Skeletal Complications in Rheumatoid Arthritis: A Comprehensive Review
Etiology of Bone Loss in RA
<p>Patients with RA experience localized and generalized bone loss.<sup>2</sup> Data have also shown that patients with well-controlled RA have significantly more bone loss than healthy individuals.<sup>4</sup> The pathology of bone loss in RA is multifactorial and complex. The pannus, a proliferation of inflamed synovial tissue, releases several proinflammatory cytokines. Some, such as TNF-α, IL-1, IL-6, and IL-17, are osteoclastogenic and promote bone resorption, partly through upregulation of nuclear factor-kB ligand.<sup>1,3,5</sup> They also inhibit anti-osteoclastogenic cytokines.<sup>1</sup> Further, TNF-α upregulates proteins that inhibit the Wnt pathway, thus suppressing osteoblast activity.<sup>1,3,5</sup> The resulting imbalance in bone remodeling, favoring bone resorption, causes bone loss and inferior bone quality. Immobility and glucocorticoid use, both common in patients with RA, also promote bone loss.<sup>1,2</sup> Standard risk factors for bone loss may exacerbate RA-induced bone loss.<sup>5</sup> </p>
Periarticular Bone Erosions
<p>Periarticular bone erosions are a diagnostic feature of RA and are detected using radiographic imaging.<sup>1,6</sup> They result from progressive periarticular osteoporosis resulting from an imbalance between bone resorption and inadequate bone formation at the joint margins.<sup>7</sup> On imaging, they appear as breaks in the cortical bone accompanied by loss of subchondral trabecular bone and bone marrow edema.<sup>1,6</sup> Although bone erosions occur in healthy people or patients with other joint diseases, they are more severe in patients with RA.<sup>6</sup></p> <p>Bone erosions arise early in the course of RA (within a few weeks to a few months of onset in some patients).<sup>1,7</sup> They most often affect metacarpophalangeal joints and predict more severe disease.<sup>1,7</sup> Approximately 63% of patients with RA have erosions at diagnosis.<sup>1</sup> Seropositivity and smoking increase the risk for bone erosions.<sup>1</sup> Evidence suggests DMARDs and the nuclear factor-kB ligand inhibitor denosumab can prevent progression of bone erosions, but no treatment appears to repair erosions.<sup>1,2,7</sup></p>
<p>Joint or cervical spine ankylosis may occur in RA.<sup>1</sup> Joint ankylosis usually affects small joints of the hand, wrists, ankle, or forefoot. Although joint ankylosis was once common, widespread DMARD use has nearly eliminated this complication. Studies suggest that bone ankylosis is infrequent (0.8%) and usually occurs in patients with long-standing RA.<sup>1</sup></p> <p>Patients with joint ankylosis of the wrist appear more likely to develop cervical ankylosis.<sup>1</sup> The reported prevalence of cervical spine ankylosis ranges from 9% to 80%, depending on the imaging modality used.<sup>1</sup> Patients develop bony erosions, ligamentous laxity, and complete fusion.<sup>8</sup> Ankylosis of the cervical facet joints typically occurs at the atlanto-occipital and atlanto-axial joints.<sup>9</sup> Patients are often asymptomatic, but may have pain, neuropathy, or severe myelopathy and require surgical intervention. Use of DMARDs appears to prevent cervical ankylosis, but does not prevent its progression.<sup>8</sup></p>
<p>Chronic insult to the joints from RA inflammation may cause secondary osteoarthritis (OA), which can lead to the need for total knee or hip replacement.<sup>1</sup> Although RA is characterized by erosive disease, secondary OA is characterized by the formation of osteophytes and subchondral bone.<sup>10</sup> Subchondral sclerosis is a thickening of the bone where it ends at the joint space. Bone repair (sclerosis) is suppressed in RA, but the detection of osteophytes and bone thickening in patients with RA suggests anabolic activity occurs in response to erosive damage. A recent study of 202 anti-citrullinated protein antibody-positive patients with RA found a positive correlation between bone erosion and the number and size of osteophytes, which increased with age and longer RA duration.<sup>10</sup> Osteophyte formation increased with use of DMARDs and low-dose glucocorticoids, possibly because they inhibit cytokines that prevent sclerosis.<sup>10</sup></p>
<p>Osteoporosis is diagnosed in individuals with a bone mineral density (BMD) T-score of −2.5 or less.<sup>11</sup> Patients with RA are twice as likely as the general population to develop generalized osteoporosis.<sup>2</sup> Although osteoporosis is more common in women with RA, men are also at risk.<sup>12,13</sup> In RA, BMD loss is greater at the peripheral bones than the axial skeleton.<sup>2</sup> Data show 17% to 32% of patients with RA have BMD loss at the lumbar spine, and 15% to 36% have BMD loss at the hip.<sup>1</sup> Periarticular and generalized osteoporosis may share a similar mechanism.</p> <p>Glucocorticoid use accelerates BMD loss, especially in the first 3 to 6 months.<sup>18</sup> Disease duration and activity are strong predictors of osteoporosis risk, but evidence of bone loss is also seen in patients with early, asymptomatic RA.<sup>1,2</sup> Another risk factor is sarcopenia, which affects more women than men with RA.<sup>1</sup> Patient-related risk factors include postmenopausal status/age, low BMI, immobility, and family history of osteoporosis.<sup>1,2,5</sup> Anti-TNF-α blockade appears to reduce the rate of generalized bone loss, possibly by restoring equilibrium between bone resorption and formation.<sup>2</sup></p>
Increased Fracture Risk
<p>A recent meta-analysis showed that patients with RA have a significantly increased fracture risk, with similar excess risk in men and women.<sup>14</sup> Another meta-analysis found that fracture rates varied greatly between studies and anatomical location.<sup>15</sup> The pooled incidence per 1000 person-years was 33.00 for all fractures and 15.31 for fragility fractures. At major osteoporotic fracture sites of vertebrae, hip, forearm, and proximal humerus, incidence rates per 1000 person-years were 7.51, 4.33, 3.40, and 1.86, respectively.<sup>15</sup> A database study of South Korean patients with RA (n=138,240) found that glucocorticoids increased vertebral fracture risk.<sup>16</sup> A similar UK study (n=34,050) showed that glucocorticoids raised osteoporosis and fracture risks.<sup>17</sup> Both studies found that risk was dose-dependent. Elevated fracture risk in RA is a result of traditional and disease-related factors.<sup>14,15</sup> Biologic DMARDs may have protective effects on the skeleton, but their effects on fracture risk are unclear.<sup>2</sup> A registry study of 8400 female patients with RA associated anti-TNF-α therapy with a lower fracture rate than methotrexate.<sup>5</sup></p>
Screening for Osteoporosis Risk
<p>Fractures can cause significant morbidity, mortality, functional impairment, and expense in patients with RA.<sup>13</sup> No RA-specific screening guidelines for osteoporosis or fracture risk exist, and studies show that even patients with RA with known risk factors are not routinely screened for osteoporosis.<sup>5,13</sup> Heinlein and Humphrey suggest screening patients at RA diagnosis, and then periodically.<sup>1</sup></p> <p>The American College of Rheumatology (ACR) recommends using the Fracture Risk Assessment Tool (FRAX) or BMD testing to assess new glucocorticoid users who are older than 40 years.<sup>18</sup> Updated US Preventive Services Task Force (USPSTF) guidelines for osteoporotic fracture screening, which are not RA-specific, say FRAX and similar clinical tools are only moderately accurate, but that incorporating BMD may improve accuracy.<sup>11</sup> The guidelines also rate most bone tests as moderately accurate. The USPSTF recommends bone tests for women older than 65 years or for postmenopausal women younger than 65 years with an increased facture risk according to a clinical assessment tool.</p>
Preventing or Treating Bone Loss
<p>It is unclear whether disease control prevents RA-related bone loss, but data suggest it does in patients with early RA and high disease activity.<sup>1</sup> Two systemic analyses of RA studies concluded that biologic DMARDs reduce generalized and localized bone loss.<sup>2,19</sup> However, few studies were phase 3 trials, and most measured markers of bone turnover.<sup>2,19</sup> High-quality trials that measure BMD change or fracture risk are needed. Bisphosphonates, denosumab, and parathyroid hormone are agents approved for osteoporosis and glucocorticoid-induced osteoporosis. Bisphosphonates and denosumab appear to have similar efficacy at preserving BMD.<sup>1</sup> In some RA studies, denosumab also prevented and repaired erosions.<sup>2</sup></p> <p>The ACR guidelines for glucocorticoid-induced osteoporosis categorize patients as having low, moderate, or high fracture risk.<sup>18 </sup> They recommend calcium (1000 to 1200 mg/d) and vitamin D (600 to 800 IU/d) supplements for all patients, plus an osteoporosis agent (preferably an oral bisphosphonate) for patients with moderate to high fracture risk.</p>
Medication-Related Osteonecrosis of the Jaw
<p>Medication-related osteonecrosis of the jaw (MRONJ) is a rare complication of antiresorptive treatments for osteoporosis. It is characterized as an area of exposed necrotic jawbone that persists >8 weeks in someone with bisphosphonate or denosumab exposure.<sup>20</sup> Less than 0.1% of patients with osteoporosis using a bisphosphonate or denosumab develop MRONJ.<sup>20</sup> A similar condition has been observed in patients receiving anticancer drugs, glucocorticoids, methotrexate, adalimumab, etanercept, or rituximab.<sup>21</sup></p> <p>The cause of MRONJ is unclear, but may relate to the osteoclastic effects of antiresorptive agents and the antiangiogenic or immunosuppressive effects of other drugs.<sup>22</sup> MRONJ in patients with osteoporosis is usually preceded by invasive dental procedures, and antibiotic prophylaxis can reduce risk.<sup>20</sup> Periodontal disease, oral infection or trauma, and longer osteoporosis treatment also increase risk.<sup>1,20</sup> Limited data suggest patients with RA have a greater risk for MRONJ, possibly because of RA's skeletal effects.<sup>1,22</sup> Severe MRONJ may require surgery, whereas early disease is managed conservatively.<sup>20</sup></p>
<p>Although RA often causes periarticular and generalized osteoporosis, leading to severe skeletal complications, many clinicians do not routinely screen patients with RA for osteoporosis or fracture risk.<sup>13</sup> Even glucocorticoid users are not screened or managed properly, despite their elevated risk.<sup>13</sup> </p> <p>One study recruited 11,669 patients with RA in 2003 and followed them through 2014.<sup>13</sup> Less than half received BMD testing or osteoporosis medication at initial visits. During follow-up, 64% received calcium/vitamin D supplements, 58% had BMD testing, and 30% received osteoporosis treatment other than hormone replacement therapy. Investigators used National Osteoporosis Foundation guidelines and 2010 ACR guidelines for glucocorticoid-induced osteoporosis to determine risk and adequacy of osteoporosis care.<sup>13</sup> Only 55% of the approximately half of patients with RA for whom guidelines recommended an osteoporosis therapy received one, and often it was not an ACR-suggested agent. Declines in osteoporosis screening and treatment in patients with RA since 2008 indicates the need for RA-specific guidelines.<sup>13</sup> </p>
Rheumatoid arthritis (RA) is characterized by chronic synovitis and the release of proinflammatory enzymes that destroy joints and compromise bone remodeling.1-3 In healthy individuals, bone resorption by osteoclasts is tightly balanced with bone formation by osteoblasts to maintain bone homeostasis. The coupling of these processes becomes unregulated in RA, however, making bone repair more difficult.3 Therefore, patients with RA often experience progressive bone loss and erosion, culminating in poor skeletal health and manifestations such as joint and spinal ankylosis, osteoporosis, and fracture.1 Independent of the direct effects the disease process has on bone health, decreased physical activity resulting from RA symptoms such as pain, fatigue, or functional impairment exacerbates bone loss.2 In addition, use of corticosteroids, even at low doses, can rapidly accelerate bone loss and increase fracture risk.2
Studies show that early treatment with effective agents that control inflammation helps prevent bone loss,2 and skeletal complications such as joint fusion or periarticular erosions have declined since disease-modifying antirheumatic drugs (DMARDs) came into use.1 Other complications such as osteoporosis are still highly prevalent.1 A systematic review of studies evaluating biologic DMARDs for patients with RA suggested tumor necrosis factor (TNF) agonists may have a protective effect on bone at the spine and hip, whereas interleukin (IL)-6 inhibitors may protect against localized bone loss.2 A better understanding of the underlying mechanisms of bone remodeling in RA could lead to treatments that are more effective at preventing skeletal degradation.3
Studies have identified high serum levels of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) positivity as risk factors for bone damage.2 In ACPA-positive individuals, bone loss may occur even when inflammation is absent. Rheumatologists should monitor bone health in high-risk patients.1
Garrett and Christin Melton
- Heinlen L, Humphrey MB. Skeletal complications of rheumatoid arthritis. Osteoporos Int. 2017;28(10):2801-2812.
- Zerbini CAF, Clark P, Mendez-Sanchez L, et al. Biologic therapies and bone loss in rheumatoid arthritis. Osteoporosis Int. 2017;28(2):429-446.
- Goldring SR. Differential mechanisms of de-regulated bone formation in rheumatoid arthritis and spondyloarthritis. Rheumatology. 2016;55(suppl_2):ii56-ii60.
- Tada M, Inui K, Sugioka Y, et al. Use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control: the TOMORROW study. Rheumatol Int. 2017;37(6):999-1005.
- Coulson KA, Reed G, Gilliam BE, Kremer JM, Pepmueller PH. Factors influencing fracture risk, T score, and management of osteoporosis in patients with rheumatoid arthritis in the Consortium of Rheumatology Researchers of North America (CORRONA) registry. J Clin Rheumatol. 2009;15(4):155-160.
- Geusens P, van den Bergh J. Bone erosions in rheumatoid arthritis. Rheumatology. 2014;53(1):4-5.
- Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8:656.
- Gillick JL, Wainwright J, Das K. Rheumatoid arthritis and the cervical spine: a review on the role of surgery. Int J Rheumatol. 2015;2015:252456.
- Iizuka H, Nishinome M, Sorimachi Y, et al. The characteristics of bony ankylosis of the facet joint of the upper cervical spine in rheumatoid arthritis patients. Eur Spine J. 2009;18(8):1130-1134.
- Figueiredo CP, Simon D, Englbrecht M, et al. Quantification and impact of secondary osteoarthritis in patients with anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. 2016;68(9):2114-2121.
- Viswanathan M, Reddy S, Berkman N, et al. Screening to prevent osteoporotic fractures: Updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;319(24):2532-2551.
- Kweon SM, Sohn DH, Park JH, et al. Male patients with rheumatoid arthritis have an increased risk of osteoporosis: Frequency and risk factors. Medicine (Baltimore). 2018;97(24):e11122.
- Ozen G, Kamen DL, Mikuls TR, England BR, Wolfe F, Michaud K. Trends and determinants of osteoporosis treatment and screening in patients with rheumatoid arthritis compared to osteoarthritis. Arthritis Care Res (Hoboken). 2018;70(5):713-723.
- Xue AL, Wu SY, Jiang L, Feng AM, Guo HF, Zhao P. Bone fracture risk in patients with rheumatoid arthritis: A meta-analysis. Medicine (Baltimore). 2017;96(36):e6983.
- Jin S, Hsieh E, Peng L, et al. Incidence of fractures among patients with rheumatoid arthritis: a systematic review and meta-analysis. Osteoporos Int. 2018;29(6):1263-1275.
- Kim D, Cho S-K, Park B, Jang EJ, Bae S-C, Sung Y-K. Glucocorticoids are associated with an increased risk for vertebral fracture in patients with rheumatoid arthritis. J Rheumatol. 2018;45(5):612-620.
- Wilson JC, Sarsour K, Gale S, Pethö-Schramm A, Jick SS, Meier CR. Incidence and risk of glucocorticoid-associated adverse effects in patients with rheumatoid arthritis [published online June 1, 2018]. Arthritis Care Res (Hoboken). doi: 10.1002/acr.23611
- Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatsology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2017;69(8):1095-1110.
- Dubrovsky AM, Lim MJ, Lane NE. Osteoporosis in rheumatic diseases: anti-rheumatic drugs and the skeleton. Calcif Tissue Int. 2018;102(5):607-618.
- Khan AA, Morrison A, Kendler DL, et al. Case-based review of osteonecrosis of the jaw (ONJ) and application of the International Recommendations for Management From the International Task Force on ONJ. J Clin Densitom. 2017;20(1):8-24.
- Aghaloo TL, Tetradis S. Osteonecrosis of the jaw in the absence of antiresorptive or antiangiogenic exposure: a series of 6 cases. J Oral Maxillofac Surg. 2017;75(1):129-142.
- Conte-Neto N, Bastos AS, Spolidorio LC, Marcantonio RAC, Marcantonio E. Oral bisphosphonate-related osteonecrosis of the jaws in rheumatoid arthritis patients: a critical discussion and two case reports. Head Face Med. 2011;7(1):7.
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