Osteoporosis in Rheumatologic Conditions and Inflammatory Disorders


Drug

Recommendations

Notes/references

Zoledronic acid

A single 5 mg IV infusion

One major clinical trial demonstrated that ZA was superior to risedronate in increasing lumbar spine BMD over a prospective time of one year [27]

PTH teriparatide

20 mcg injection subq/day into thigh or abdominal wall

Demonstrated benefits of PTH in patients with GIO; indicated PTH was superior to alendronate in terms of changes in BMD and prevention of morphometric vertebral fractures [28, 29]

Calcium

1,000–1,500 mg/day

Caution in patients with renal disease or history of kidney stones [30]

Vitamin D (in setting of glucocorticoids)

1,000–1,500 IU/day

Give amount necessary to maintain serum vitamin D25OH at 30 ng/ml or higher [30]

Anti-TNF

 Infliximab

3 mg/kg IV infusion at baseline, two weeks, six weeks, then every eight weeks

Increases BMD [20]; improves bone metabolism and BMD in patients with RA and AS [19]

 Adalimumab

40 mg subq per 14 days

Maintains but does not increase BMD in lumbar spine and femoral neck [21]



To date, no studies on PTH (also called teriparatide, brand name Forteo) have been conducted with a specific focus on osteoporosis treatment for RA patients. In two reports [28, 29], Saag et al. illustrated the benefit of PTH in patients with GIO by demonstrating that it was superior to alendronate in terms of changes in BMD and in prevention of morphometric vertebral fractures. In a recent commentary by Gennari and Bilezekian [31] the idea that teriparatide may be a superior treatment for RA-associated osteoporosis has emerged, based on its direct action on osteoblasts and osteocytes (Fig. 1) [31].

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Fig. 1
Effects of glucocorticoids, bisphosphonates, and teriparatide on bone cells. Dashed lines indicate potential effects of bisphosphonates (Source: Gennari and Bilezekian [31]. Reprinted with permission)



Nonpharmacologic Intervention


Due to increased inflammation, restricted movement, and tight, painful joints, patients with RA have 30–75 % the muscle strength of able-bodied, similarly aged adults and one-half the endurance of age-matched adults. Reduced muscle strength in combination with the above factors leads to an overall lower level of physical activity and fitness [32]. Lack of fitness and an increased sedentary lifestyle contribute to the 50–60 % increased incidence of cardiovascular-related mortality observed in individuals with RA [33]. Exercise can help reduce these rates if a physical training program is appropriately tailored to increase muscle strength in a way that will prevent further joint trauma and educate patients about safe forms of exercise in cardiovascular disease. A 2009 Cochrane review examined eight clinical trials [34] related to exercise in patients with RA and concluded that both overall fitness and more specific strength training are required to improve functional outcome. Moreover, if dynamic activity is carried out properly, no increased disease activity or pain should ensue.

The preceding recommendations are largely based on the less involved patients with RA. The American College of Rheumatology has published guidelines on the four levels of functional capacity of patients with RA as given in Table 2 and the majority of studies to date have focused on patients at the less severe Class I or II level of the disease [35].


Table 2
Criteria for functional status classification in rheumatoid arthritis


















Class I

Full functional ability to perform activities of daily living, including self-care, vocational, and avocational

Class II

Limited functional ability to perform avocational activities. Relatively normal ability to perform typical vocational and self-care activities

Class III

Limited functional ability to perform both vocational and avocational activities. Relatively normal ability to perform typical self-care activities

Class IV

Limited functional ability to perform vocational, avocational, and typical self-care activities


Source: Hochberg et al. [35]

In a study conducted by de Jong et al., subjects who underwent a 75 min, twice weekly exercise session involving bike training, circuit training, volleyball, basketball, or other ball sports, experienced increased physical well-being and functional status [36]. The majority of subjects saw no radiologic progression of joint appearance, but a subset of those with baseline severe radiologic damage did see a progression of disease. In general, aerobic and resistance exercise conditioning has been shown to improve functional capacity, muscle strength [32, 37], and cardiovascular conditioning, particularly in terms of blood pressure and lipid profiles [38]. However, caution is required in subjects with Class III or IV RA since patients with more severe disease at baseline remain at high risk of disease exacerbation and increased joint damage [36].




Systemic Lupus Erythematosus (SLE)



Etiology and Pathogenesis


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, 4750] summarizes risks of low BMD in lumbar spine and separately in the hip, based on the results of individual investigations.


Table 3
Summary of studies of BMD in SLE patients


























































Source

Design

No. of patients

BMD lumbar region

BMD hip

Bultink et al. (2005) [48]

Transversal

107

39 % osteopenia and 4 % osteoporosis in any location

74 % osteopenia, 3 % osteoporosis

Mok et al. (2005) [42]

Cross-sectional

34

33 % osteopenia, 42 % osteoporosis

74 % osteopenia, 3 % osteoporosis

Becker et al. (2001) [45]

Cross-sectional

67

11 % osteopenia, 6 % osteoporosis

13 % osteopenia, 3 % osteoporosis

Lakshminarayanan et al. 2001 [47]

Cross-sectional

92

32 % osteopenia, 15 % osteoporosis

35 % osteopenia, 12 % osteoporosis

Sinigaglia et al. (2000) [3]

Cross-sectional

84

23 % osteoporosis in any location
 

Pons et al. (1995) [49]

Cross-sectional and longitudinal

43

18 % osteoporosis in patients with corticosteroids
 

Formiga et al. (1995) [55]

Cross-sectional

74

12.1 % osteoporosis in any location
 


Fractures in SLE Patients


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].


Table 4
Risk factors for fractures in SLE




















































Risk factor

Frequency or relative risk based on chosen study outcome

Notes

Age at diagnosis

RR not calculated

Older age is more likely to cause fracture

Cumulative glucocorticoid exposure

RR 1.17–1.3

Prolonged use is worse

Use of oral contraceptives

RR not calculated

Lower use associated with higher fracture risk

Timing of menopause

RR not calculated

Early menopause more likely to be associated with fracture

Dementia

RR 1.67
 

Seizures

RR 2.01
 

History of one or more cerebrovascular events

RR 1.49
 

Prior osteoporotic low velocity fracture

RR 4.26
 

Use of oral diabetic agents

RR 1.39
 

Concurrent malignancy

RR 1.23
 


Sources: Adapted from Ramsey-Goldman et al. [51], Bultink et al. [55]

RR Relative Risk

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).


Treatment



Initial Measures


Prior to considering pharmacologic treatment, the traditional first steps are optimizing overall nutrition, limiting alcohol, and eliminating smoking, if applicable. Beyond these measures, optimizing calcium and vitamin D stores is advised [57]. Calcitriol has been found to reduce bone loss in subjects with SLE who were on corticosteroids. Lambrinoudaki and colleagues found improvement of BMD at the lumbar spine in premenopausal women with SLE who took 0.5 mcg calcitriol daily for two years, compared with controls [58]. Conversely in a study of hypogonadal amenorrheic women, hormone replacement therapy but not calcitriol led to improvements in BMD of the lumbar spine. No increase in BMD in either the hip or radius was noted.


Estrogens and Androgens


No specific studies on selective estrogen receptor modulators exist, but recent interest has emerged in exploring the use of dehydroepiandrosterone (DHEA) for treatment of disease activity and osteoporosis due to SLE [57]. Along with its metabolite dehydroepiandrosterone sulfate (DHEAS), DHEA is the most abundant circulating adrenal steroid in humans [59]. Normal human levels of DHEA are 1–50 nM, but levels of DHEA, DHEAS, and androgens decline in states of chronic inflammation including RA and SLE and are reduced even further by steroids [60]. In a number of clinical trials described in the review by Sawalha and Kovats [59], the average daily use of corticosteroids was significantly reduced in the months following initiation of a daily dose of DHEA, but studies differed on the effectiveness of trial doses of DHEA in improving the Systemic Lupus Erythematosus Activity Index.

In terms of whether DHEA and DHEAS exert direct effects on bone, studies demonstrate conflicting results. In a small study of 19 SLE patients [61], the nine subjects who received DHEA showed no change in BMD at six months, whereas the ten placebo subjects experienced significant reduction in BMD. The subjects in this study all had advanced forms of active, systemic lupus affecting multiple organ systems. A second study of 37 subjects by Formiga et al. [62] found a positive correlation between DHEAS levels and BMD in the lumbar spine and femoral neck. The same study demonstrated a negative correlation in DHEAS and serum PTH, which may explain the potential role that DHEA may play in protecting bone. However, other studies have shown less of a benefit from DHEA, particularly one investigation looking at subjects with quiescent SLE [63]. Researchers are now attempting to determine (1) which groups of SLE patients may benefit from DHEA and (2) at what stage of the disease, in terms of duration and severity, are DHEA and its metabolite DHEAS most likely to make a significant difference in function and bone health [59].


Bisphosphonates


Although a number of investigations have examined the benefits of bisphosphonates on BMD in subjects receiving corticosteroids for rheumatoid conditions, no single study focuses solely on those with SLE. However, patients with SLE represent 5–15 % of subjects in several investigations. The majority of these analyses did not separate groups of patients but instead, often combined men, premenopausal, and postmenopausal women, and in doing so, complicated the ability to draw conclusions. Overall, positive effects on BMD were seen in most subsets of patients [22, 27, 64]. However, no conclusions could be drawn regarding the effectiveness of bisphosphonates for fracture prevention due to the absence of fractures in both the control and treatment groups, reported in the prevention studies on GIO. To date, no dedicated studies on the value of PTH, growth hormone, or insulin-like growth factor have been undertaken in SLE patients or in patients with GIO that include a notable percentage of participants with SLE. However, interest in exploring the potential for agents that work on the osteoblast continues to grow.


Ankylosing Spondylitis


Ankylosing spondylitis (AS) is an inflammatory, arthritic condition involving the axial skeleton and traditionally affecting males, often starting before age 40 [65]. Inflammation is both erosive leading to osteopenia and proliferative, with abnormal bony overgrowth and bridging syndesmophytes that fuse the vertebrae to create the appearance of a “bamboo spine.” [65]. The result is rigid kyphotic posture as well as mid back and shoulder pain, limiting spinal flexibility and functional mobility. The structural changes may also affect the ribs and can compromise breathing mechanics. Patients may be subject to atelectasis and pneumonia, and, in severe cases, the architectural changes actually predispose the spine to spinal cord injury [66]. Perhaps even more frustrating for patients is that AS is often diagnosed late, in its advanced stages. The most effective treatment agents, TNF-α blockers, have limited impact if given late but are fairly successful if administered early in the disease process [65]. Although AS only affects 0.5 % of the US population, it results in work disability, eventual withdrawal from the workforce, substantial health costs, and a reduced quality of life [67].

The causes of AS are a mix of genetic and environmental factors, influenced by both autoimmune and autoinflammatory factors. Genetic evidence points to specific immune pathways, namely, interleukins 17 and 23 upregulation, activation of nuclear factor kappa B, and genes controlling CD8 and CD4 T-cell subsets. Autoreactive T cells and autoantibodies denote an autoimmune process, while autoinflammatory processes are characterized by mutations in single immunomodulatory genes and accelerated cytokine production [65]. In terms of environmental factors that contribute to the disease or accelerate an already established case, certain microbes can trigger a disease flare. Internal and external mechanical stress can promote inflammation throughout the body, particularly in the axial spine and fibrocartilaginous enthuses and enhance production of interleukin IL-23R+ T cells. In addition animal studies suggest that weight-bearing and biomechanical stress contribute to the inflammatory component of AS [68].


Diagnosis of Osteoporosis in AS


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.

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Fig. 2
CT scan of cervical spine demonstrating ankylosing spondylitis. In a 75-year-old male with longstanding disease. Image demonstrates an age-indeterminate fracture of C5 anterior osteophyte with upper thoracic ankylotic changes (Source: Thomas Jefferson University Department of Radiology, Philadelphia, PA. Used with permission)


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Fig. 3
CT of thoracolumbar spine in a patient with ankylosing spondylitis. Image illustrates the middle and lower thoracic as well as the lumbosacral spine demonstrating ankylosing spondylitis throughout multiple areas, along with superimposed multi-level degenerative changes (Source: Thomas Jefferson University Department of Radiology, Philadelphia, PA. Used with permission)


Etiology and Pathophysiology of Osteoporosis in AS


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, 7678].


Table 5
Factors associated with osteoporosis in patients with AS

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Aug 17, 2017 | Posted by in PHYSICAL MEDICINE & REHABILITATION | Comments Off on Osteoporosis in Rheumatologic Conditions and Inflammatory Disorders
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