Review

Management of osteoporosis in rheumatoid arthritis patients

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Jos N Hoes†, Irene EM Bultink & Willem F Lems †

VU University Medical Center, Department of Rheumatology, Amsterdam, The Netherlands

1.

Introduction

2.

Epidemiology and pathophysiology

3.

Evaluation of fracture risk

4.

Bone mineral density measurement and vertebral fracture analysis

5.

Prevention of fractures

6.

Medical treatment

7.

Conclusion

8.

Expert opinion

Introduction: In rheumatoid arthritis (RA) patients, the risk of both vertebral and non-vertebral fractures is roughly doubled, which is for an important part caused by inflammation-mediated amplification of bone loss and by immobilization. New treatments have become available in the last two decades to treat both RA and osteoporosis. Areas covered: Epidemiology and assessment of osteoporosis and fracture risk (including the influence of RA disease activity and bone-influencing medications such as glucocorticoids), the importance of vertebral fracture assessment in addition to bone density measurement in patients with RA, the use of disease-modifying antirheumatic drugs and their effects on generalized bone loss, and current and possible future anti-osteoporotic pharmacotherapeutic options are discussed with special focus on RA. Expert opinion: Assessment of osteoporosis in RA patients should include evaluation of the effects of disease activity and bone-influencing medications such as (the dose of) glucocorticoids, above standard risk factors for fractures or osteoporosis as defined by the FRAX instrument. Disease-modifying antirheumatic drugs are now well able to control disease activity using treat to target strategies. This lowering of disease activity by antirheumatic medications such as anti-TNF-a results in hampering of generalized bone loss; however, no fracture data are currently available. When treating osteoporosis in RA patients, additional focus should be on calcium supplementation, particularly in glucocorticoid users, and also on sufficient vitamin D use. Several antiosteoporotic medications are now on the market; oral bisphosphonates are most commonly used, but in recent years, more agents have entered the market such as the parenteral antiresorptives denosumab (twice yearly) and zoledronic acid (once yearly), and the anabolic agent parathyroid hormone analogues. New agents, such as odanacatib and monoclonal antibodies against sclerostin, are now being tested and will most likely enlarge the possibilities of osteoporosis treatment in RA patients. Keywords: fracture prevention, osteoporosis, rheumatoid arthritis Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease in which arthritis of particularly the small joints of the hands and feet cause a significant functional impairment. Long-standing RA has a high burden of disease resulting in a lower quality of life and increased health cost. Peri-articular bone loss is a key feature of RA and is the result of local inflammation [1]. Generalized bone loss leading to osteoporosis is one of the extra-articular manifestations of RA [2] and may lead to the occurrence of fragility fractures, which further increase the burden of the disease. This review will discuss the assessment of fracture risk and management of osteoporosis with regard to RA and focus particularly on fracture-preventive treatment through both hampering inflammation and increasing bone strength. 10.1517/14656566.2015.997709 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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In rheumatoid arthritis (RA) patients the threshold to start anti-osteoporotic treatment should be lower, particularly in patients with high disease activity. In osteopenic high-risk patients vertebral fracture assessment is of additional value in deciding whether treatment should be initiated or not. Adequate lowering of disease activity with diseasemodifying drugs, either synthetic or biologic, hampers both local and generalized bone losses. In RA patients, additional focus should be on calcium supplementation, particularly in glucocorticoid users, and also on sufficient vitamin D use. Oral bisphosphonates are the most commonly used antiosteoporotic agents; alternatives are parenteral antiresorptives denosumab and zoledronic acid, and parathyroid hormone-analogues. New anti-osteoporotic agents, such as odanacatib en monoclonal antibodies against sclerostin, are now being evaluated in postmenopausal osteoporotic women.

(http://www.shef.ac.uk/FRAX) can be used to calculate a 10-year probability for both hip and major fractures, for example, hip, proximal humerus, wrist and clinical vertebral fracture. Unfortunately, there is no widely accepted treatment treshold, but for instance, the American National Osteoporosis Foundation advises treating patients with 10-year risk FRAX scores of 3% or more for hip fracture and/or 20% or more for major osteoporotic fracture, to reduce their fracture risk [6]. Using FRAX scores for shared-decision-making could improve adherence to treatment, which is important since non-adherence is a well-known problem in osteoporosis treatment [7]. The FRAX tool, nevertheless, has some limitations [8]; amongst others, the tool does not correct for the presence of recent falls and of vertebral fractures, and the (cumulative) dose of glucocorticoids. The FRAX tool does comprise RA as a risk factor, but disease activity and disease duration are not taken into account, although these disease features have clearly been demonstrated to influence fracture risk.

This box summarizes key points contained in the article.

RA-related risk factors Several factors add to the risk of developing osteoporosis in RA patients (Figure 2). In addition to general osteoporosis risk factors being common in RA -- such as female gender and low BMI -- the risk is further increased by prolonged active disease, immobility and decreased functional capacity, and frequent treatment with glucocorticoids [9]. 3.2

2.

Epidemiology and pathophysiology

Osteoporosis-related fragility fractures, both vertebral and non-vertebral, are an important disease complication in patients with RA, with a doubled occurrence of both hip and vertebral fractures compared to age and gender-matched controls [3]. This fracture risk is multifactorial and increases with disease duration, low body mass index (BMI), immobility and frequent glucocorticoid use [3]; additional factors are risk of falling due to decreased mobility and sarcopenia (frequently also caused by glucocorticoids). Also, an important part of the accountability for the increased fracture risk is reduced bone strength, which can be explained by disturbances in bone remodeling. It is known for some time that upregulation of pro-inflammatory cytokines leads to increased bone resorption, but more recently, it became known that formation of bone is also hampered in RA patients [4]. This is orchestrated by osteocytes, cells in lacunae in the bone matrix, which send their signals based upon loading and unloading: resulting in changes in receptor activator of NF-kB ligand (RANKL)/osteoprotegerin (OPG) and the Wnt pathway (Figure 1) [4]. Inhibitors of the Wnt signaling pathway, such as dickkopf-1 and sclerostin, are upregulated in active RA [5], and lead to apoptosis of osteoblasts and hence to decreased bone formation. Additionally, OPG is inhibited by increased receptor activation for RANKL expression, which leads to a prolonged lifespan of osteoclasts. 3.

Evaluation of fracture risk

General risk factors and the FRAX tool General risk factors for osteoporotic fractures are numerous; to quantify this risk, the FRAX instrument 3.1

2

Bone mineral density measurement and vertebral fracture analysis

4.

Bone mineral density measurement Bone mineral density (BMD) is mostly measured by dual energy X-ray absorptiometry at the lumbar spine and at the non-dominant hip (total and femoral neck) and expresses standard deviations from peak bone mass (T-score) with age-matched (Z-score) normal values. The proximal and distal radius are alternative sites for BMD measurement; however, the distal radius is not suitable for BMD measurement in RA patients because of local bone loss due to inflammation, which makes this site not representative for BMD measurement in general. The lowest of the measured T-scores is regarded when diagnosing according to WHO criteria: T-score ‡ -1 = normal BMD; -2.5 < T-score 40% height loss) [19]; discriminating wedge, biconcave and crushed-shaped vertebrae. Moderate and severe fractures are considered clinically relevant. 5.

Prevention of fractures

Lifestyle, dietary measures, calcium and/or vitamin D supplements

5.1

Extra focus should be put on adequate calcium intake in RA patients, since calcium absorption has been demonstrated to be impaired in postmenopausal women with RA (mean time since disease onset 14.2 months) compared with controls; in these RA patients, circulating levels of 1,25-dihydroxyvitamin D (calcitriol) were higher than in controls, implying a primary malabsorption of calcium [20]. Focus on adequate calcium intake is particularly needed in glucocorticoid-using RA patients. Older studies have shown glucocorticoid-related reduced intestinal calcium absorption [21,22], reduced vitamin D levels [21] and secondary increase in serum parathyroid hormone (PTH) concentrations [22]. Optimal vitamin D levels are also important in RA patients since they frequently have lower 25(OH) vitamin D levels, which in addition were 4

associated with disease activity [23]. This decreased serum concentration of vitamin D is probably caused by a decrease in exposure to sunlight due to decreased physical activity, which is a result of the disease rather than a pathogenic factor [24]. Although a widespread use of vitamin D supplements has recently been questioned [25], calcium and vitamin D supplementation have been associated with a small but significant reduction of hip and all other fractures in postmenopausal women and in men [26]. These effects are likely to be extrapolated to RA patients, and therefore, all RA patients with BMD values in the osteopenic and osteoporotic range should have a daily dietary intake of calcium of 1200 -- 1500 mg, which equals 4 units of dairy food such as a glass of milk, a cheese sandwich and a cup of yoghurt. Because dietary calcium intake is insufficient in many individuals, prophylactic supplementation with at least calcium (500 mg daily) is often indicated. The reason calcium supplementation in higher doses is not recommended lies in the still controversial link between high calcium intake and an increased incidence of cardiovascular death [27,28]. This observed association deserves special attention in RA patients, because this disease has been associated with an increased risk of developing cardiovascular disease [29]. Most vitamin D is gained from sunlight exposure of the skin, 5 -- 15 min (unprotected) exposure of which suffices vitamin D production by the skin in the period from April until October. Additional vitamin D can be obtained through diet, for example, particularly fat fish such as herring, mackerel and halibut. As both dietary- and sunlightrelated supplementations are insufficient in the majority of subjects, vitamin D supplementation should aim at increasing 25(OH)D levels to the 50 -- 75 nmol/l range, which is achievable with a vitamin D dose of 800 IU/day [30]. Additional measures include advice for sufficient physical activity for improving bone strength, muscle strength and balance [31]. Weight-bearing physical activity is advised such as walking and running at least three times a week; this is in line with results from the RAPIT-trial that showed a slowing down of hip BMD loss with long-term high-intensity weightbearing exercise in RA patients [32]. Balance can be improved through improving muscle strength (e.g., by swimming, biking) and by balance training (e.g., by Tai Chi). Anti-inflammatory/RA treatment In general, there is a clear positive relation between the course of RA and the degree of both local and generalized bone losses, that is, a cumulative increased disease activity is associated with bone loss. Therefore, treatment with disease-modifying antirheumatic drugs (DMARDs) is of major importance, not only to control disease activity but also to limit generalized bone loss. The most effective treatments are biological DMARDs and combinations of synthetic DMARDs. RA patients who have high titers of antibodies against citrullinated protein (ACPA) have a more aggressive course of the disease. The exact role that ACPA play in bone pathophysiology is 5.2

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Management of osteoporosis in rheumatoid arthritis patients

currently under investigation; recent studies used micro-CT analysis of the bone microstructure in the metacarpophalangeal joints and showed that BMD was significantly reduced in ACPA positive healthy individuals compared with ACPAnegative healthy controls [33]. The authors suggest that ACPA play a role in priming joints susceptible for bone loss irrespective of on-going arthritis/inflammation. In line with these results, another paper showed that ACPA directly induced osteoclastogenesis in vitro and induced osteopenia and increased osteoclastogenesis when introduced in mice [34]. This suggests that in RA patients who are ACPA positive, the latter could be an extra argument to consider lowering the threshold for treatment of osteoporosis in these patients. Synthetic DMARDs Methotrexate (MTX) is a so-called anchor drug in the treatment of RA and as such it is prescribed very frequently in both newly diagnosed and long-standing RA. MTX resembles folic acid and as such suppresses the metabolism of folic acid; its anti-inflammatory properties are mediated by induction of adenosine. This anti-inflammatory effect, which results in retardation of radiographic joint damage, is supposed to inhibit negative effects on bone. However, only a few studies were focused on the effect of MTX on bone density and their results did not confirm the supposed beneficial effect of MTX use on bone mass in RA. One small longitudinal study showed no effect of MTX on bone turnover markers in serum nor in synovial tissue; no effect was shown on the BMD either when corrected for disease activity [35]. Another, cross-sectional, study showed no association between lowdose MTX use and BMD scores (t-score < -2.5) of the lumbar spine or femoral neck [36]. Other synthetic DMARDs used nowadays are leflunomide, sulfasalazine and hydroxychloroquine; combinations of synthetic DMARDs have shown very efficacious in combatting disease activity [37]. Unfortunately, none of these agents the effect on BMD has been studied. However, leflunomide has shown favorable in vitro effects on bone resorption parameters [38]. Nevertheless, the adage of treat to target, that is, adjusting treatment intensity aiming at remission of disease, is now believed to be able to effectively treat RA [39]. Increase in bone density has been demonstrated in RA patients in whom long-term remission was achieved [40]. However, there are no preferred (combinations of) DMARDs to achieve remission and even lowering inflammation with the addition of long-term 10 mg prednisone daily to MTX treatment does not lead to generalized bone loss in early RA patients using bisphosphonates [41]. 5.3

5.4

Biologic DMARDs TNF-a inhibitors

5.4.1

Biological DMARDs (biologicals) are antibodies or proteins that are produced with recombinant DNA technology in living organisms, which hamper inflammation through inhibition of cytokines or their receptors, or through immunomodulation

by interference with lymphocyte development. These drugs are administered only parenterally, and although biosimilars are now starting to become available, they remain costly medications. The first biological which came available for RA treatment about two decades ago was infliximab, a monoclonal antibody binding TNF-a; nowadays, four other TNF-a inhibitors are available: adalimumab, etanercept, certolizumab and golimumab. A recent systematic review has summarized the results of all trials on the effect of anti-TNF-a on BMD and bone markers in RA [42]. Several studies -- mainly shortterm open label trials or longitudinal cohort studies -- have showed that anti-TNF-a treatment, mostly combined with MTX, protected against generalized bone loss (showing unaffected BMD values at the hip and/or the spine) [2,43,44]. While most studies were of short duration, up to 1 year, the BMDsparing effect seemed to maintain thereafter in a cohort of 184 established RA patients: Only a small decrease of hip BMD and a stable spine BMD was shown after a mean follow-up of 4 years of anti-TNF-a treatment [45]. Nevertheless, it remains to be determined whether this is an effect of anti-TNF-a treatment itself or the effect of the treatment strategy (treat-to-target), since the strategy-trial BeST showed similar results on BMD of anti-TNF-a therapy combined with MTX compared to other treatments: BMD loss, in general, was limited after 2 years [46]. Patients with a good response to treatment had more improvement of BMD of the hip than patients without such response [2], and there was a relation between reduced disease activity and improved values of bone markers, that is, a positive relation with bone formation/resorption marker ratio [2,47,48]. Figure 1 also summarizes the above-mentioned evidence. The real question to be answered, for which the abovementioned trials were probably underpowered, remains whether anti-TNF-a therapy is able to prevent the occurrence of fractures. Answers are currently unavailable but might be obtained from studies in population-based cohorts; in one such cohort-study, a comparable non-vertebral fracture incidence for anti-TNF-a-treated patients was found compared to patients treated with either MTX or other synthetic DMARDs [49]. This suggests a preventive effect, since antiTNF-a is mostly prescribed in RA patients with more active disease, who are prone to increased bone loss as a consequence of this high disease activity. Other biologicals The effect of other biologicals on bone mass in RA is even less well studied than for anti-TNF-a. The effect on generalized bone loss by inhibition of the co-stimulatory protein CTLA-4 on T-lymphocytes with abatacept has not been studied. A positive effect of B-cell depletion with rituximab on bone markers has been shown [50], and a recent review also mentioned an abstract of a small study that showed response-related BMD protective effects [4]. Anti-IL6 treatment with tocilizumab showed a decrease of bone resorption markers [51], and in a 1-year open-label prospective study of 5.4.2

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Table 1. Effect of anti-rheumatic and/or anti-osteoporotic treatments on bone density and fracture occurrence in patients with RA and in postmenopausal women. Medication

RA

Postmenopausal

Evidence level

Bisphosphonates (alendronate, risedronate, zoledronate)

No data; GIOP: increased BMD (Zoledronate) Protect against joint erosions

Fractures: significantly reduced risk

RANKL inhibitor; denosumab

BMD: increase Protect against joint erosions

Fractures: significantly reduced risk

Strontium ranelate

No data

Parathyroid hormone analogues

(GIOP) Fractures: reduced risk versus alendronate; RA = postmenopausal BMD: increased versus postmenopausal Bone formation markers increased

Fractures: significantly reduced risk Fractures: significantly reduced risk (vertebral and nonvertebral) [76,77]

Fractures (postmenopausal): 1 [54,55,85], BMD (GIOP): 1 [86], Erosions: 1 [72], BMD: 1 (RA, [69] and postmenopausal) [68] Fractures: 1 [68], Erosions: 1 [73] 2 [87,88]

Synthetic DMARDs Methotrexate Leflunomide, sulfasalazine, hydroxychloroquine Biologic DMARDs TNFa inhibition

Rituximab

Abatacept Tocilizumab

Fractures (postmenopausal): 1 [76,77], (GIOP) [79] BMD: 1 (GIOP) [79], 2 (RA) [78] Bone markers (RA): 2 [78]

No negative effects on BMD (corrected for disease activity) No data

N/A

2 [35], 3 [36]

N/A

N/A

BMD: unchanged and higher in therapy-responsive patients; anti-TNF-a not superior to other treatment strategies; long-term BMD-sparing effects. Bone markers: improvement. Fractures: comparable incidence of non-vertebral fractures to other effective treatments Bone markers: improvement BMD: protective effect; therapyresponse related No data BMD: protective effect, increase in osteopenic patients Bone markers: decrease of bone resorption

N/A

BMD: 4 [2,43,44], long-term: 2 [45] Bone markers: 4 [47,48] Fractures: 3 [49], Treat-to-target: 1 [46]

N/A

BMD: 4 (abstract) Bone markers: 4 [50]

N/A N/A

BMD: 2 [89], Bone markers: 1 [51]

Level of evidence: 1. randomized controlled trial; 2. cohort study; 3. case-control study; 4. case series. BMD: Bone mineral density; DMARD: Disease modifying antirheumatic drug; GIOP: Glucocorticoid-induced osteoporosis; N/A: Not applicable; RA: Rheumatoid arthritis; RANKL: Receptor activator of NF-kB ligand.

86 active MTX-treated RA patients, BMD was unchanged and even increased in osteopenic patients. Summarizing the above, when regarding DMARDs, particularly biologicals, inhibition of bone resorption markers are indirect evidence of osteoclast inhibition, which might well explain the favorable effect of these therapeutic agents against localized bone loss in RA [4,52]. In vivo, their anti-osteoporotic effects might be best explained by reduction of inflammation. This conclusion has recently also been suggested by the results of a 10-year follow-up study showing less BMD reduction during the second 2 years of RA treatment than during the first 2 years of treatment (in which period disease activity was higher) after diagnosis [10]. However, further studies are necessary to confirm these presumed anti-osteoporotic effects of DMARDs. 6

6.

Medical treatment

The main or ultimate goal of osteoporosis treatment is to prevent fractures by increasing bone strength, and there are several pharmacotherapeutic ways to achieve this (Table 1). When anti-resorptive treatment is not tolerated in oral form then parenteral alternatives are available, as is anabolic treatment with teriparatide.

6.1

Anti-resorptive treatment Bisphosphonates

6.1.1

Bisphosphonates disrupt bone resorption by osteoclasts by attaching to hydroxyapatite binding sites of bone, which

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Management of osteoporosis in rheumatoid arthritis patients

prevents osteoclasts from forming a so-called ruffled border and to adhere to the bony surface [53]. Fracture risk reductions in postmenopausal osteoporotic women have been clearly shown with high level evidence for alendronate and risedronate, the most frequently used bisphosphonates, particularly for secondary prevention of (vertebral and non-vertebral, including hip) fractures [54,55]. Yearly administrated parenteral zoledronic acid, also prevented vertebral and non-vertebral, including hip, fractures occurrence better than placebo [52], and also leads to a reduction in mortality in hip fracture patients with normal cognitive status [56]. These effects could be superior to oral bisphosphonates due to improved compliance and adherence to treatment, since non-adherence is a well-known reason for inefficacy of oral bisphosphonates. The frequent use of glucocorticoids in RA patients is an additional argument for the use of bisphosphonates in this patient group, since bisphosphonates are considered effective in glucocorticoid-treated patients as well [57]. Alternative parenteral bisphosphonates are ibandronate and neridronate, which have shown to increase BMD in patients with an inflammatory rheumatic condition in small studies [58,59]. Adverse effects are an important consideration with bisphosphonate use, since these could both affect treatment adherence and necessitate accurate surveillance during treatment. Oesophageal inflammation is a mild-to-moderate adverse effect, which is a frequent cause of non-adherence. The risk of osteonecrosis of the jaw (ONJ) is slightly increased [60]; estimated between 1 in 10,000 and smaller than 1 in 100,000 in patients with osteoporosis [61,62], and much higher risk for cancer treated with high-dose bisphosphonates (1 -- 10 per 100 patients) [61]. Since the increased risk for ONJ is multifactorial and bisphosphonates are not the only risk factor, a check of risk factors and additional advice should take place before bisphosphonate treatment is started: Discontinuing smoking, limiting alcohol intake and good oral hygiene should be emphasized as lifestyle measures to prevent ONJ for all patients receiving bisphosphonate therapy [63]. Another important side effect of bisphosphonates is atypical femoral fractures. It has been suggested that long-term inhibition of osteoclasts could lead to non-vital bone in which accumulation of micro-damage theoretically jeopardizes bone strength, which eventually may also increase the risk of atypical long bone mid-shaft fractures; however, other risk factors for the occurrence of atypical long bone mid-shaft fractures are use of glucocorticoids, proton pump inhibitors and other anti-resorptive agents, and female sex [64,65]. The true incidence of atypical femoral fractures in bisphosphonate-treated patients with osteoporosis is low [65]: The risk increases with duration of use [66], and long-term use of bisphosphonates has been estimated to have an absolute risk of ~ 100 per 100,000 patient-years [65]. Nevertheless, the pathogenesis remains unclear, and atypical femoral fractures also occur in patients who have never used bisphosphonates [66]. Another issue that prevents from prescribing bisphosphonates for pre-menopausal women with childbearing potential

is teratogenicity for the fetus in animal reproduction studies [67]. In addition, since bisphosphonates reside in mineralized bone for years, their use is also relatively contraindicated in premenopausal women prior to possible future conception [67]. Denosumab The human monoclonal antibody denosumab acts through inhibition of RANKL, resulting in decreased osteoclastogenesis. Its subcutaneous administration twice yearly makes it an attractive alternative to bisphosphonate therapy, particularly for those who did not tolerate or have a contraindication against bisphosphonates. Fracture prevention in denosumabtreated patients was evident in a large randomized controlled trial of 3 years comparing denosumab with placebo treatment in postmenopausal women with osteoporosis [68]. In a Phase II trial in 218 MTX-treated RA patients, the effects of 1-year treatment with either twice yearly 180 mg or the standard dose of twice yearly 60 mg of denosumab or placebo on BMD and bone markers were studied [69]. The results of this study showed a significant increase in both spine and hip BMDs for both denosumab-treated groups compared with a minor decrease of BMD in the placebo-treated group, as expected. An important possible adverse effect of denosumab use is hypocalcemia [70], which should be monitored during treatment. Moreover, as with bisphosphonate therapy, a possibly increased risk for atypical long bone mid-shaft fractures should be kept in mind in patients on long-term treatment [65], as well as the risk for ONJ [71]. Of course the question is, whether the effects of antiresorptives in RA are comparable to postmenopausal subjects, but no studies have been done in RA with fractures as end point, for obvious reasons. In our opinion, the extrapolation of these results to RA patients seems plausible, because probably the mechanism of action of anti-resorptives does not differ when compared to their use in postmenopausal women. Furthermore, additional arguments could apply in favor of the use of zoledronic acid and denosumab in RA. An extra argument for treatment with zoledronic acid is that it has shown to hamper radiographic erosions when given in addition to MTX. In a small study [72], 39 MTX-using early RA patients with clinical synovitis of the hand or wrist were randomized to receive two infusions with either zoledronic acid (5 mg) or placebo; one infusion at baseline and one after 13 weeks. After 26 weeks, the increase in MRI-measured erosions of the hand and wrist was lower in the zoledronic-acid-treated patients compared to placebo. There were also suggestions of both less MRI-visualized bone edema and less increase in the number of conventional radiographic erosions. Similarly, an extra argument in favor of the use of denosumab in RA patients is that denosumab has been demonstrated to protect against joint erosions in a small post-hoc analysis of the above-described trial [73]. After 6 months, the mean of MRI hand erosion scores were near the baseline values in the denosumab-treated patients (21 patients in the 60 mg group and 22 patients in the 180 mg 6.1.2

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group) and increased 3.8% from baseline in the 13-patient placebo group. The mean modified Sharp erosion scores in the hands at 12 months remained near the baseline values in the denosumab groups and increased 1.4% in the placebo group. Although these findings need to be replicated in larger trials, they nevertheless strongly suggest additional value of these agents in RA treatment. Strontium ranelate Strontium ranelate is incorporated in bone at the position of calcium. Although it has been demonstrated that strontium ranelate reduces the vertebral fracture rate and nonvertebral fracture rate in postmenopausal women [66,67], there are no data in RA patients, observing changes in BMD or fracture rate during the use of strontium ranelate treatment. Neither are we aware of any studies showing an effect of strontium ranelate on inflammatory arthritis or on local bone involvement in RA. The use of strontium does have some disadvantages. First, use of strontium ranelate causes an overestimation of BMD when performing bone density measurement because of the increase of X-ray beams by strontium atoms in bone [74]. Second, there are restrictions to the use of strontium ranelate; a recent analysis of randomized controlled trial data showed an increased incidence of myocardial infarction in strontium-ranelate-treated patients compared to non-users, which led the European Medicine Agency to advise against its use in patients with uncontrolled hypertension or current or past history of ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease [75]. Therefore, monitoring for cardiovascular disease is warranted during treatment. Since cardiovascular risk is elevated in RA, and since the use of strontium ranelate is associated with increased cardiovascular risk, one should be cautious in prescribing strontium ranelate in RA patients with osteoporosis.

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6.2

Anabolic treatment: PTH analogues (teriparatide) Daily injections of PTH analogues increase bone formation and bone strength through decreasing osteoblast and osteocyte apoptosis. Both recombinant full-length PTH (amino acids 1 -- 84) and teriparatide, the shortened version molecule PTH (N-terminal amino acids 1 -- 34), are used for treating osteoporosis. Large trials in postmenopausal osteoporotic women have shown that both agents reduced the incidence of both vertebral and nonvertebral, but not hip, fractures [76,77]. With respect to RA, one open-label trial has been performed that compared 18-month treatment with teriparatide in 70 RA patients with teriparatide treatment in 62 postmenopausal women. Both groups had osteoporotic range BMD and documented fracture [78]; RA patients showed a greater increase of bone formation markers after 1 and had an increased BMD of the femoral neck after 18 months compared to postmenopausal women. Indirect evidence of fracture prevention has been provided by the results of a large trial in patients with glucocorticoid-induced osteoporosis (GIOP) comprising 46% RA patients [79], comparing the effect of teriparatide versus 6.3

8

alendronate on bone mass and radiological vertebral fracture occurrence. GIOP patients treated with teriparatide during 36 months had a significantly higher increase in BMD and a significantly reduced incidence of new vertebral fractures versus the active comparator alendronate treated patients. No subanalysis for the RA-subgroup was performed, however. Unlike zoledronic acid and denosumab, no bone erosion healing effects of PTH therapy are known. Only one small study of 52 weeks assessed the topic and did not show additional effects against structural joint damage on MRI when teriparatide was added to etanercept (Table 1) [80]. PTH analogues are mainly used for bisphosphonate refractory osteoporosis or in case of adverse effects of bisphosphonates, because of their high cost. They are particularly useful for patients with many vertebral fractures. The possible adverse effects of teriparatide are considered mild; particularly, temporarily serum calcium increase may occur several hours after injection [81]. Future treatment options Odanacatib is a selective inhibitor of the collagenase cathepsin K that is highly expressed by osteoclasts (Figure 1) and results in the uncoupling of bone resorption and bone formation. The latter is of particular interest in RA. Very recently, the results of a 5-year duration Phase III trial in postmenopausal women have been shown at the recent ASBMR meeting and these showed risk reductions of vertebral, hip and nonvertebral fractures compared to placebo [82]. A new anabolic agent could be romosozumab, a sclerostin monoclonal antibody, which stimulates osteoblasts and through this bone formation (Figure 1). Romosozumab has been tested in a short-term Phase II study [83], which showed a higher increase in lumbar spine, total hip and femoral neck BMD than placebo, and, moreover, than active comparators teriparatide and alendronate. Another sclerostin inhibitor, blosozumab, is also underway and has recently been studied in a Phase II trial against placebo [84]. Although studies on the effects of these treatment modalities in RA patients have not been reported yet, these results suggest that the future for osteoporosis treatment in RA could be very bright. 6.4

7.

Conclusion

The disease-related increased risk of both vertebral and nonvertebral fractures in RA patients asks for alertness for and prevention of osteoporosis in these patients. Prevention of osteoporosis entails lowering both disease activity, and lowering the use of bone-influencing medications such as (high-dose) glucocorticoids. Furthermore, focus should be on a healthy life style, including adequate calcium supplementation, particularly in glucocorticoid users, and also on sufficient vitamin D use, exercise therapy, and avoidance of smoking/alcohol. Currently, first-choice treatment to treat osteoporosis in RA patients is with alendronate or risedronate, but there are arguments -- such as anti-erosive effects -- for the use of

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Management of osteoporosis in rheumatoid arthritis patients

zoledronic acid and denosumab as first-choice alternatives in ACPA positive RA patients with high disease activity; in addition, possibly very powerful new treatments are now underway. It is very encouraging to realize that in two decades time, osteoporosis treatment has resulted in significant and clinically relevant fracture reductions in RA. Also, if the promises of the current medications under development are coming true, the future for osteoporosis treatment in RA is very bright.

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8.

Expert opinion

In RA patients, the risk of both vertebral and non-vertebral fractures is doubled, which is for an important part caused by inflammation-mediated amplification of bone loss; which occurs particularly in patients with active RA. Disease activity lowering treatment is therefore key to preventing or treating osteoporosis in RA patients; hence, we suggest that the best way to prevent both local and generalized bone losses in RA is to achieve disease remission as quickly as possible. Biologicals are known for their powerful disease control, which results in both local controls, that is, less peri-articular bone loss and erosions, and prevention of generalized bone loss. Indirect evidence of the prevention of generalized bone loss has been demonstrated particularly for anti-TNF-a. However, no fracture data are currently available for any of the DMARD therapies. Although several studies have been done (post-hoc) on bone sparing effects of anti-TNF-a, the antiosteoporotic effects due to lowering of disease activity might most likely be achieved by any (combination) of DMARDs, provided that these drugs are leading to low disease activity or clinical remission. The assessment of fracture risk differs between RA patients and other subjects. Particularly in case of more additional risk factors, such as vertebral fractures on VFA or past high (cumulative) dosed glucocorticoid use, clinicians should be more suspicious of the presence of osteoporosis as a comorbidity of RA. In such cases, the threshold for anti-osteoporotic measures should be lower. When managing osteoporosis in RA patients, special focus should be put on sufficient calcium supplementation, especially in patients using glucocorticoids. Vitamin D supplementation is of equal importance, both because of its beneficial effects on bone and because patients with more active RA have lower vitamin D levels. An RA patient with clearly elevated fracture risk (such as a t-score lower than -2,5 or a high FRAX score) should be treated with additional

anti-osteoporotic drugs as in postmenopausal women. There are no fracture data in RA patients to support this, however. Since many fractures occur due to impaired quality of bone in a subgroup of osteopenic patients and since bone quality could be jeopardized by disease activity in RA, bisphosphonate treatment should be considered in osteopenic RA patients with a t-score lower than -2 or even -1.5 with high disease activity. Because of its effects against erosions, twice yearly subcutaneous denosumab should be considered especially in RA patients with severe inflammation and/or ACPA-positive patients. An alternative parenteral treatment, which also has demonstrated anti-erosive properties, is yearly zoledronic acid. One should be alert for (serious) adverse events such as ONJ and atypical long bone mid-shaft fractures as a result of avital bone, particularly in case of long-term use of anti-resorptive drugs. The use of teriparatide is restrained by its high medication costs; nevertheless, teriparatide is a powerful anabolic anti-osteoporotic agent that is particularly useful for patients with many vertebral fractures. No antierosive effects of teriparatide are known up to date. Strontium ranelate has not been studied in RA and is a less favorable alternative -- in a RA population that already suffers from more cardiovascular disease -- due to its association with myocardial infarction. New agents such as the Cathepsin K and sclerostin inhibitors have shown promising results in Phase III and II trials respectively, and these agents might become available the coming years as treatment alternatives. The question whether these agents have additional value in RA patients will most likely be a subject for further research. Until then, osteoporosis in RA is well treated using lifestyle/dietary measures, strict lowering of disease activity, and the currently available antiosteoporotic drugs. Most importantly, it is very encouraging to realize that in two decades time, osteoporosis treatment has resulted in significant fracture reductions. Also, if the promises of the current medications under development are coming true, the future for osteoporosis treatment in RA is very bright.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation

Jos N Hoes†1,2 MD PhD, Irene EM Bultink1 MD PhD & Willem F Lems3 MD PhD † Author for correspondence 1 VU University Medical Center, Department of Rheumatology, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands E-mail: [email protected] 2 University Medical Center Utrecht, Department of Rheumatology and Clinical Immunology (F02.127), PO Box 85500, 3508 GA, Utrecht, The Netherlands 3 Professor, VU University Medical Center, Department of Rheumatology, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

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