Abstract
Inflammatory joint diseases, such as seronegative spondyloarthropathies, rheumatoid arthritis and systemic lupus erythematosus, are characterized by bone complications including osteoporosis and fragility fractures.
Access provided by CONRICYT-eBooks. Download chapter PDF
Similar content being viewed by others
1 Introduction
Inflammatory joint diseases, such as seronegative spondyloarthropathies (SnSp), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis, and vasculitides, are characterized by bone complications including osteoporosis (OP) and fragility fractures (FF).
The course of OP is closely connected with the activity of the underlying disease and other risk factors, including low body mass index (BMI) (<18 kg/m2), early menopause (<45 years), low-energy fractures, renal failure, diabetes, smoking and alcohol use, high bone turnover, vitamin D deficiency, low intake or impaired absorption of calcium, and low calcium concentration. However, active inflammation, glucocorticoids (GC) therapy, long disease duration, immobilization, and reduced physical activity are considered the main risk factors altering both the quality and the amount of bone mineral density (BMD) associated to these diseases [1]. It is well-known that inflammatory cytokines, such as the tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-7, and IL-17, are involved in the regulation of the bone homeostasis, with increasing osteoclast activity through receptor activator of the nuclear factor kappa-B ligand (RANKL) and receptor activator of the nuclear factor kappa-B (RANK) pathway, with the prevalence of bone resorption on bone formation in rheumatic diseases [2]. Therefore, treatment with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) is of major importance, not only to control disease activity but also to limit generalized bone loss. GC are frequently used in the treatment of rheumatic diseases because they suppress the systemic inflammation with a subsequent beneficial effect on bone mass, even though one of the principal complications of GC long-term use consists of an important alteration of bone metabolism. FF risk is positively related to their daily dose and increases during the first 6 months of therapy, and the relative risk of fractures is higher for forearm, hip, and vertebral sites and depends on the duration of GC therapy itself [3].
This paper focuses on three inflammatory joint diseases, SnSp, RA and SLE, because OP and FF represent the main extra-articular complications of these diseases.
2 Osteoporosis in Seronegative Spondyloarthropathies
SnSp are a heterogeneous group of disorders with clinical features that include axial and peripheral arthritis, psoriasis, inflammatory bowel disease, and uveitis. The group, which affects approximately 0.5–1.5% of the Western population, comprises chronic inflammatory diseases such as ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, inflammatory bowel disease-related spondyloarthropathies, and undifferentiated spondyloarthritis. In the context of SnSp, AS and PsA are the most frequently observed conditions; both are immunoinflammatory disorders characterized by bone involvement and associated with different prevalence of low bone mineral density (BMD), OP, and an increased risk of OP-related FF.
Chronic and persistent inflammation is an important risk factor for bone loss in AS and PsA due to its deleterious effect on bone remodelling. As a consequence, bone balance is negatively affected; indeed, imbalance between osteoblast bone formation and osteoclast bone resorption with net prevalence of osteoclastogenesis occurs [1]. Furthermore, additional and relevant risk factors for OP and FF to take into account are GC treatment, low levels of vitamin D, sarcopenia, intestinal malabsorption, hypo(immo)bilization, and reduced physical activity due to compromised mobility, joint pain, and functional impairment.
Emerging and increasing evidence highlights the harmful role on the bone played by inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-17, and IL-23. In fact, chronic inflammation is characterized by overexpression of inflammatory cytokines involved in the upregulation of the receptor activator of the nuclear factor kappa-B ligand (RANKL); RANKL is responsible for inducing osteoclastogenesis by binding to receptor activator of the nuclear factor kappa-B (RANK) on the surface of cells of the osteoclast lineage [2, 4].
It is not fully defined the role of dickkopf-1 (Dkk-1), the potent inhibitor of the Wnt/β-catenin pathway, whose levels in AS are below those of the healthy control population. It was speculated that the decrease in Dkk-1 results in increased Osteoprotegerin (OPG) and up-regulation of the Wnt pathway leading to activation of β-catenin, which transcriptionally enhances OPG gene expression [5]. Even less known is the role of Dkk-1 in PsA.
Since TNF-α, IL-17, and IL-23 are cytokines involved in the pathogenic mechanism of the typical lesions of AS and PsA, including the skeletal ones, it follows that neutralizing their effects with more innovative drugs can provide favourable results on maintaining bone homeostasis. Available data suggest that the anti-inflammatory treatment with TNF-α inhibitors, while having a positive effect on BMD at the spine and the hip, is less effective in reducing the risk of fracture [6].
Traditional anti-osteoporotic drugs for OP and FF prevention according to local recommendations and in combination with calcium and vitamin D are indicated.
3 Osteoporosis in Ankylosing Spondylitis
AS, the prototype disease in the spectrum of SnSp, is a progressive inflammatory rheumatic disorder that primarily affects the axial skeleton, including the sacroiliac joints. AS usually presents during the third decade of life and rarely after the age of 45 years. Its prevalence is generally reported between 0.1 and 1.4%. There is some gender disparity with a 2–3:1 male-to-female ratio rather than the previously thought 5–6:1.
Many studies have shown decreased BMD levels by dual-energy X-ray absorptiometry (DEXA), with an OP prevalence range from 19 to 62% [6]. The frequencies differ widely as a consequence of different duration, activity and extent of disease and of the degree of the impaired back mobility.
One of the main features of bony damage in early AS is the excessive loss of the trabecular bone in the centre of the vertebral body causing osteopenia or OP [7]. In long-standing disease the presence of structural bone lesions, such as syndesmophytes (new bone formation “bridging” two or more adjacent vertebrae), may be responsible for increased BMD. Therefore, in early AS, DEXA measurements should include both the spine and the hip, while in long-standing disease, only the hip BMD level should be considered; however, active or past hip osteoarthritis can represent a confounding factor.
Generally low BMD levels are associated with high disease activity expressed by relevant inflammation indices and abnormal values of Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Metrology (BASMI) [8]. In early SA, risk factors for low BMD seem to be related to male gender and decreased functional capacity [9].
A systematic review showed a high prevalence of osteopenia versus OP for the lumbar spine (39% and 16%, respectively) and for the femoral neck (38% and 13% respectively), particularly in patients with a short disease duration. This high prevalence was not expected in a relatively young and predominantly male population [10].
A study in a cohort of 204 patients (57% men, mean age 50 ± 13 years) found a prevalence of OP of 21% in participants aged ≥50 [11]. Low BMD was associated with age, disease duration, and inflammatory parameters.
In a study of 103 patients, osteopenia at the hip and spine was found in 56% and 41%, respectively, of patients with disease duration <5 years, with an additional 11 and 15% having OP. In patients with a longer disease duration (>10 years), 29% were osteoporotic at the hip and only 4% at the lumbar spine [12].
Given the low BMD, the alteration of the biomechanical properties of the spine, and the structural bony damage, patients with AS have a fourfold FF risk, during their lifetime, compared with the general population, even from minor injury.
Vertebral FF are a common finding in AS, but their prevalence is highly variable up to more than 40% [13]. The discrepancies in prevalence rate reflect inadequate design or lack of power of the studies, inconsistency in the definition of vertebral FF, differences in recruitment, sex distribution, age, and vertebral FF assessment methods. Vertebral FF may depend on the low BMD and/or the increased spine vulnerability secondary to the bone lesions, with reduced shock absorption, induced by the disease; however, they appear to be related more to the duration and structural severity of the disease rather than to BMD. Vertebral FF should be promptly and carefully considered in any patient with neck or back pain that is changed in intensity or character as they are often associated with neurological signs and symptoms.
A case-control study of 53,108 patients with fractures concluded that the risk of fractures was higher in AS than in rheumatoid arthritis (RA), with the largest increase for vertebral fractures (odds ratios 7.1 and 2.7, respectively) [14].
Recent data suggest both low BMD and high prevalence of vertebral FF even in patients with early-onset disease [15].
Patients with AS are also at increased risk of nonvertebral FF; in a large study, this risk was found to be statistically significant, even after adjustment for potential confounding factors (smoking, alcohol consumption, body mass index, and use of oral steroids) [16]. According to the results of the same study, the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) seems to eliminate the excess vertebral and nonvertebral FF risk with an unknown mechanism.
Increased levels of RANKL and low levels of OPG have been detected in the sera of patients with AS. Furthermore, cross-sectional studies have highlighted an association between low vitamin D concentrations and both susceptibility and disease activity, suggesting a potential role of vitamin D related to its skeletal and immunological effects [17]. Paradoxically, although subjects with AS generally exhibit localized regions of enhanced bone formation at sites of spinal involvement, some of them may have low BMD at the spine [18]. It is possible to speculate that this happens when and if the local inflammatory process is still active and persistent.
TNF-α inhibitors appear to increase lumbar spine and hip BMD [5]; so far there is no clear evidence of an anti-fracture effect. It is likely that also the novel biotechnological drugs targeting IL-17 and IL-23/17 axis can exert the same effects. More research is needed to assess the effects of these agents on bone quality and fracture risk.
4 Osteoporosis in Psoriatic Arthritis
PsA is an inflammatory chronic rheumatic disease affecting both peripheral and axial joints in addition to skin. PsA usually occurs in the age of 40–50 years old; male-to-female ratio is from 0.7:1 to 2.1:1.
Prevalence of low BMD is not well defined; studies addressing the topic have shown conflicting results as far as the prevalence of OP in patients with PsA is concerned. Though most of the studies have found no significant increase in OP concluding that the magnitude of the problem seems to be mild, others suggest a higher prevalence than previously thought [19, 20].
OP, when present, recognizes pathophysiological mechanisms similar to those of AS and appears to be related to the duration, extent, and activity of the disease.
A study of 155 patients found no differences in BMD values between patients and reference population [21]. Prevalence of OP was 16%; it was higher in postmenopausal women (28%) than in men (9%) or premenopausal women (4%). Prevalence of clinical fractures was 13%, mainly found in postmenopausal women; however, spine X-ray was not performed so that morphometric vertebral FF were not considered.
A study including 91 patients found no significant differences in mean lumbar spine and femoral neck BMD between PsA patients and controls; however, the prevalence of FF was significantly higher in patients (14.3%) than in controls (4.4%) [22].
A previous study carried out in 45 postmenopausal women with PsA concluded that patients did not have lower BMD even if they had a higher prevalence of FF [23]. In contrast, a study in 100 postmenopausal women with PsA showed that the prevalence of vertebral and nonvertebral FF on radiographic readings did not differ between cases and controls [24].
The higher prevalence of fractures compared with controls found in some studies indicates that alterations of bone quality are a characteristic of the disease, regardless of BMD values.
According to a recent systematic review, high likelihood of bias and inconsistent results of the available studies suggest a need for well-designed longitudinal studies on bone health in PsA [25].
Limited available data on vitamin D status in PsA suggest that patients have low levels of vitamin D with an inverse correlation between the serum level and the activity of the disease [26].
There are limited data on the effect of traditional therapies for OP in PsA patients. However, treatment with the currently available TNF-α inhibitors can potentially positively interfere on skeletal damage related to the disease; it is likely that a similar favourable effect can be exerted by the novel inhibitors of IL-17, IL-23/17 axis, and phosphodiesterase 4.
5 Osteoporosis in Rheumatoid Arthritis
RA is an autoimmune, systemic disease that is characterized by distal and symmetrical synovitis with joint destructions. It affects 0.5–2% of the general population, with a female preponderance and an increased prevalence with age. This disease is associated with subchondral bone erosion, cartilage degradation, and systemic bone loss. Periarticular bone loss, adjacent to the inflamed and swelling joints, is a key feature of RA and the result of local inflammation [27]. Generalized bone loss, leading to OP, is the main extra-articular manifestation of RA and may lead to the occurrence of FF, exacerbating pain and disability and impairing the quality of life of these patients [28]. In the USA, data from the National Data Bank for Rheumatic Diseases indicated that FF are the third cause of mortality in RA patients, after respiratory problems and myocardial infarctions, and the second cause of invalidity, after depression [29].
Even if the patients with RA are at high risk of OP and FF, having several well-known risk factors, such as menopausal status, low BMI, reduced physical activity and disability, vitamin D deficiency, and GC therapy, the inflammatory disease activity may be the most important factor associated with bone loss in RA [30, 31]. Another risk factor for developing OP is represented by the rheumatoid factor (RF) status: the frequency of OP and reduced bone mass is higher in RF-positive than RF-negative patients [32].
The prevalence of OP in RA patients is reported to be approximately twice that in the general population [32]. The frequency of OP in patients with RA ranges from 12.3 to 38.9% at the lumbar spine and from 6.3 to 36.3% at the hip [33,33,34]. According to a recent report, the frequency of OP in Korean postmenopausal women with RA was of 46.8% [31]. Above all, there is at least a twofold increase in the risk of vertebral FF in RA patients, and a higher risk, up to sixfold, has been reported in patients with a long-standing disease [34,35,36]. Recently, RA has been taken into account as an independent risk factor in the assessment of fracture risk [37, 38].
An important part of the accountability for the increased fracture risk is the reduced bone strength, which can be explained by disturbances in bone remodelling. It is known that upregulation of pro-inflammatory cytokines, such as TNF-α, IL-1, Il-6, and IL-17, is responsible for the overexpression of RANKL that promotes osteoclasts differentiation and leads to an increased bone resorption. More recently, it became known that formation of the bone is also hampered in RA patients [39]. This is orchestrated by osteocytes, which send their molecular signals based upon loading and unloading forces, resulting in changes in RANKL/OPG and the Wnt pathway. Inhibitors of the Wnt signalling pathway, such as Dkk-1 and sclerostin, result to be upregulated in active RA [40], leading to apoptosis of osteoblasts and hence to a decreased bone formation. Additionally, OPG is inhibited by increased receptor activation for RANKL expression, which leads to a prolonged lifespan of osteoclastic cells.
GC are frequently used in the treatment of RA. It is well demonstrated that GC have an action both in retarding the progression of erosive joint damage in early RA and a control of disease activity [41,42,43]. The use of GC is restrained by the occurrence of their side effects, and one of the principal complications of long-term GC use consists of an important alteration of bone metabolism. GC mainly suppress bone formation because they determine a decrease in osteoblastogenesis, interfering with osteoblastic differentiation and maturation and inducing loss of function and apoptosis of osteocytes [44, 45]. Risk of fracture in patients who received long-term GC therapy is about 33–50%, positively relating to daily and cumulative dose [46, 3].
Several studies have shown a lower BMD in RA as compared to controls [47,48,49], the largest effect being measured at the hip. The observed BMD reduction is approximately of 2–17% at the hip and from no reduction to 10% at the spine; in a population of 394 female RA patients, no significant reduction in spine BMD was found, in contrast with a significant reduction of 3.7–8.5% at the hip and 4.2–5.0% at the femoral neck (according to the age group) [32]. In a study focused on perimenopausal women, a BMD reduction of 5.5% was observed at the lumbar spine [50]. In the largest study conducted on 94 male patients with RA, no reduction was observed at the spine BMD, and a significant decrease at the hip (6.9%) was observed in the oldest patients only [51]; one longitudinal result suggests that BMD loss is lower in males than in pre- and postmenopausal women [52]. A recent study showed that in premenopausal women with RA both spine and hip BMD values were significantly lower than in age-matched controls and that such a difference was maintained at the hip after adjustment of BMD for GC therapy and disease activity indices [53]. This suggests that the disease itself is responsible of the significant bone loss, in particular at predominantly cortical skeletal sites. An association between low-dose GC use (≥6 months) and OP has not been observed [54]. This may be explained by a control of the disease activity and an improvement of function of the co-treatment with low-dose GC and GC-induced OP (GIO) preventive therapy [55, 56].
A common observation in all studies is the large interindividual variations, explaining why there is an apparent discrepancy between a relatively modest mean reduction in BMD and a high prevalence of OP. Among the confounding factors affecting the interpretation of BMD results in RA patients is the long duration of the disease, including the course of the disease itself, and an association has been observed between the severity of RA and the risk of OP [57].
Patients with RA are at increased risk of FF at the hip, vertebrae, and pelvis [35, 58, 59]. Humerus and tibia/fibula fracture risk is also increased in some but not all the [35, 58] studies. The risk of wrist fracture seems not to be increased in RA as compared to controls [35, 58].
In the General Practice Research Database, 30,262 patients with RA (ages ≥40 years) were compared to controls, with a mean duration of follow-up of 4.3 years; the increased risk of clinical fracture was of 1.5 (1.4–1.6) [35]. Indicators of a substantially elevated risk of hip fracture were the long duration of the disease, low BMI, and the use of oral GC. Two important observations for the potential mechanisms of bone fragility have been made in this study: the risk of fracture is the same in men and women; the fracture risk remains elevated after excluding patients who had taken GC at any time during the follow-up.
RA is characterized by a higher severity of spine involvement with a higher risk of having two or more fractures compared to controls [34, 60]. The incidence of vertebral FF is 6.7 per 100 patient-years according to a study with a mean follow-up of 2–3 years [61]. Patients with incident vertebral FF are those with older age, lower BMD, higher disability, and previous nonvertebral fractures. Being diagnosed as having RA, the risk is related to vertebral deformities independent of BMD and GC use [34]. Presence of vertebral FF is inversely related to the use of DMARDs and GC, enhancing the hypothesis that an appropriate control of the disease may be a protective factor against bone fragility [60]. Low bone quality might be the cause of the frequent prevalence of vertebral FF in patients with RA [62]. Vertebral FF may not emerge to clinical attention in RA because of analgesics use for painful joints. Thus, vertebral fracture assessment technology on DEXA devices should be used in these patients at the time of BMD measurement.
The incidence rate of nonvertebral FF in IORRA cohort study is 3.5/100 patient-years and does not change in 10 years, despite a striking improvement in RA disease control [63]. This study could indicate that OP treatment and nonvertebral fracture prevention remain important, regardless of RA disease activity.
DMARDs, as methotrexate (MTX), and biotherapies, as anti-TNF therapies, have proved to be successful in retarding joint destruction in RA while being able to control inflammation. The goal of the treatments is the remission of the disease and the prevention of the structural damage; prevention of bone complications is therefore expected.
Infliximab was able to decrease bone resorption; at its introduction as therapy in a population of patients with RA for 11 ± 7 years and failure of other DMARDs, an increase in the ratio between markers of bone formation and bone resorption was observed [64]. There was no BMD change over 1 year. In a small group of 20 patients, with early and active disease, BMD loss was significantly reduced in patients receiving MTX and infliximab, as compared to those treated by MTX alone, at the femoral neck and the hip: −0.35 vs. −3.43% and −0.23 vs. −2.62% [65]¸ there was no change at the spine level. Other studies showed that infliximab and etanercept were able to arrest BMD loss at the spine [66, 67]. The BeSt study compared prospectively the efficacy of four treatment strategies in RA: (a) sequential monotherapy of several DMARDs, (b) step-up combination therapy, (c) initial combination therapy with tapered high-dose prednisone, and (d) initial combination therapy with infliximab. In the group with better suppression of inflammation, the BMD loss was less than in other groups [68]. In a study of 50 patients with active RA who started adalimumab in addition to stable MTX e prednisone (less than 10 mg/day) at baseline, BMD was associated with disease activity and duration; after 12 months, adalimumab arrested further decrease in BMD, with an inverse association between decrease in serum C reactive protein (CRP) levels and increase in BMD, but a greater increase at femur BMD was observed in patients who received concomitant low doses of prednisone [69]. While most studies were of short duration, up to 1 year, the BMD sparing 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 treatment [70]. In a large sample size study, the use of biologic DMARDs (infliximab, adalimumab, etanercept, golimumab, certolizumab, rituximab, abatacept, tocilizumab, anakinra) did not lead to a reduction in the risk of nonvertebral osteoporotic fractures [71]. In a group of 8419 RA women, it was found that the use of anti-TNF in combination with MTX was not associated with a reduction in the risk of FF [72]. Another recent study also did not report any advantages of TNF inhibitors over traditional nonbiologic therapies for the prevention of bone loss and fracture in RA patients [73].
At this stage, there is increasing evidence on the beneficial effect of anti-TNF agents to prevent bone loss, even if the clinical impact, in terms of fracture risk reduction, has yet to be confirmed. Therefore, the administration of bisphosphonates (BP), as well as other agents, such as teriparatide and denosumab (a monoclonal antibody against RANKL), might be important for OP treatment and consequent fracture reduction in RA patients.
6 Osteoporosis in Systemic Lupus Erythematosus
SLE is an autoimmune disease characterized by chronic inflammation and the production of a wide array of autoantibodies. SLE can virtually involve any organ/system; in its clinical picture, active disease, chronic damage, and comorbidities overlap [74].
SLE typically affects young women in their childbearing age, with a peak of incidence between 15 and 40 years of age and a male to female ratio of 1:9. Disease onset is less common in childhood and in elderly population with female to male ratios of 2–6:1 and 3–8:1, respectively [74]. Because the survival of patients with SLE has improved dramatically over recent decades, attention is now focused on disease complications leading to increased morbidity and mortality.
Of note, the musculoskeletal system is frequently involved, and OP is one of the most common comorbidities, found in 1.4–68% of this population [75,76,77]. This wide variation in prevalence may be related to the study design, sample size, GC use, disease activity and duration, patient demographics, and under-recognition as more than 75% of patients are thought to have suboptimal screening [78]. A systematic review and meta-analysis, which evaluated the mean difference of the BMD level between SLE patients and controls, has been recently published [79]. Literature showed that SLE patients had significantly lower BMD levels than controls (p < 0.001).
In SLE, FF also occur in younger patients as compared with those with primary OP, and 4–30% of patients may develop FF despite normal BMD [76, 77, 80,81,82]. The most common sites of FF are the hip, vertebra, ankle, rib, foot, and arm [76, 80]. OP and associated FF may result in severe pain, disability, impaired quality of life, and increased mortality [83, 84].
The pathogenesis of OP and the occurrence of FF in SLE are likely to be multifactorial, involving both non-disease-related and disease-related factors.
It has been established that the old age, postmenopausal status, low body mass index, reduced physical activity, and constitutional symptoms are the possible risk factors for OP [75,76,77, 85, 86].
Pro-inflammatory cytokines including IL-6, IL-1, and TNF-α are overexpressed by activated immune cells in SLE patients and have a direct action on the bone, increasing on one side osteoclastic bone resorption and on the other reducing osteoblastic bone formation [2, 7, 77, 85, 87]. It is well known that upregulated RANKL/RANK/OPG signalling and downregulated Wnt/β-catenin pathway are responsible for bone loss associated with inflammatory rheumatic diseases [2, 7, 85, 87]; in addition, polymorphisms in the RANKL and OPG genes appear to play an important role in bone remodelling process and in FF occurrence in SLE [88].
OP and atherosclerosis are common clinical problems and share bidirectional correlation [89, 90]. Cardiovascular disease is a well-recognized complication of SLE, and there has been a growing interest in the biology and mechanisms underlying premature and accelerated atherosclerosis in this disease [91, 92]. To date, the role of inflammatory immunological pathways has been recognized for both the increased risk of cardiovascular disease and low BMD [86, 92, 93]. Oxidized low-density lipoprotein (LDL) and LDL cholesterol (LDL-c) play an important role in the generation and progression of atherosclerosis; additionally, it has been shown that high serum LDL-c level may also be a risk factor for low BMD and for nonvertebral FF [80, 86]. Oxidized lipids are able to activate T cells, which in turn can induce increased production of TNF-α and RANKL; moreover, oxidized lipids may negatively influence osteogenesis by reducing osteoblast differentiation and maturation. As a consequence, LDL and LDL-c may be considered the link between OP and atherosclerosis, and in fact in active SLE patients, high serum levels of LDL and LDL-c were inversely correlated with BMD [80, 86, 93].
Although some clinical and cross-sectional studies failed to demonstrate a relationship between disease activity and bone loss in SLE [80, 94, 95], a recent 5-year prospective study in Chinese women with SLE demonstrated an association between high disease flare rate and increased bone loss in spine and hip [96]. In addition, low complement C4 levels were a predictor of low lumbar spine BMD in the Hopkins Lupus Cohort, and low complement C4 was an independent contributor to the association between low BMD and carotid atherosclerosis [93, 97].
The relationship between organ damage and reduced BMD is still debated. While several studies report such a relation [96, 98], the results of other studies [75] failed to identify organ damage as a risk factor for OP and FF [76, 94, 95]. Lupus nephritis occurs in up to 60% of SLE patients during the disease course and can result in renal failure. In chronic renal failure, the development of both secondary hyperparathyroidism and low 1,25[OH]2D levels will adversely affect bone mass. However, an association between impaired renal function and low BMD was reported in only one study, in older female SLE patients [99].
Hypovitaminosis D is highly prevalent in SLE as a result of avoidance of sunshine, photoprotection, renal insufficiency, and the use of GC, anticonvulsants, calcineurin inhibitors, and, probably, antimalarials which alter the metabolism of vitamin D or downregulate the functions of the vitamin D receptor [82, 87, 100]. Studies that included healthy controls reported lower vitamin D levels in SLE patients in 12/14 (86%) [101]. Vitamin D insufficiency (25OH-D serum levels <30 ng/mL) was also recently documented in 60% of non-supplemented female SLE patients in the Mediterranean region [102]. A cross-sectional evaluation of bone metabolism parameters in 186 SLE patients showed vitamin D insufficiency in 79% with a mean level of 21.8 ± 15.7 ng/mL; of note, 25OH-D levels <20 ng/mL were found in 52.2% of patients [82].
With respect to bone mass, hypovitaminosis D, which predisposes to secondary hyperparathyroidism, represents an additional risk factor for OP. A significant association between low 25OH-D levels and low vertebral BMD was found in [103]. A positive correlation was also observed between 25OH-D levels and lumbar spine and total hip BMD in Chinese young male SLE patients [104]. Furthermore, a 6-year prospective study in 126 Dutch SLE patients confirmed that low 25OH-D levels at baseline were significantly associated with bone loss in the lumbar spine and hip [105].
The active form of vitamin D [1.25(OH)2D] is a steroid hormone that, in addition to its actions on calcium and bone metabolism, exhibits a wide spectrum of immunomodulatory and anti-inflammatory effects, as extensively documented by experimental studies [100, 101, 106,107,108]. Although these effects have been also reported in clinical studies and reviews specifically evaluating SLE patients, the relationship between vitamin D status and the onset, activity, and complications of the disease is currently theoretical, and further well-designed trials are needed [100, 101, 106, 108,109,110].
Most patients develop SLE in their premenopausal years, and some of them do so in the years preceding the achievement of peak bone mass. Both the disease and its treatment (e.g., cyclophosphamide) can also induce amenorrhoea and premature menopause, which cause bone loss. Furthermore, it has been suggested that other endocrine dysfunctions may affect negatively bone mass in SLE. The hormonal status of SLE patients has been described as a relatively high oestrogenic and low androgenic state; low plasma androgens in active and inactive SLE and an association between low dehydroepiandrosterone sulphate levels and low BMD have been reported [80, 85, 87].
The antimalarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) are frequently used in SLE patients as immunosuppressants. The mechanism of action has been linked to an effect on DNA, antigen processing, cytokines, lysosomal membranes, and T-cell proliferation [85]. Additionally, CQ and HCQ were thought to interfere with the synthesis of 1,25(OH)2D, by inhibiting hydroxylase α1 [85, 87].
With regard to the skeletal effects, studies in SLE patients demonstrated conflicting results [77, 80, 85]. Two cross-sectional studies in SLE female patients reported a significant correlation between HCQ and higher BMD in the spine and hip [111, 112]; additionally, treatment duration was significantly associated with higher BMD in the spine [112]. Conversely, a cross-sectional and a 6-year prospective study in Dutch SLE patients showed a negative correlation between BMD and HCQ use [105, 113]. In a 5-year prospective study, no influence of HCQ treatment on BMD was found [96]. Thus, it is still unclear whether the antimalarial drugs ultimately affect bone metabolism, and further studies on this possible adverse effect are needed [77, 80, 85, 87].
In SLE patients, GC, commonly used at high doses for the treatment of disease flares, significantly improved survival and the quality of life [85]. However, there is no doubt that GC and other immunosuppressants could represent an additional risk factor for bone loss and FF [3, 44, 45, 77, 85, 114]. Longer duration of GC therapy and cumulative and high-dose GC use appear to be associated with bone loss and FF in SLE patients [3, 44, 45, 77, 80, 82, 96, 114, 115]. Moreover, cumulative dose [116] and duration of GC therapy independently predicted higher FF risk in SLE patients compared with controls, using the FRAX tool, the most widely used algorithm for assessing the 10-year individual FF risk [37, 117, 118].
For cyclosporine A (CyA), a possible deleterious effect on the skeleton has also been suggested based on the high frequency of FF occurring in transplant recipients treated with this drug. However, in rheumatic diseases including SLE, CyA is used at lower doses than in transplant recipients, and present data do not allow to confirm the relationship between CyA and bone loss in SLE patients [77, 82, 85].
Cyclophosphamide, commonly used to treat severe SLE comorbidities including renal and neurologic involvement, may contribute to treatment-related OP by inducing amenorrhoea and premature menopause secondary to ovarian failure [77].
Chronic treatment with antiepileptics and anticoagulants may also contribute to bone loss and FF occurrence by negatively affecting bone mass, as documented in some studies [77, 80, 82, 85].
Although estimates for the prevalence of OP and FF in SLE patients indicate that their burden may be dramatically elevated, bone health care in SLE is still suboptimal, and quality-improvement efforts should address OP screening, prevention, and treatment [78]. There is no consensus regarding the optimal method of identifying bone loss and risk of FF in SLE; the FRAX and the DeFRA (the Italian algorithm derived from FRAX) could represent useful tools to establish the need for pharmacological treatments [38].
At present, there are no specific guidelines regarding OP prevention and treatment in SLE patients.
Calcium and vitamin D are recommended in all patients treated with GC [44, 45, 114, 119, 120]; special attention must be paid to obtain the target 25OH-D serum level above 30 ng/mL, as recommended by multiple scientific societies [121, 122].
BP are considered the first choice to prevent bone loss and reduce FF risk in GIO [44, 45, 114, 119, 120].
However, when considering premenopausal women, there is no generally recommended treatment, and BP should only be prescribed in patients with high risk of FF, as these drugs may be long term stored in the bone and are associated with foetal abnormalities in animal models [77, 85, 87, 119].
Teriparatide, which counteracts the most relevant pathophysiological mechanisms of GIO [45, 114, 119, 120], has been shown to be superior to BP in both FF rate and BMD in patients with GIO [114, 119, 120] and SLE [123].
Denosumab could represent an attractive effective agent in the treatment of GIO [114, 120, 123]; additionally, since denosumab is not incorporated in the bone, this drug may be also advantageous in premenopausal patients [77, 114, 119, 120, 124]. A recent study has shown that denosumab is superior to BP in SLE [125].
Conclusion
Several, if not all, inflammatory rheumatic diseases may be complicated by increased bone loss and elevated FF risk. We focus on RA, SLE, AS, and PsA because OP and associated FF are largely documented in these diseases.
The pathogenesis of OP and the occurrence of FF are likely to be multifactorial, involving both non-disease-related and disease-related factors. In addition to disease state, several factors including genetic, metabolic, and hormonal factors may have a deleterious effect on the bone. Increasing evidence highlights the role of complex interactions involving chronic inflammation, RANKL/RANK/OPG signalling, and Wnt/β-catenin pathway. Even if clinical studies have demonstrated that adequate immunosuppressive therapy prevents both local and generalized bone loss, there is no doubt that the chronic use of GC and other immunosuppressants could represent an additional risk factor for bone health.
There are no specific guidelines regarding OP prevention and treatment in rheumatic diseases.
A healthy lifestyle and calcium and vitamin D supplementations are diffusely recommended in almost all patients; BP are considered the first choice in patients at risk of FF with caution in their use both in premenopausal and younger patients. Denosumab and teriparatide might be an attractive additional option.
Whether TNF-α inhibitors and other biologic agents are ultimately effective in reducing FF risk remains so far inconclusive.
References
Maruotti N, Corrado A, Cantatore FP. Osteoporosis and rheumatic diseases. Reumatismo. 2014;66:125–35.
Schett G, Saag KG, Bijlsma JWJ. From bone to biology to clinical outcome: state of the art and future perspectives. Ann Rheum Dis. 2010;69:1415–9.
Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk fractures. J Bone Miner Res. 2000;15:993–1000.
Briot K, Roux C. Inflammation, bone loss and fracture risk in spondyloarthritis. RMD Open. 2015;1(1):e000052. https://doi.org/10.1136/rmdopen-2015-000052.
Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–63.
Haroon NN, Sriganthan J, Al Ghanim N. Effect of TNF-alpha inhibitor treatment on bone mineral density in patients with ankylosing spondylitis: a systematic review and meta-analysis. Semin Arthritis Rheum. 2014;44:155–61.
Amarasekara DS, Yu J, Rho J. Bone loss triggered by the cytokine network in inflammatory autoimmune diseases. J Immunol Res. 2015;2015:832127. https://doi.org/10.1155/2015/832127.
Ghozlani I, Ghazi M, Nouijai A, et al. Prevalence and risk factors of osteoporosis and vertebral fractures in patients with ankylosing spondylitis. Bone. 2012;44:772–6.
van der Weijden MA, van Denderen JC, Lems WF, et al. Low bone mineral density is related to male gender and decreased functional capacity in early spondylarthropathies. Clin Rheumatol. 2011;30:497–503.
van der Weijden MA, Claushuis TA, Nazari T, et al. High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review. Clin Rheumatol. 2012;31:1529–35.
Klingberg E, Geijer M, Göthlin J, et al. Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton. J Rheumatol. 2012;39:1987–95.
Karberg K, Zochling J, Sieper J, et al. Bone loss is detected more frequently in patients with ankylosing spondylitis with syndesmophytes. J Rheumatol. 2005;32:1290–8.
Leone A, Marino M, Dell’Atti C, et al. Spinal fractures in patients with ankylosing spondylitis. Rheumatol Int. 2016;5(1):51–5. [Epub ahead of print].
Weiss RJ, Wick MC, Ackermann PW, et al. Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases – a case-control study with 53,108 patients with fracture. J Rheumatol. 2010;37:2247–50.
van der Weijden MA, van der Horst-Bruinsma IE, van Denderen JC, et al. High frequency of vertebral fractures in early spondylarthropathies. Osteoporos Int. 2012;23:1683–90.
Muñoz-Ortego J, Vestergaard P, Rubio JB, et al. Ankylosing spondylitis is associated with an increased risk of vertebral and nonvertebral clinical fractures: a population-based cohort study. J Bone Miner Res. 2014;29:1770–6.
Zhao S, Duffield SJ, Moots RJ, et al. Systematic review of association between vitamin D levels and susceptibility and disease activity of ankylosing spondylitis. Rheumatology. 2014;53:1595–603.
Goldring SR. Osteoimmunology and bone homeostasis: relevance to spondyloarthritis. Curr Rheumatol Rep. 2013;15:342–7.
Ogdie A, Schwartzman S, Eder L, et al. Comprehensive treatment of psoriatic arthritis: managing comorbidities and extraarticular manifestations. J Rheumatol. 2014;41:2315–22.
Borman P, Babaoğlu S, Gur G, et al. Bone mineral density and bone turnover in patients with psoriatic arthritis. Clin Rheumatol. 2008;27:443–7.
Busquets N, Vaquero CG, Moreno JR, et al. Bone mineral density status and frequency of osteoporosis and clinical fractures in 155 patients with psoriatic arthritis followed in a university hospital. Rheumatol Clin. 2014;10:89–93.
Riesco M, Manzano F, Font P, et al. Osteoporosis in psoriatic arthritis: an assessment of densitometry and fragility fractures. Clin Rheumatol. 2013;32:1799–804.
Pedreira PG, Pinheiro MM, Szejnfeld VL. Bone mineral density and body composition in postmenopausal women with psoriasis and psoriatic arthritis. Arthritis Res Ther. 2011;13:R16. https://doi.org/10.1186/ar3240.
Del Puente A, Esposito A, Costa L, et al. Fragility fractures in patients with psoriatic arthritis. J Rheumatol Suppl. 2015;93:36–9.
Chandran S, Aldei A, Johnson SR, et al. Prevalence and risk factors of low bone mineral density in psoriatic arthritis: a systematic review. Semin Arthritis Rheum. 2016;46(2):174–82. https://doi.org/10.1016/j.semarthrit.2016.05.005. [Epub ahead of print].
Kincse G, Bhattoa PH, Herédi E, et al. Vitamin D3 levels and bone mineral density in patients with psoriasis and/or psoriatic arthritis. J Dermatol. 2015;42:679–84.
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2015;365:2205–19.
Deodhar AA, Woolf AD. Bone mass measurement and bone metabolism in rheumatoid arthritis: a review. Br J Rheumatol. 1996;35:309–22.
Michaud K, Wolfe F. Comorbidities in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21:885–906.
Kleyer A, Schett G. Arthritis and bone loss: a hen and egg story. Curr Opin Rheumatol. 2014;26:80–4.
Lee JH, Sung YK, Choi CB, et al. The frequency of and risk factors for osteoporosis in Korean patients with rheumatoid arthritis. BMC Musculoskelet Disord. 2016;17:98. https://doi.org/10.1186/s12891-016-0952-8.
Haugeberg G, Uhlig T, Falch JA, et al. Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County rheumatoid arthritis register. Arthritis Rheum. 2000;43:522–30.
Sinigaglia L, Nervetti A, Mela Q, et al. A multicenter cross sectional study on bone mineral density in rheumatoid arthritis. Italian Study Group on Bone Mass in Rheumatoid Arthritis. J Rheumatol. 2000;27:2582–9.
Ørstavik RE, Haugeberg G, Uhlig T, et al. Vertebral deformities in rheumatoid arthritis: a comparison with population based controls. Arch Intern Med. 2004;164:420–5.
van Staa T, Geusens P, Bijlsma JW, et al. Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:3104–12.
Pell NF, Moore DJ, Barrington NA, et al. Risk of vertebral fracture and relationship to bone mineral density in steroid treated rheumatoid arthritis. Ann Rheum Dis. 1995;54:801–6.
Kanis JA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385–97.
Adami S, Bianchi G, Brandi ML, et al. Validation and further development of the WHO 10-year fracture risk assessment tool in Italia postmenopausal women: project rationale and description. Clin Exp Rheumatol. 2010;28:561–70.
Vis M, Guler-Yuksel M, Lems WF. Can bone loss in rheumatoid arthritis be prevented? Osteoporos Int. 2013;24:2541–53.
Miao CG, Yang YY, He X, et al. Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal. 2013;25:2069–78.
Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N Engl J Med. 1995;333:142–6.
Wassenberg S, Rau R, Steinfeld P, et al. Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:3371–80.
Svensson B, Boonen A, Albertsson K, et al. Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum. 2005;52:3360–70.
Canalis E, Mazziotti G, Giustina A, et al. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2013;18:1319–28.
Compston J. Management of glucocorticoid-induced osteoporosis. Nat Rev Rheumatol. 2010;6:82–8.
Pereira RMR, de Carvalho JF, Canalis E. Glucocorticoid-induced osteoporosis in rheumatic diseases. Clinics. 2010;65:1197–205.
Martin JC, Munro R, Campbell MK. Effects of disease and corticosteroids on appendicular bone mass in postmenopausal women with rheumatoid arthritis: comparison with axial measurements. Br J Rheumatol. 1997;36:43–9.
Hall GM, Spector TD, Griffin AJ, et al. The effect of rheumatoid arthritis and steroid therapy on bone density in postmenopausal women. Arthritis Rheum. 1993;36:1510–6.
Sambrook PN, Eisman JA, Champion GD, Yeates MG, et al. Determinants of axial bone loss in rheumatoid arthritis. Arthritis Rheum. 1987;30:721–8.
Kroger H, Honkanen R, Saarikoski S, et al. Decreased axial bone mineral density in perimenopausal women with rheumatoid arthritis—a population based study. Ann Rheum Dis. 1994;53:18–23.
Haugeberg G, Uhlig T, Falch JA, et al. Reduced bone mineral density in male rheumatoid arthritis patients. Arthritis Rheum. 2000;43:2776–84.
Gough AK, Lilley J, Eyre S, et al. Generalised bone loss in patients with early rheumatoid arthritis. Lancet. 1994;344:23–7.
Fassio A, Idolazzi L, Jaber MA, et al. The negative bone effects of the disease and of chronic corticosteroid treatment in premenopausal women affected by rheumatoid arthritis. Reumatismo. 2016;68:65–71.
Peng J, Gong Y, Zhang Y, et al. Bone mineral density in patients with rheumatoid arthritis and 4-year follow-up results. J Clin Rheumatol. 2016;22:71–4.
van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, et al. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002;136:1–12.
Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2012;156:329–39.
Lodder MC, de Jong Z, Kostense PJ, et al. Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density. Ann Rheum Dis. 2004;63:1576–80.
Orstavik RE, Haugeberg G, Uhlig T, et al. Self reported non-vertebral fractures in rheumatoid arthritis and population based controls: incidence and relationship with bone mineral density and clinical variables. Ann Rheum Dis. 2004;63:177–82.
Huusko TM, Korpela M, Karppi P, et al. Threefold increased risk of hip fractures with rheumatoid arthritis in Central Finland. Ann Rheum Dis. 2001;60:521–2.
Ghazi M, Kolta S, Briot K, et al. Prevalence of vertebral fractures in patients with rheumatoid arthritis: revisiting the role of glucocorticoids. Osteoporos Int. 2012;23:581–7.
Orstavik RE, Haugeberg G, Mowinckel P, et al. Vertebral deformities in rheumatoid arthritis. Arch Intern Med. 2004;164:420–5.
Okano T, Inui K, Tada M, et al. High frequency of vertebral fracture and low bone quality in patients with rheumatoid arthritis—results from TOMORROW study. Mod Rheumatol. 2016;2:1–7. [Epub ahead of print].
Ochi K, Inoue E, Furuya T, Ikari K, et al. Ten-year incidences of self-reported non-vertebral fractures in Japanese patients with rheumatoid arthritis: discrepancy between disease activity control and the incidence of non-vertebral fracture. Osteoporos Int. 2015;26:961–8.
Chopin F, Garnéro P, le Henanff A, et al. Long-term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis. Ann Rheum Dis. 2008;67:353–7.
Haugeberg G, Conaghan PG, Quinn M, et al. Bone loss in patients with active early rheumatoid arthritis: infliximab and methotrexate compared with methotrexate treatment alone. Explorative analysis from a 12-month randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2009;68:1898–901.
Vis M, Havaardsholm EA, Haugeberg G, et al. Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:1495–9.
Seriolo B, Paolino S, Sulli A, et al. Bone metabolism changes during anti-TNF-alpha therapy in patients with active rheumatoid arthritis. Ann N Y Acad Sci. 2006;1069:420–7.
Güler-Yüksel M, Bijsterbosch J, Goekoop-Ruiterman YPM, et al. Bone mineral density in patients with recently diagnosed, active rheumatoid arthritis. Ann Rheum Dis. 2007;66:1508–12.
Wijbrandts CA, Klaasen R, Dijkgraaf MGW, et al. Bone mineral density in rheumatoid arthritis patients 1 year after adalimumab therapy: arrest of bone loss. Ann Rheum Dis. 2009;68:373–6.
Krieckaert CL, Nurmohamed MT, Wolbink G, et al. Changes in bone mineral density during long-term treatment with adalimumab in patients with rheumatoid arthritis: a cohort study. Rheumatology (Oxford). 2013;52:547–53.
Roussy JP, Bessette L, Bernatsky S, et al. Biologic disease-modifying anti-rheumatic drugs and the risk of nonvertebral osteoporotic fractures in patients with rheumatoid arthritis aged 50 years and over. Osteoporos Int. 2013;24:2483–92.
Coulson KA, Reed G, Gilliam BE, et al. 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;15:155–60.
Kim SY, Schneeweiss S, Liu J, et al. Effects of disease-modifying antirheumatic drugs on nonvertebral fracture risk in rheumatoid arthritis: a population-based cohort study. J Bone Miner Res. 2012;27:789–96.
Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet. 2014;384:1878–88.
Bultink IEM, Harvey NC, Lalmohamed A, et al. Elevated risk of clinical fractures and associated risk factors in patients with systemic lupus erythematosus versus matched controls: a population-based study in the United Kingdom. Osteoporos Int. 2014;25:1275–83.
Cramarossa C, Urowitz MB, Su J, et al. Prevalence and associated factors of low bone mass in adults with systemic lupus erythematosus. Lupus. 2016;26(4):365–72. pii: 0961203316664597. [Epub ahead of print].
Edens C, Robinson AB. Systemic lupus erythematosus, bone health, and osteoporosis. Curr Opin Endocrinol Diabetes Obes. 2015;22:422–31.
Schmajuk G, Yelin E, Chakravarty E, et al. Osteoporosis screening, prevention and treatment in systemic lupus erythematosus: application of systemic lupus erythematosus quality indicators. Arthritis Care Res (Hoboken). 2010;62:993–1001.
Wang X, Yan S, Liu C, et al. Fracture risk and bone mineral density levels in patients with systemic lupus erythematosus: a systemic review and meta-analysis. Osteoporos Int. 2016;27:1413–23.
Bultink IEM, Lems WF. Systemic lupus erythematosus and fractures. RMD Open. 2016;1(Suppl 1):e000069. [Epub ahead of print].
Li EK, Tam LS, Griffith JF, et al. High prevalence of asymptomatic vertebral fractures in Chinese women with systemic lupus erythematosus. J Rheumatol. 2009;36:1646–52.
Carli L, Tani C, Spera V, et al. Risk factors for osteoporosis and fragility fractures in patients with systemic lupus erythematosus. Lupus Sci Med. 2016;3(1):e000098. [Epub ahead of print].
García-Carrasco M, Mendoza-Pint C, Riebeling C, et al. Influence of prevalent vertebral fractures on the quality of life patients with systemic lupus erythematosus. Isr Med Assoc J. 2011;13:333–7.
Meacock R, Dale N, Harrison MJ. The humanistic and economic burden of systemic lupus erythematosus: a systematic review. PharmacoEconomics. 2013;31:49–61.
Di Munno O, Mazzantini M, Delle Sedie A, et al. Risk factors for osteoporosis in female patients with systemic lupus erythematosus. Lupus. 2004;13:724–30.
Sun YN, Feng XY, He L, et al. Prevalence and possible risk factors of low bone mineral density in untreated female patients with systemic lupus erythematosus. Biomed Res Int. 2015;2015:510514. [Epub ahead of print].
Bultink IEM, Vis M, van der Horst-Bruinsma IE, et al. Inflammatory rheumatic disorders and bone. Curr Rheumatol Rep. 2012;14:224–30.
Bonfá AC, Seguro LPC, Caparbo V, et al. RANKL and OPG gene polymorphisms: associations with vertebral fractures and bone mineral density in premenopausal systemic lupus erythematosus. Osteoporos Int. 2015;26:1563–71.
Fisher A, Srikusalanukul W, Davis M, et al. Cardiovascular diseases in older patients with osteoporotic hip fracture: prevalence, disturbances in mineral and bone metabolism, and bidirectional links. Clin Interv Aging. 2013;8:239–56.
Farhat GN, Newman AB, Sutton-Tyrrell K. The association of bone mineral density measures with incident cardiovascular disease in older adults. Osteoporos Int. 2007;18:999–1008.
Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review. Semin Arthritis Rheum. 2013;43:77–95.
Magder LS, Petri M. Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus. Am J Epidemiol. 2012;176:708–19.
Ajeganova S, Gustafsson T, Jogestrand T, et al. Bone mineral density and carotid atherosclerosis in systemic lupus erythematosus: a controlled cross-sectional study. Arthritis Res Ther. 2015;17:84–96.
Bultink IEM, Lems WF, Kostense PJ, et al. Prevalence of and risk factors for low bone mineral density and vertebral fractures in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;54:2044–50.
Bhattoa HP, Kiss E, Bettembuk P, et al. Bone mineral density, biochemical markers of bone turnover, and hormonal status in men with systemic lupus erythematosus. Rheumatol Int. 2001;21:97–102.
Zhu TY, Griffith JF, Au SK. Bone mineral density change in systemic lupus erythematosus: a 5-year followup study. J Rheumatol. 2014;41:1990–7.
Petri M. Musculoskeletal complications of systemic lupus erythematosus in the Hopkins lupus cohort: an update. Arthritis Care Res. 1995;8:137–45.
Mendoza-Pinto C, García-Carrasco M, Sandoval-Cruz H, et al. Risk factors of vertebral fractures in women with systemic lupus erythematosus. Clin Rheumatol. 2009;28:579–85.
Almehed K, Forsblad d’Elia H, Kvist G, et al. Prevalence and risk factors of osteoporosis in female SLE patients-extended report. Rheumatology (Oxford). 2007;46:1185–90.
Mok CC. Vitamin D and systemic lupus erythematosus: an update. Expert Rev Clin Immunol. 2013;9:453–63.
Reynolds JA, Bruce IN. Vitamin D treatment for connective tissue diseases: hope beyond the hype? Rheumatology (Oxford). 2016;56(2):178–86. pii: kew212. [Epub ahead of print].
Salman-Monte TC, Torrente-Segarra V, Almirall M, et al. Prevalence and predictors of vitamin D insufficiency in supplemented and non-supplemented women with systemic lupus erythematosus in the Mediterranean region. Rheumatol Int. 2016;36:975–85.
Yeap SS, Othman AZ, Zain AA, et al. Vitamin D levels: its relationship to bone mineral density response and disease activity in premenopausal Malaysian systemic lupus erythematosus patients on corticosteroids. Int J Rheum Dis. 2012;15:17–24.
Guo Q, Fan P, Luo J, et al. Assessment of bone mineral density and bone metabolism in young male adults recently diagnosed with systemic lupus erythematosus in China. Lupus. 2016;26(3):289–93. pii: 0961203316664596. [Epub ahead of print].
Jacobs J, Korswagen LA, Schilder AM, et al. Six-years follow-up study of bone mineral density in patients with systemic lupus erythematosus. Osteoporos Int. 2013;24:1827–33.
Cutolo M. Further emergent evidence for the vitamin D endocrine system involvement in autoimmune rheumatic disease risk and prognosis. Ann Rheum Dis. 2013;72:473–5.
Prietl B, Treiber G, Pieber TR, et al. Vitamin D and immune function. Forum Nutr. 2013;5:2502–21.
Watad A, Neumann SG, Soriano A, et al. Vitamin D and systemic lupus erythematosus: myth or reality? Isr Med Assoc J. 2016;18:177–82.
Ritterhouse LL, Crow SR, Niewold TB, et al. Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus. Ann Rheum Dis. 2011;70:1569–74.
Durcan L, Petri M. Immunomodulators in SLE: clinical evidence and immunologic actions. J Autoimmun. 2016;74(16):30088–9. https://doi.org/10.1016/j.jaut.2016.06.010. [Epub ahead of print].
Mok CC, Mak A, Ma KM. Bone mineral density in postmenopausal Chinese patients with systemic lupus erythematosus. Lupus. 2015;14:106–12.
Lakshminarayanan S, Walsh S, Mohanraj M, et al. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus. J Rheumatol. 2001;28:102–8.
Mok CC, Ying SK, To CH, et al. Bone mineral density and body composition in men with systemic lupus erythematosus: a case control study. Bone. 2008;43:327–31.
Mazzantini M, Di Munno O. Glucocorticoid-induced osteoporosis: 2013 update. Reumatismo. 2014;66:144–52.
Zhu TY, Griffith JF, Qin L, et al. Cortical thinning and progressive cortical porosity in female patients with systemic lupus erythematosus on long-term glucocorticoids: a 2-year case-control study. Osteoporos Int. 2015;26:1759–71.
Mak A, Lim JQ, Liu Y, et al. Significantly higher estimated 10-year probability of fracture in lupus patients with bone mineral density comparable to that of healthy individuals. Rheumatol Int. 2013;33:299–307.
Lee JJ, Aghdassi E, Cheung AM, et al. Ten-year absolute fracture risk and hip bone strength in Canadian women with systemic lupus erythematosus. J Rheumatol. 2012;39:1378–84.
FRAX® tool. http://www.shef.ac.uk/FRAX. Assessed 9 Sept 2011
Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010;62:1515–26.
Rizzoli R, Adachi JD, Cooper C, et al. Management of glucocorticoid-induced osteoporosis. Calcif Tissue Int. 2012;91:225–43.
Francis RM, Aspray TJ, Boering CE, et al. National Osteoporosis Society practical clinical guideline on vitamin D and bone health. Maturitas. 2015;80:119–21.
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.
Saag KG, Zanchetta JR, Devogelaer JP, et al. Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum. 2009;60:3346–55.
Baron R, Ferrari S, Graham R, et al. Denosumab and bisphosphonates: different mechanisms of actions and effects. Bone. 2011;48:677–92.
Mok CC, Ho LY, Ma KM. Switching of oral bisphosphonates to denosumab in chronic glucocorticoid users: a 12-month randomized controlled trial. Bone. 2015;75:222–8.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this chapter
Cite this chapter
Di Munno, O., Malavolta, N., Minisola, G. (2018). Rheumatic Diseases and Osteoporosis. In: Lenzi, A., Migliaccio, S. (eds) Multidisciplinary Approach to Osteoporosis. Springer, Cham. https://doi.org/10.1007/978-3-319-75110-8_14
Download citation
DOI: https://doi.org/10.1007/978-3-319-75110-8_14
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-75108-5
Online ISBN: 978-3-319-75110-8
eBook Packages: MedicineMedicine (R0)