Screening and Diagnosis Using FRAX and Dual-energy X-ray Absorptiometry (DXA)

There are several fracture risk assessment tools available, but the most widely used is the FRAX algorithm. FRAX estimates the 10-year absolute risk of hip fracture and other major osteoporotic fracture. The instrument is available online ( www.shef.ac.uk/FRAX ), and it includes demographic parameters such as age, sex, weight, prior fracture, as well as glucocorticoid use and diagnosis of RA. Although its use has been advocated internationally, FRAX has potential shortcomings for the practicing clinician to consider .

FRAX may underestimate fracture risk in patients with a history of multiple fractures. Smoking and alcohol intake appear to have a dose-dependent effect on fracture risk, but FRAX accounts for these risk factors in a binary fashion, and it does not account for the duration and level of use. Similarly, and more pertinent to patients with RA, glucocorticoid use is also taken into account in a binary fashion, considering the average effect of 7.5 mg of prednisolone, and it does not account for dose or duration . A modification to FRAX that adjusts the fracture risk of higher or lower glucocorticoid doses has been proposed . The diagnosis of RA itself is part of the FRAX calculation; however, this is also a dichotomous variable, which does not take into account disease activity, duration, or related disability . A recent publication by The International Society of Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) analyzed the literature to determine if disease parameters could be used to better characterize fracture risk in RA patients . Disability measures such as the HAQ (Health Assessment Questionnaire) correlated with clinical fractures, but not morphometric vertebral fractures . Data on the correlation of the effect of duration of disease were mixed, with several observational cohorts showing no association , but one large study, including 30,262 patients with RA from the British General Practice Research Database, found a significant threefold association of incident fractures with the duration of disease >10 years. There was little evidence to correlate other measures of disease such as disease activity score (DAS), visual analogue scale (VAS), or acute phase reactants with increased fracture risk .

The conclusion reached by the authors was that FRAX likely underestimates the fracture risk in RA patients with impaired functional status, but that the level of this effect was not quantifiable with current data .

ISCD and National Osteoporosis Foundation (NOF) recommend BMD assessment for all women aged 65 and older and all men aged 70 and older. Both groups also recommend BMD testing in postmenopausal women and men aged 50–69 with risk factors for osteoporosis, defined as low body weight, prior fracture, high-risk medication use, and diseases associated with bone loss . In slight contrast, the United States Preventive Task Force (USPTF) recommends BMD assessment in women under age 65 based on FRAX assessment, with BMD testing recommended for patients whose 10-year risk of major osteoporotic fracture is greater than that of a 65-year-old white woman without other risk factors (9.3%). Somewhat controversially, the USPTF does not currently recommend osteoporosis screening in men .

RA is considered to be a condition associated with systemic bone loss, and glucocorticoids are considered high-risk medications for bone loss. Thus, from a practical standpoint, following the guidelines set forth by the ISCD and NOF, every postmenopausal RA patient and every male RA patient aged 50 or older should have BMD testing performed.

DXA measures BMD, and it is expressed in grams of mineral per centimeter square. Comparison of an individual patient׳s bone density to age-, sex-, and ethnicity-matched reference population generates the Z -score, but more commonly used for treatment decisions is the T -score, which compares a patient׳s bone density with a young adult population of the same sex . The T -score at the lowest measured site is used in diagnosing osteoporosis using World Health Organization (WHO) criteria, with T -scores between −1.0 and −2.5 corresponding to osteopenia and <−2.5 considered osteoporosis. Although BMD correlates with fracture risk , it is a surrogate marker of bone strength, and it does not fully assess bone quality. This becomes evident when one considers that the majority of fragility fractures occur in patients with T -scores better than −2.5 in postmenopausal women . This highlights the need to consider other risk factors and to contemplate absolute rather than relative fracture risk.

Recommended sites for BMD measurement are the lumbar spine and nondominant hip. In patients where one of these sites is not suitable for measurement, the proximal and distal radii are alternative sites for measurement; however, caution is advised using the distal radius in RA patients, as increased local bone loss due to inflammation makes this site less representative of general BMD .

Screening and Diagnosis Using FRAX and Dual-energy X-ray Absorptiometry (DXA)

There are several fracture risk assessment tools available, but the most widely used is the FRAX algorithm. FRAX estimates the 10-year absolute risk of hip fracture and other major osteoporotic fracture. The instrument is available online ( www.shef.ac.uk/FRAX ), and it includes demographic parameters such as age, sex, weight, prior fracture, as well as glucocorticoid use and diagnosis of RA. Although its use has been advocated internationally, FRAX has potential shortcomings for the practicing clinician to consider .

FRAX may underestimate fracture risk in patients with a history of multiple fractures. Smoking and alcohol intake appear to have a dose-dependent effect on fracture risk, but FRAX accounts for these risk factors in a binary fashion, and it does not account for the duration and level of use. Similarly, and more pertinent to patients with RA, glucocorticoid use is also taken into account in a binary fashion, considering the average effect of 7.5 mg of prednisolone, and it does not account for dose or duration . A modification to FRAX that adjusts the fracture risk of higher or lower glucocorticoid doses has been proposed . The diagnosis of RA itself is part of the FRAX calculation; however, this is also a dichotomous variable, which does not take into account disease activity, duration, or related disability . A recent publication by The International Society of Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) analyzed the literature to determine if disease parameters could be used to better characterize fracture risk in RA patients . Disability measures such as the HAQ (Health Assessment Questionnaire) correlated with clinical fractures, but not morphometric vertebral fractures . Data on the correlation of the effect of duration of disease were mixed, with several observational cohorts showing no association , but one large study, including 30,262 patients with RA from the British General Practice Research Database, found a significant threefold association of incident fractures with the duration of disease >10 years. There was little evidence to correlate other measures of disease such as disease activity score (DAS), visual analogue scale (VAS), or acute phase reactants with increased fracture risk .

The conclusion reached by the authors was that FRAX likely underestimates the fracture risk in RA patients with impaired functional status, but that the level of this effect was not quantifiable with current data .

ISCD and National Osteoporosis Foundation (NOF) recommend BMD assessment for all women aged 65 and older and all men aged 70 and older. Both groups also recommend BMD testing in postmenopausal women and men aged 50–69 with risk factors for osteoporosis, defined as low body weight, prior fracture, high-risk medication use, and diseases associated with bone loss . In slight contrast, the United States Preventive Task Force (USPTF) recommends BMD assessment in women under age 65 based on FRAX assessment, with BMD testing recommended for patients whose 10-year risk of major osteoporotic fracture is greater than that of a 65-year-old white woman without other risk factors (9.3%). Somewhat controversially, the USPTF does not currently recommend osteoporosis screening in men .

RA is considered to be a condition associated with systemic bone loss, and glucocorticoids are considered high-risk medications for bone loss. Thus, from a practical standpoint, following the guidelines set forth by the ISCD and NOF, every postmenopausal RA patient and every male RA patient aged 50 or older should have BMD testing performed.

DXA measures BMD, and it is expressed in grams of mineral per centimeter square. Comparison of an individual patient׳s bone density to age-, sex-, and ethnicity-matched reference population generates the Z -score, but more commonly used for treatment decisions is the T -score, which compares a patient׳s bone density with a young adult population of the same sex . The T -score at the lowest measured site is used in diagnosing osteoporosis using World Health Organization (WHO) criteria, with T -scores between −1.0 and −2.5 corresponding to osteopenia and <−2.5 considered osteoporosis. Although BMD correlates with fracture risk , it is a surrogate marker of bone strength, and it does not fully assess bone quality. This becomes evident when one considers that the majority of fragility fractures occur in patients with T -scores better than −2.5 in postmenopausal women . This highlights the need to consider other risk factors and to contemplate absolute rather than relative fracture risk.

Recommended sites for BMD measurement are the lumbar spine and nondominant hip. In patients where one of these sites is not suitable for measurement, the proximal and distal radii are alternative sites for measurement; however, caution is advised using the distal radius in RA patients, as increased local bone loss due to inflammation makes this site less representative of general BMD .

Vertebral fracture assessment

Vertebral fractures are prevalent in patients with osteoporosis, and they often are clinically silent, with only 20–30% producing clinical symptoms . Vertebral fractures are associated with functional disability, increased mortality, and increased risk of future vertebral and non-vertebral fractures independent of BMD and other clinical risk factors . There is evidence from several cohorts of patients with RA that there is an increased risk of vertebral fractures in the order of 13–36% with a positive correlation with disease duration . While some authors have found a significant rise in vertebral fractures with disease duration, as demonstrated in Fig. 1 , other large cohorts have failed to find the same association . Thus, clinicians should be aware of screening guidelines for vertebral fracture assessment (VFA), and they should apply them to patients with established RA.

Adapted from Abdellah El Maghraoui et al. Rheumatology 2010;49:1303–131.

The “scout image” of standard DXA may miss vertebral fractures, which are frequently clinically silent. Although plain radiographs are the gold standard for the diagnosis of vertebral fractures, VFA using software present on most modern DXA devices can be performed in combination with a DXA scan, thereby increasing convenience for patients and with less overall radiation exposure . The discovery of asymptomatic vertebral fractures can improve secondary fracture risk prediction, and it identifies a group of patients for whom fracture prevention therapies are highly appropriate . Although the image quality is slightly less than conventional radiographs, the sensitivity for moderate to severe deformities has been reported to be comparable . The grading of vertebral fractures can be done using the Genant classification, which scores the loss of vertebral height as mild (20–25% height loss), moderate (25–40% height loss), and severe (>40% height loss), with moderate and severe fractures being considered clinically relevant .

There is no clear consensus on VFA screening. The ISCD put out updated guidelines on VFA screening in 2013, simplifying prior guidelines from 2007. In the updated guidelines, VFA was recommended for patients with a T -score of <−1.0 in the following populations: all women aged ≥70 and all men aged 80, patients with a historical height loss of >4 cm, self-reported prior vertebral fracture, and glucocorticoid use equivalent to >5-mg prednisone per day for >3 months . NOF guidelines are similar, recommending VFA in postmenopausal women and men aged ≥50 with a historical height loss of >4 cm, glucocorticoid use, but with the addition of low-trauma fracture after the age of 50 and a prospective height loss (difference in documented height measurements) of >2 cm .

Bone turnover markers

BMD testing is the current standard mechanism by which to assess fracture risk and response to osteoporosis treatment. Bone density correlates strongly with bone strength and fracture risk, but there are several other factors affecting fracture risk . Given that changes in BMD with pharmacotherapy can take 2–3 years, there is a need for more rapid methods to assess treatment response. A potential solution to this problem is the employment of bone turnover markers (BTMs) to more rapidly assess the metabolic activity of bone and thereby assess response to treatment and fracture risk .

Changes in BTM are strongly associated with fracture risk in large clinical trials, with more fractures seen with elevated levels of bone resorption . The most widely used markers of resorption are C-telopeptide (CTX) and N-telopeptide (NTX). These form as the result of type I collagen, which have cross-linked with pyridinium, which are released into serum and excreted in urine. The two markers most frequently used for studies in osteoporosis have been P1NP and CTX, as recommended by the IOF and the IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) .

BTM can be measured in serum or urine; however, serum assays are preferred as urine excretion is highly variable based on the individual patient, and they must be corrected for creatinine excretion . CTX is dependent on food and time of day, and it should ideally be collected after an overnight fast .

While BTM are frequently used in osteoporosis trials as a way to quickly and conveniently assess treatment adherence and response to therapy, there is currently high variability in available assays, which limits the use of BTM in clinical practice for an individual patient. A recent systematic review of BTM concluded that there was insufficient evidence to use BTM in routine clinical practice to monitor osteoporosis treatment response .

Although BTM are not currently recommended for routine use in clinical practice, they show promise as a way to monitor adherence to therapy, therapeutic efficacy, and possibly when to resume therapy much more quickly than BMD testing alone after initiating “drug holidays” .

Adequate control of inflammation

The exact mechanism by which RA leads to an increased risk of fracture is not known, but it is likely secondary to immobility and effects of systemic inflammation on bone . Studies have shown that fracture risk increases with both disease activity and duration of disease, which support this idea, making it logical to assume that a tight control of a patient׳s underlying RA should lead to decreased bone loss and decreased fracture risk . However, to date, there are no data showing the prevention of bone loss or decreased fracture risk in patients treated with traditional disease-modifying antirheumatic drugs (DMARDs). Several smaller studies have shown no effect on BMD or fracture risk in patients taking MTX . Leflunomide, sulfasalazine (SSZ), and hydroxychloroquine (HCQ) have no data to date on the effect on BMD or fracture reduction .

Although there are abundant data on the deleterious effects of glucocorticoids on bone, there are conflicting data regarding the effects of glucocorticoids in the RA population. As noted previously, RA increases the risk of fracture via multiple mechanisms, including systemic inflammation and the interaction of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and receptor activator of nuclear factor kappa-B ligand (RANKL). Prednisone has known anti-inflammatory effects, and it has been shown to decrease the loss of hand bone density in RA patients compared with placebo at a dose of 7.5 mg/day ( Fig. 2 ). Along the same lines, a study of female RA patients on low-dose glucocorticoids (8.0 ± 0.5 mg/day) of prednisone followed for a year did not show significantly more decline in BMD compared with RA patients not taking glucocorticoids . However, cross-sectional studies show a decline in BMD at the lumbar spine and an increase in vertebral fractures in RA patients on chronic glucocorticoids compared with non-users. A large Norwegian cohort also found significantly decreased BMD at the total hip and lumbar spine for RA patients taking chronic glucocorticoids . It is worth noting that the initiation of treatment for the prevention of GIOP in patients on long-term (>3 months) supraphysiologic doses of prednisone is effective in preventing bone loss. This was demonstrated by the CAMERA-II trial, which showed that if calcium and vitamin D supplementation and bisphosphonate therapy are begun in RA patients on MTX and prednisone of 10 mg daily, there is no significant bone loss compared with patients treated with MTX and no glucocorticoids .

Adapted from Haugeberg G et al. Arch Intern Med. 2005; 165: 1293–1297.

Unlike MTX, there are limited data suggesting that anti-TNF therapy helps to prevent systemic bone loss as measured by DXA in patients with RA . There are also emerging data that IL-6 blockade also prevents systemic bone loss in RA patients. One study in 86 MTX-treated patients with RA, BMD was preserved in osteopenic patients >1 year . Although the positive data on systemic bone loss are encouraging, there are currently no data showing an effect on fracture risk .

Fall risk reduction and weight-bearing exercise

Falls are a major risk factor for fracture, and steps taken to prevent falls in patients with RA may prove invaluable. Patients with RA can develop altered biomechanics as a result of an increased lower extremity arthritis activity, placing them at risk of falls . Therefore, adequate control of the underlying RA may also help decrease fall risk. Several simple tests, which can be performed in the office, can be used to assess common risks for falls, such as visual acuity and postural blood pressure measurement .

A recent Cochrane review concluded that interventions such as Tai Chi and home-safety assessment by an occupational therapist significantly reduced fall risk in community-dwelling adults over age 65. Weight-bearing exercise such as walking or running has been shown to decrease BMD loss at the hip in patients with RA . Exercises should be tailored to the individual patient taking into account comorbidities such as cardiovascular or pulmonary disease.

Multidisciplinary fall prevention programs have been evaluated in controlled trials, and while they have not demonstrated significant reductions in a general elderly population , they have demonstrated significant reductions in fall rates in patients with osteoporosis and previous falls .

Hip protectors are plastic shields that are usually fitted in pockets in specially designed underwear, which were developed to reduce the risk of hip fracture in high-risk patients. Several trials have evaluated their utility for fracture reduction in older adults with mixed results. A recent Cochrane review concluded that there was a small reduction in the risk of hip fracture in older adults living in institutional settings, but that there was no reduction in risk in community-dwelling older adults .

Calcium and vitamin D supplementation

Although vitamin D and calcium are necessary for optimal bone health, neither vitamin D nor calcium supplementation by itself is associated with a reduced fracture risk. The combination was associated with a small but significant reduction in hip and all other fractures in postmenopausal women and men who were in nursing homes . Calcium absorption is impaired in patients with RA using glucocorticoids . The recommended consumption of calcium as per the NOF and Institute of Medicine (IOM) is 1000 mg/day in men aged 50–70 and 1200 mg/day in women >age 51 and men >71 . Dietary sources rich in calcium include yogurt, milk, and fortified juices . The average daily intake of calcium via diet in adults over age 50 is 600–700 mg/day, with increased dietary sourcing being preferred to supplementation . There is no added benefit of calcium intake >1200 mg/day with respect to fracture reduction, and there may be an increased risk of renal calculi and cardiovascular disease at higher intakes .

The primary source of vitamin D is obtained from solar ultraviolet-B (UV-B) radiation that triggers the conversion of provitamin D3 to pre-vitamin D3, to vitamin D3 . There is some controversy about the optimal dietary intake and serum levels of vitamin D. Then NOF recommends 800–1,000 IU/day for adults 50 and older, while the IOM recommends 600 IU/day until age 70 and 800 IU/day over age 70 .

In patients with normal renal function, the preferred assay is serum 25(OH), which reflects both dietary intake and skin synthesis. RA patients frequently have low vitamin D levels, especially in higher disease activity . In patients requiring supplementation, the aim for serum 25(OH) vitamin D level should be between 50 and 75 nmol/L .

Pharmacotherapy

The decision on when to start medical therapy for low BMD should be based on an individual provider׳s clinical judgment, and it should be individualized to each patient׳s case, with potential risks and benefits of medication discussed before initiating therapy. Guidelines set forth by the NOF recommend considering pharmacologic therapy in postmenopausal women and men >50 in the following circumstances:

• •
  

  Hip or vertebral fractures (clinical or asymptomatic and found on vertebral imaging)

  
  
• •
  

  T -score ≤−2.5 at the femoral neck, total hip, or lumbar spine

  
  
• •
  

  Osteopenia ( T -score between −1.0 and −2.5 at the femoral neck or lumbar spine), and a 10-year probability of hip fracture ≥3% or major osteoporotic fracture >20% based on FRAX

In addition to the abovementioned guidelines, treatment may be initiated in patients on chronic glucocorticoids for the prevention of GIOP. Guidelines for the management of GIOP have been published by the American College of Rheumatism (ACR) as well as the IOF and Foundation and the European Calcified Tissue Society ( Fig. 3 ). These guidelines will not be addressed in detail in this review, but, in general, any postmenopausal woman or man >50 taking the equivalent of prednisone of 7.5 mg/daily or more for >3 months should be evaluated for fracture risk, and they should be considered for pharmacologic treatment. Data on premenopausal women and men under age 50 are less robust, but both sets of guidelines recommend that clinicians consider treatment in these patient groups if there is a history of previous fracture. Clinicians should be especially cautious of using bisphosphonates in women of childbearing age as these drugs cross the placenta, and they have been associated with teratogenicity in animal models .

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