Risk for fracture due to bone loss is significantly heightened in patients with rheumatoid arthritis (RA).1-3 A pooled analysis from 25 studies published in 2018 by Jin et al2 indicated a much higher incidence of fragility fractures in people diagnosed with RA compared with the general population, particularly among women.3 A recent review by Raterman et al4 cited the risk for fracture in RA patients as double that of healthy counterparts.

Bone loss occurs in all individuals as a function of advancing age, as well as female sex and low body mass index (BMI), but most of the recent literature focuses on RA-specific risks as the most appropriate targets for assessment and intervention. In a 2021 review, Wysham and colleagues 3 pointed to a number of recently identified risk factors for osteoporotic fractures, including inflammatory mechanisms of RA, evolving changes in body composition related to the disease, and the continued use of glucocorticoid disease-modifying therapies.1,3

The Role of Inflammation in Fracture Risk

Inflammation, a key feature of RA, has been directly tied to periarticular bone erosion that both precedes clinical signs of RA and predicts the development of osteoporosis and fractures in these patients.4 Specifically, osteoclastic activity is increased as a result of inflammation in RA that enhances bone resorption, often appearing in the smaller metacarpal and wrist bones first.4


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Anticitrullinated protein antibodies (ACPAs) in RA have become suspect in many investigations because they are believed to directly promote osteoclastic activity by binding to the molecules. Based on this idea, the presence of ACPAs may be monitored as a potential biomarker of severe RA and higher levels of ensuing bone loss.4 A 2019 study from Japan reported a direct correlation between bone loss of the hip and elevated ACPA levels.5

Glucocorticoid Therapies

Glucocorticoids (GCs) have been a mainstay of treatment for RA due to their efficacy as disease-modifying therapies. Recently, however, their use has been implicated in the most common form of secondary osteoporosis, which develops through the mechanisms of increased bone resorption as well as reduced bone formation.6 These effects occur early in the treatment period and have been associated with an increased risk for fracture after 6 months of use.6

These findings have influenced proposed changes to the guidelines in 2021 for treatment of RA inflammation in a direction that favors limiting the use of GCs in RA.7 Katherine Wysham, MD, of the VA Puget Sound Health Care System told Rheumatology Advisor, “The most difficult aspects of achieving a GC-free regimen will be convincing an established patient with RA to taper off GCs (even low doses) and also refraining from starting GCs in those with newly diagnosed RA who do not have severe inflammation, instead considering rapid initiation of [disease-modifying antirheumatic drugs or] DMARDs upfront, if indicated.”

New Therapeutic Strategies

Current RA therapies do not target improving bone mineral density (BMD) in people with RA, Dr Wysham said. “Rather, research supports achieving remission/low disease activity ideally without the use of GCs. The choice of disease-modifying agent and level of immunosuppression needs to be balanced with patient-specific risk factors for complications of therapy such as infections, cancers, and thrombotic risk,” she said.

Screening for Fracture Risk

As biomarkers and early clinical signs of fracture risk are becoming evident, they present new opportunities to screen for risk. According to Dr Wysham, “BMD screening, most commonly by DXA [dual-energy x-ray absorptiometry], and fracture risk calculation using FRAX [Fracture Risk Assessment Tool] are important tools in the prevention of fracture in RA. Having DXA-based BMD measures and then calculating a BMD-adjusted 10-year fracture risk using FRAX with my patient provides a nice foundation to discuss potential therapies.”

These consults engage the patients and puts their high-risk for fracture into context. “It makes them more willing to consider treatment for a disease they cannot feel until it is too late and they sustain an osteoporotic fracture,” she added, noting that it does take a significant amount of clinical time.

Although these tools are readily available, substantial underscreening of BMD has been reported.8 “I am not aware of a study assessing the frequency of fracture risk calculation by FRAX or other similar tools in rheumatology practice, but I imagine these tools are underutilized in routine clinical care of patients with RA both due to time constraints and to lack of comfort/familiarity with them. I find that the Mayo Clinics’ Bone Health Choice Decision Aid9 is a nice tool for those who will likely start bisphosphonate therapy because it calculates the FRAX, provides a visualization of fracture risk with and without treatment, and also lists risks/benefits and correct administration of oral bisphosphonate therapy,” she said.

Managing Fracture Risk in a Postpandemic Environment

Management of fractures has been hampered during the 2020 lockdowns and in the continuing postpandemic environment, shifting the emphasis to preventive strategies. “We have been very proactive about preventing treatment disruptions in our patients on high-risk osteoporosis drugs through the use of a clinical dashboard,” Dr Wysham reported from the osteoporosis clinic of the VA Puget Sound Health Care System, where she also consults.

She observed that many patients on IV bisphosphonates have decided to delay doses until the pandemic is under better control and they are vaccinated (and she is thankful that nearly all are). “DXA monitoring of our established patients has also been delayed. I am sure, outside of those with established osteoporosis, that screening rates are even lower and that, unfortunately, potentially preventable osteoporotic fractures will occur.”

When asked where she thought the next efforts in reducing fracture risks in RA should be directed, Dr Wysham said, “The first place to start is providing the rheumatology community with clear guidelines for the screening and management of osteoporosis in persons with RA. Additionally, studies focused on identifying RA-specific risk factors for osteoporosis and fracture within the spectrum of RA disease are important to promote individualized treatment recommendations.”

References

  1. Adami G, Saag KG. Osteoporosis pathophysiology, epidemiology, and screening in rheumatoid arthritis. Curr Rheumatol Rep. 2019;21(7):34. doi:10.1007/s11926-019-0836-7.
  2. 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. doi:10.1007/s00198-018-4473-1
  3. Wysham KD, Baker JF, Shoback DM. Osteoporosis and fractures in rheumatoid arthritis. Curr Opin Rheumatol. 2021;33(3):270-276. doi:10.1097/BOR.0000000000000789
  4. Raterman HG, Bultink IE, Lems WF. Osteoporosis in patients with rheumatoid arthritis: an update in epidemiology, pathogenesis, and fracture prevention. Expert Opin Pharmacother. 2020;21:1725-1737. doi:10.1080/14656566.2020.1787381
  5. Tomizawa T, Ito H, Murata K, et al. Distinct biomarkers for different bones in osteoporosis with rheumatoid arthritis. Arthritis Res Ther. 2019;21(1):174. doi:10.1186/s13075-019-1956-1
  6. Adami G, Rahn EJ, Saag KG. Glucocorticoid-induced osteoporosis: from clinical trials to clinical practice. Ther Adv Musculoskelet Dis. 2019;11:1759720X19876468. doi:10.1177/1759720X19876468
  7. New rheumatoid arthritis guideline emphasizes maximizing methotrexate biologics, minimizing steroids [press release]. Atlanta, GA: American College of Rheumatology; November 6, 2020. https://www.newswise.com/articles/new-rheumatoid-arthritis-guideline-emphasizes-maximizing-methotrexate-and-biologics-minimizing-steroids
  8. Schmajuk G, Tonner C, Trupin L, Yazdany J. Variations in radiographic procedure use for Medicare patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2017;69(5):642-648. doi:10.1002/acr.22988
  9. Bone Health Choice Decision Aid. Mayo Clinic. https://osteoporosisdecisionaid.mayoclinic.org/