Pharmacological Management of Osteoporosis in Rheumatoid Arthritis Patients: A Review of the Literature and Practical Guide

In RA patients, decreased mean BMD values of the spine and hips, compared with healthy individuals, has been known to be a very common EAM of RA for several years. In earlier studies, before the introduction of biologics, the prevalence of loss of BMD has been estimated to be doubled in both male and female RA patients compared with healthy controls at both the lumbar spine and the hip [16, 17]. In these studies, up to 32% of subjects experience loss of BMD, compared with only 16% in the ‘healthy’ reference group. Moreover, it was observed that RA patients have double the risk of both hip fractures and vertebral fractures, with prevalence estimates ranging from 13 to 36% depending on clinical parameters such as disease burden and duration, concomitant medication, history of (non)vertebral fractures, and age [19, 22‐24].

In the Oslo RA register, postmenopausal female RA and non-RA patients were included, with a mean age of ≥ 63 years in both groups. In this study, substantially more vertebral deformities were observed in RA patients compared with non-RA patients, i.e. 147 and 51 vertebral deformities, respectively. Fifty-five (22.1%) patients with RA, compared with 38 (15.3%) controls, had at least one vertebral deformity measured morphometrically [odds ratio (OR) 1.74, 95% confidence interval (CI) 1.02–3.04], and 28 (11.2%) versus 12 (4.8%) had two or more deformities (OR 2.60, 95% CI 1.21–6.04) [22].

In the British General Practice Research Database (BGPRD), fracture rates were compared between RA and non-RA patients in different age groups. This registry observed that RA patients had comparable increases in fracture risk, with an adjusted relative risk (RR) for clinical osteoporotic fracture of 1.4 (95% CI 1.2–1.7) in male RA patients and 1.5 (95% CI 1.4–1.6) in female RA patients, in all age groups, when compared with non-RA patients. Interestingly, it was shown that there were an increasing number of fracture rates in patients of higher age groups, especially in patients aged 70 years and older [19].

The burden of OP (i.e. OP-related fractures) in RA patients can be explained by several reasons (Fig. 1). First, RA is a chronic disabling inflammatory disease that is associated with decreased mobility and physical activity, as well as lower muscle mass and sarcopenia, all factors known to have detrimental effects on bone mass [25‐28]. Second, for several years now, the direct effects of inflammation on bone density have been known, especially in newly diagnosed RA patients [29]. Moreover, it has been observed that inflammation and bone loss share common pathways in pathogenesis [30‐32].

Intriguingly, van Staa et al. observed that RA patients without prior GC use had an increased risk for both vertebral fractures (RR 1.5, 95% CI 1.2–1.9) and hip fractures (RR 1.7, 95% CI 1.5–2.0) compared with controls without a history of RA, at any time during follow-up. In addition, increased risk was also seen in early glucocorticoid (GC) users, not just in chronic users, suggesting that the underlying active disease with ongoing inflammation and muscle weakness should be considered a relevant risk factor for increased prevalence of OP and the incidence of fractures [19]. Third, it is known that GCs have direct and indirect negative effects on bone density [33, 34]. Indeed, previous studies have estimated that 30% of all patients treated with GCs for at least 6 months will develop OP [35]. Therefore, RA patients with (long-term) GC exposure have an accelerated risk for glucocorticoid-induced OP (GIOP) during their lifetime. For the abovementioned reasons, in relation to RA and the presence of classical risk factors for OP (e.g. familial OP or hip fracture and postmenopausal age), many RA patients suffer from both OP and an augmented fracture rate.

OP is defined as a musculoskeletal disorder characterized by compromised bone strength, predisposing individuals to an increased fracture risk [36]. Individuals can be divided into three groups according to the WHO criteria, dependent on the BMD value: T score ≧ − 1 = normal BMD; − 2.5 < T score < − 1 = osteopenia and T score ≦ − 2.5 = OP. However, most fractures occur paradoxically in patients not suffering from OP but suffering from osteopenia, and this can be partly explained by the fact that these patients also have impaired quality of bone, which is not measured with DXA [37, 38]. Moreover, in all patients, vertebral fracture assessment (VFA) is recommended. The gold standard for detecting vertebral fractures is a conventional radiograph of the thoracolumbar spine. In clinical practice, the Genant score is used, in which the degree of height loss is assessed and can be graded as mild (grade 1, 20–25% height loss), moderate (grade 2, 25–40% height loss), or severe (grade 3, > 40% height loss) [39]. However, VFA is an elegant alternative because this technique has been proven to be safe, with less radiation exposure, is less time-consuming, and has lower costs than conventional radiographs with comparable accuracy in detecting moderate-to-severe vertebral fractures [40]. Another way to assess fracture risk is to calculate the 10-year probability for a major fracture (i.e. vertebral, hip, humerus, or wrist fracture) using the computer-based algorithm FRAX^® [41]. This algorithm includes several clinical risk factors, including, among others, previous fractures, parental history of hip fracture, age, smoking, GC use, and secondary causes for OP, including RA. Although FRAX^® is very useful in daily clinical practice, this calculation tool has some disadvantages for RA patients as it does not take into account the cumulative disease burden and disease activity, which are notorious independent risk factors for bone loss in RA. Therefore, it has been suggested that FRAX^® might underestimate the fracture risk in these patients [42, 43]. Other limitations of this fracture risk calculation tool include the fact that it does not take into account fall risk, vertebral fractures, and the dose of GC in the FRAX algorithm. Moreover, it was observed that the risk of a subsequent fracture after an initial fracture, is strongly upregulated in the first 2 years [44]. Although the FRAX^® has some limitations, in daily clinical practice FRAX® is an adequate algorithm to identify high-risk RA patients and to determine which RA patients should be treated according to (inter)national guidelines [45].

Although no randomized controlled studies have been performed on nonpharmacological interventions and fracture reduction, some general measures have been advocated in OP patients. First, a healthy lifestyle, including nonsmoking, little to no alcohol intake, and a nonsedentary and active lifestyle with exercises, should be advised in all patients in order to reduce bone loss [46‐48]. Moreover, adequate calcium intake up to a daily dose of 1000–1200 mg is necessary; if daily intake is below this threshold, calcium supplementation is needed. Although calcium supplementation is needed in patients with a low calcium intake, high dietary calcium intake has been debated as supplementation has been associated with an elevated risk of cardiovascular disease (CVD) [49]. This is a concern, particularly in RA patients, as RA has been associated with an increased risk of CVD that equals the CVD risk of diabetes mellitus [50]. Moreover, a recent study showed an increased risk of CVD in RA patients with fragility fractures [51]. Another nonpharmacological modifiable factor is vitamin D deficiency, as a large meta-analysis has shown that vitamin D supplementation (800 IU/day) in patients who also received calcium supplementation is associated with a 20% reduction in falls and nonvertebral fractures [52, 53]. Therefore, supplementation of calcium and vitamin D is needed, along with general advice regarding low alcohol intake, cessation of smoking, and performing exercises to reduce fracture risk in RA patients.

Despite the effective treatment options available nowadays compared with 2–3 decades ago, RA patients still suffer from an increased risk for fractures [108]. One of the most threatening reasons for the high incidence of fractures, next to aging, and the low adherence of osteoporotic drugs, is the ongoing use of corticosteroids, resulting in GIOP. Although the observation that GC use in early and active RA may not diminish BMD levels [109], ongoing GC use, even at low doses, is associated with an elevated fracture risk [110].

To prevent new fractures in RA patients, the following steps may help to identify high-risk OP patients, and may serve as a practical guide for OP treatment in RA.

In our opinion, three measures should be taken into account in the management of OP, as summarized in Table 1: general measures, RA disease-related factors, and OP-related factors.

First, some general lifestyle advice should be given; a normal body mass index (BMI), smoking cessation, and avoiding excessive alcohol intake should be advocated. Moreover, a non-sedentary and active lifestyle should be advised in all patients in order to reduce bone loss. For this reason, every RA patient should be encouraged to perform physical activities, along with daily, weight-bearing exercises if possible.

Second, some RA-related factors should be taken into account. Most important is to aim at remission or the lowest disease activity as possible, as ongoing inflammation jeopardizes bone quality and should be considered a relevant risk factor for osteoporotic-related fractures [19]. Although no superiority for a specific treatment regimen has been demonstrated, some (indirect) evidence exists that bDMARDs may be more pivotal for preventing bone loss when looking carefully at fracture data of cDMARDs compared with bDMARDs. The question remains whether this is only explained by the fact that bDMARDs are excellent and better immunosuppressives in reducing inflammation. Unfortunately, bDMARDs are less often prescribed in the elderly; this is critical since the elderly, in particular, are at high fracture risk. Next, in order to aim at the lowest possible disease activity, efforts should be made to prescribe GCs at the lowest possible dose. Again, GCs are often used in the elderly, which may have devastating effects. If possible, doses higher than 7.5 mg should be avoided and prednisolone sparing-agents (e.g. cDMARDs, bDMARDs, or tsDMARDs) should be added if long-term treatment for higher doses is expected. Moreover, GCs should preferably only be used as an induction therapy and for a short period of time when possible.

As mentioned above, ongoing inflammation in RA patients due to disease activity threatens bone quality and accelerates bone loss. For this reason, it can be advocated that certain RA patients with high disease burden should be treated with osteoporotic medication to decrease fracture risk. Therefore, in (certain) RA patients, lower treatment thresholds (e.g. a T score < − 2.0) can be recommended to decide whether RA patients should be treated with osteoporotic medication [111]. Another validated tool to assess (future) fracture risk in RA patients is the FRAX^® calculation tool, which should be recommended in all RA patients with a T score > − 2.5, to assess future fracture risk. In RA patients, adequate calcium intake, up to a daily intake of 1000–1200 mg, is needed. Below this threshold, calcium supplementation is needed. Particularly in GC-treated patients, it has been suggested that the daily calcium intake should be above 1000–1200 mg/day [112, 113]. This recommended dose is slightly higher than the dose recommended for postmenopausal women not using GCs, and is related to the lower intestinal calcium absorption and increased urinary calcium excretion in GC-treated patients. An adequate 25-hydroxyvitamin D3 serum level > 50 nmol/L is advised throughout the whole year, and also at the end of winter [114]. If an osteopenic RA patient suffers from a high risk of fracture, or an RA patient has OP, in general the oral BP alendronic acid (or another oral BP such as risedronate) is the first choice as this agent has been shown to improve BMD levels in RA patients. However, sparse data indicate that the modern treatment agents denosumab and teriparatide might be superior, in RA patients, for increases in BMD and fracture rate reduction, compared with the active comparators alendronate or risedronate. Although these pivotal osteoporotic drugs are attractive as first-line therapy, the evidence is too little to include them as first-line drugs for OP in RA. Moreover, these drugs are too costly to be used in all patients. However, in certain patients with a very high fracture risk, i.e. elderly patients with RA, a (very) low BMD, or a recent nonvertebral osteoporotic fracture or known VF, second-line anti-osteoporotic agents are a very attractive option to reduce fracture risk.

We are hopeful that good implementation of the above measures will serve as an ideal form of fracture risk management and will ultimately lead to a reduction in fracture risk in vulnerable RA patients.