Systemic lupus erythematosus (SLE) is a chronic autoimmune condition involving inflammation in multiple body parts including the skin, joints, heart, lung, blood, kidney, and brain. The increased antibody production that precipitates the chronic inflammation leads to pain as well as adverse effects on the joints, with both problems contributing to generalized immobility of patients with SLE. Survival and morbidity rates have improved drastically over recent years, and evidence is emerging that long-term health conditions, including osteoporosis, are receiving appropriate attention in management of persons with lupus. The etiology of bone loss in SLE represents the combined effects of traditional risk factors of osteoporosis (advanced age, postmenopausal status in women, low body weight, dietary deficiencies) as well as those inherent in rheumatoid conditions, including inflammation, metabolic factors, hormonal factors, serologic titers, and adverse effects of medication [39].

Chronic systemic inflammation leads to increased levels of tumor necrosis factor (TNF). It also increases oxidized low-density lipoproteins (oLDLs), which, in turn, induce elevated production of receptor activator of nuclear factor-kB ligand (RANKL) and further increase levels of TNF. Because both RANKL and TNF activate osteoclasts, increased bone resorption occurs. At the same time, oLDLs decrease bone formation by reducing osteoblast maturation. The combined effects result in lower BMD [39]. Additional evidence of decreased osteoblast activity stems from observations of decreased osteocalcin titers, indicating low bone formation, as supported by a study of premenopausal women with untreated SLE [40].

Hormonal factors have been shown to predispose SLE patients to bone loss as is the case in other populations. Specifically SLE patients experience more frequent episodes of months of amenorrhea, earlier (premature) menopause, and hyperprolactinemia. Males may experience low plasma androgen levels. Decreased vitamin D levels are another contributor to low BMD. Patients with SLE are consistently counseled to avoid sunlight, and others may be prescribed drugs such as hydroxychloroquine that directly blocks conversion of inactive to active forms of vitamin D [39, 41]. In addition, foods rich in vitamin D may add to GI distress given the prevalence of GI inflammation in SLE.

Serologically, the presence of anti-Ro antibodies is associated with a lower femoral BMD. This finding may be due to serologic adverse effects or it may be an indirect consequence of avoidance of sunlight. According to Mok et al. [42], anti-Ro antibodies are more commonly present in Chinese relative to Caucasian patients, perhaps because Chinese practice guidelines advise against sun exposure in SLE patients with anti-Ro antibodies. Ordinarily, a substantial percentage of vitamin D is absorbed from sunlight in certain seasons. Thus lack of exposure to sun may contribute to vitamin D deficiency as one factor in osteoporosis development. The presence of anti-Smith antibodies (a highly specific marker of SLE) and the absence of anti-Ro antibodies were found to correlate with improved femoral neck BMD [42].

In terms of medications that contribute to osteoporosis in SLE, Jardinet et al. reported a loss of lumbar spine bone in premenopausal SLE patients given corticosteroid therapy over a prolonged period of time [43, 44] but exactly how long is uncertain. Studies are divided as to whether corticosteroids confer an overall positive effect on BMD by reducing inflammation and enabling patients to be more active while allowing inflammatory markers to remain at lower levels. In their review of 16 articles focusing on the effect of corticosteroid use on osteoporosis in SLE, Garcia-Carrasco et al. [41] reported that seven studies found no association, but nine others demonstrated an adverse effect of steroids. In general, prolonged use of higher doses of steroids appears to have a deleterious effect on BMD in either hip, lumbar spine, or both [41], whereas pulsed steroids given for short-term exacerbations or complications have a decreased long-term effect [41, 44].

In addition to corticosteroids, cyclophosphamide, typically used to address life-threatening organ involvement, is associated with premature menopause and osteoporosis. Cyclosporine reduces new bone formation by activating osteoclasts and suppressing osteoblasts. High-dose methotrexate, also associated with bone loss and fractures, is occasionally given to patients with advanced SLE [46]. In contrast to other agents used to treat SLE symptoms, use of hydroxychloroquine is noted to have a positive effect on BMD at the spine [42, 47] as well as the hip [47]. Table 3 [3, 42, 45, 47–50] summarizes risks of low BMD in lumbar spine and separately in the hip, based on the results of individual investigations.

The prevalence of fractures in SLE patients ranges from 6 % to 26 %, with symptomatic fractures occurring in only 6–12.5 % of these patients [51]. Despite this elevated occurrence, only a few high-quality studies on fracture prevalence, prevention, and treatment, as described below, have been conducted Ramsey-Goldman [51] and coauthors determined that fracture risk was related to duration of treatment with glucocorticoids, whereas Zonana-Nacach et al. [52] examined the cumulative exposure to corticosteroids in terms of overall dose, finding that for every 36.5 g of corticosteroid consumed, the risk of fracture nearly doubled.

Subsequently, Lee et al. [46], along with Ramsey-Goldman and colleagues [51], considered the frequency of fractures in a cohort study of 304 women with established SLE who were followed for six years. Overall 12.3 % experienced fractures and among those BMD Z-scores at the hip but not at the spine were significantly lower in the group of SLE patients with fractures compared to those without fractures. Borba et al. [53] investigated the presence of vertebral fractures in a cross-sectional study of 70 patients having established SLE and 22 controls. Although the mean age of subjects was only age 32, fracture deformity in image screening was found in 21 % of subjects with SLE but in none of the aged-matched healthy controls.

Focusing on risk factors for vertebral fractures, Mendoza-Pinto and colleagues [54] studied 210 subjects with a mean age 48 in which osteopenia was present in 50.3 % of subjects with vertebral body fracture and osteoporosis in 17.4 %. At least one vertebral fracture was detected in 26.1 %. Patients with vertebral fractures had a higher mean age (50 ± 14 vs. 41 ± 13.2 years, p = 0.001), higher disease damage (57.1 % vs. 34.4 %, p = 0.001), lower BMD at the total hip (0.902 ± 0.160 vs. 982 ± 0.137 g/cm², p = 0.002), and postmenopausal status (61.9 % vs. 45.3 %, p = 0.048). Stepwise logistic regression analysis revealed that only age (p = 0.001) and low BMD at the total hip (p = 0.007) remained as significant factors for the presence of vertebral fracture [54]. A summary of risk factors for fractures is given in Table 4 [51, 55].

Evidence suggests that fractures in SLE are not necessarily a function of low BMD. A study of Dutch patients found that 20 % of subjects had vertebral fracture, defined as greater than 20 % reduction of vertebral body height—a criterion developed by Genant et al. [56]. Using this measure, the threshold for identifying a fracture by radiographs is lower than that in other studies, potentially accounting for the higher fracture occurrence. Nevertheless, it should be noted that of the 107 participants, 73 % of those with fractures by the Genant et al. semiquantitative identification tool had height reductions of 20–25 % in at least one vertebra, 23 % of subjects had 25–40 % vertebral body height reduction, and 4 % had vertebral body height reduction greater than 40 %. Yet among the entire sample, only 4 % of subjects had a DXA scan with T-scores below 2.5, the threshold for meeting the definition of osteoporosis. In this investigation, males had a higher fracture rate than did females. Moreover, findings reported that 11 % of subjects had a prior nonvertebral fracture. This study also identified a number of conditions commonly seen among rehabilitation patients that further increase risk of fractures (Table 4).

Although osteoporosis is common in AS, it is often diagnosed late due to visual confounding by syndesmophytes and ankyloses. Consequently, BMD measurements may be artificially high and the extent of osteopenia or osteoporosis may not be appreciated [69].

Because spinal hyperostosis in AS is often positioned around the zygapophyseal joints, the vertebral endplates of disks, and the annulus fibrosus, with relative sparing of the lateral sides, lateral DXA scans may be more useful than anteroposterior (AP) views in terms of evaluating possible osteoporosis. Moreover lateral scanning permits exclusive examination of the vertebral body, comprised of 80 % trabecular bone [70]. In Klingberg et al.’s [70] study of 87 AS women and 117 men using both lateral and AP lumbar BMDs, the lateral view revealed significantly more cases of osteoporosis in men with AS than did the AP view. At the same time, the AP view revealed high rates of osteoporosis in women, whereas the lateral view did not, indicating that certain modalities of imaging are better suited to males versus females in making an early diagnosis. In a number of senses, both the lateral and AP view may be needed since the combination will allow a three-dimensional volumetric BMD which is a superior measure to a two-dimensional area BMD.

Emohare and coauthors [71] went a step further and tested computerized tomography (CT) attenuation models in lieu of DXA as a tool to assess osteoporosis and fractures in AS patients. In a group of 17 patients, they diagnosed 82–88 % of subjects with osteoporosis based on the threshold sensitivity of the machine selected. Pickhardt et al. [72] has proposed the novel concept that data from abdominal CT images, which included the L1 vertebra but were obtained for other purposes, can be used to identify patients with osteoporosis without additional radiation exposure or expense: If the L1 vertebra was not fractured, an estimate of lumbar bone density can be made without having the patient undergo another scan.

Challenges exist not only in the diagnosis of osteoporosis but, also, at times in the identification of fractures. A number of cases illustrate the challenges that syndesmophytes and the spinous overgrowth create. In the cervical spine, new fractures may be missed in the immediate hours after an injury such as a fall. Pain may be present, but radiographs may not reveal a fracture until 24 hour later, and then, often only by MRI or CT [73]. In the case described by Fatemi et al., a nondisplaced fracture was missed by plain imaging and CT; not until 20 hour later, when the fracture had become displaced and the patient had returned to the hospital with new neurologic symptoms, was an MRI performed. Harrop et al. [74] have also described a case of a missed surgical fracture but only a high-definition multidetector CT revealed the deformity; standard CT, plain radiographs, and MRI all failed to diagnose the fracture. The question of whether MRIs should be done after any injury to the neck or lower spine in AS patients is raised in the literature. While the cost of an MRI is not insignificant, it bears no comparison to the potential cost to patients and society of a spinal cord injury arising from an undiagnosed fracture. Figures 2 and 3 demonstrate cervical spine fracture as well as extensive ankylosing spondylitis in thoracic and lumbar portions of this patient’s spine. This question warrants further analysis in future investigations.

The study by Klingberg et al. [70] found that low BMD in AS patients was associated with female sex, older age, low body mass index, heredity for fractures, scores on the physical activity at home and work index [75], and the number of years since menopause. Additional factors relate to function and medications: disease duration, high Bath Ankylosing Spondylitis Metrology Index (BASMI), high modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), elevated inflammatory parameters (ESR, CRP), and low hemoglobin. Factors that influenced osteoporosis in AS, as well as others that were examined and not relevant to AS, are summarized in Table 5 [69, 70, 76–78].