a year in the femoral neck (measured by DPA) of untreated patients with RA, and control patients, respectively.4s Total bone mass, reflected by total body calcium as measured by neutron activation analysis, correlates significantly with disease duration and parameters of disease activity, including articular index, functional state, erythrocyte sedimentation rate, and rheumatoid factor titre.46 CORTICOSTEROIDS
AND OSTEOPOROSIS
Corticosteroid-induced osteoporosis has been recognized since 1932 when Cushing first described skeletal decalcification occurring secondarily to excess corticosteroid secretion. The pathogenesis of corticosteroid-induced osteoporosis has recently been reviewed in detail by Lukert et a1,47and is due to a number of adverse effects on calcium homeostasis. The abnormalities in calcium homeostasis induced by corticosteroids include effects on gonadal hormone secretion, calcium absorption, renal handling of calcium, and direct effects on bone. Corticosteroids and Gonadal Hormone Secretion
Corticosteroids blunt secretion of luteinizing hormone (LH) in response to luteinizing hormone-releasing hormone (LHRH) in both men and women.4s,49 Corticosteroids also suppress serum testosterone secreted by the testes,49-5’ mediated by suppression of follicle-stimulating hormone (FSH) and LH. FSH-induced estrogen production in cultured rat granulosa cells is inhibited by corticosteroids.” This state of “hypogonadism” induced by corticosteroids may play an important role in the development of osteopenia. Acute estrogen deficiency results in increased bone turnover, as evidenced by bone histomorphometry and elevated serum BGP levels.53-“5In the rat, estrogen deficiency and corticosteroids were additive in increasing the rate of bone 10~s.~~
Disease Duration and Severity
Corticosteroids and Intestinal Calcium Absorption
In untreated patients with RA, bone loss, as measured by CT at the distal radius and DPA at
Corticosteroids decrease intestinal calcium absorption but the precise mechanism(s) have
JOFFE AND EPSTEIN
not been clarified. Suppression of serum 1,25(OH),D, levels have been implicated,57.58 although this has been disputed by Findling et a1.59
Urinary excretion of calcium and phosphorus is increased in patients receiving corticosteroid therapy.s9’60 This results in secondary hyperparathyroidism59‘61 that can be improved by thiazide or lo-hydroxyvitamin D, (lc+(OH)D,) therapy.61 Some of the bone changes seen with corticosteroid treatment may thus be due to secondary hyperparathyroidism.
It is now clear that corticosteroids only accentuate the propensity towards the development of osteoporosis in RA, occurring in up to 40% of patients with RA receiving corticosteroids.46’75-77 However, it has been difficult to identify which patients are susceptible, as well as the effect of different corticosteroid regimes on the development of osteoporosis. The reasons for these discrepancies include differences in the methods used to assess osteoporosis and differences in the patient groups studied, particularly with respect to severity of RA, menopausal status and corticosteroid dosage.” Most studies have been cross-sectional, a further drawback when considering a longitudinal effect on bone loss.
Corticosteroids and Direct Effects on Bone
Low Versus High Dose Corticosteroids
A number of direct effects of corticosteroids on bone have been observed. In the presence of corticosteroids, the ability of macrophages to bind to bone is enhanced-this binding of macrophages may be one of the initial events in the bone degradative process.“’ In cultured neonatal rat calvaria, Hahn et al showed that physiological concentrations of cortisol produce an enhancement of osteoblast metabolism and increased osteoblast sensitivity to PTH.63 Physiological doses of corticosteroids appear to suppress osteoclastic activity, with no further suppression at pharmacological dosesF4 Chuyn et aY5 showed that in fetal rat calvaria, cortisol inhibited the proliferation of precursor cells for osteoblasts. Corticosteroids have other complex effects on bone, including an increase in receptor number for 1,25-(OH),D,,” and an augmentation in CAMP levels in an osteoblastlike cell line.67 Corticosteroids reduce serum insulin-like growth factor 1 (IGF-1),68 and increase IGF-1 receptor concentrations in cultured fetal rat osteoblastlike cells.69 High-dose cortisone acetate treatment in the rat suppresses bone formation as reflected histomorphometrically and by low serum BGP levels.” In humans, steroid-induced bone loss occurs primarily in trabecular bone.‘l Histologically, there is a reduction of trabecular bone volume.72,73Trabecular osteoclastic resorption surfaces are increased73 with a tendency towards a nonsignificant increase in osteoclastic number,74 suggesting increased bone resorption.
A number of studies have addressed the important issue of the influence of corticosteroid dose on the development of osteoporosis in RA (Table 2). Sambrook et al measured bone mineral density by DPA in the lumbar spine and femoral neck in predominantly postmenopausal women with RA.” Patients receiving low-dose prednisolone (mean dose 8.0 -r- 0.5 mg/d) and nonsteroid receivers all significantly lost bone mineral density compared with normal controls. The loss of bone mineral density was similar in both steroid and nonsteroid receivers, thus suggesting no deleterious effect of low-dose corticosteroids on bone mineral metabolism. All patient groups had similar disease duration, but the group receiving steroids had greater disease severity. Premenopausal and postmenopausal women receiving corticosteroids all lost comparable values of bone mineral density. There was no significant difference in the vertebral fracture incidence between corticosteroid and noncorticosteroid users. In a longitudinal study over 2 years, there was no difference in bone mineral density at the lumbar spine or femoral neck (measured by DPA), in women with RA receiving low-dose prednisolone (mean dose 6.6 mg/d) when compared with age and sex-matched controls with RA not receiving corticosteroids.45 All groups with F&Ahad significantly lower initial bone mineral densities when compared with control patients. The mean change in bone density was 0.2, 0.1, and -0.1% a year in the spine, and -2.0, -1.9, and -1.0% a year in the
Corticosteroids and Renal Excretion of Calcium and Phosphorus
OSTEOPOROSIS
AND RHEUMATOID
261
ARTHRITIS
Table 2: Effect of Low-Dose Corticosteroids
on Osteoporosis
In RA
Number
Reference
Method
of
Dose
Patients
of
of
Study
on
Steroid
Bone
Design
Steroids
(mg/dl*
Difference from Control
Measurement
45
Lt
15
6.6
DPA of L, F
NS
46
CS
31
4.6-9.5
NAA
S
76
CS
54
