Introduction
Sarcoidosis is a T-cell driven chronic inflammatory disease. Although chronic inflammation has been associated with decreased bone mineral density as a result of the effects of cytokines on bone metabolism [
1‐
4], we and others could not demonstrate changes in BMD in subjects with this condition, even if treated with glucocorticoids (GCs). In a cross-sectional study of 124 subjects with sarcoidosis, BMD values similar to an age- and sex-matched reference population were found [
5]. Comparable observations were made in three small studies in untreated patients [
6‐
8]. These studies also found a normal BMD relative to age and sex-matched controls, except for a small group of postmenopausal women in which BMD was moderately decreased at the spine in longstanding sarcoidosis only [
7].
Although in our cross-sectional study normal BMD values were observed, increased levels of the bone resorption marker serum carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) and the bone formation marker serum procollagen type I amino-terminal propeptide (PINP) suggestive of increased bone turnover were found [
5]. ICTP levels correlated with markers of disease activity such as soluble IL-2 receptor (sIL2R) and angiotensin converting enzyme (ACE). In addition, vertebral deformities suggestive of fracture were demonstrated in 20% of the subjects studied in this series. This may imply that the fracture risk in sarcoidosis is increased due to an increased bone turnover with consequent changes in microarchitecture and decrease of bone strength which is not reflected by changes in BMD [
9,
10].
If so, this may result in progressive vertebral deformities during the course of the disease. For this reason we re-examined individuals with sarcoidosis four years after the initial measurements to determine the incidence of new and/or progressive vertebral deformities and their relation with changes in BMD.
Discussion
In this cohort of subjects with sarcoidosis, a high prevalence of morphometric vertebral deformities suggestive of fracture was found, as well as a substantial increase in vertebral deformities during a follow-up period of four years. In 2002 20% of subjects were diagnosed with vertebral deformities according to the criteria of Genant [
17], which increased to 32% of all subjects in 2006. In parallel, the total number of deformities in these subjects almost doubled. However, BMD of the trochanter and femoral neck did not change over time and BMD of the lumbar spine at follow-up measurement did not differ from the reference population. These data are suggestive of an increased risk of progressive vertebral deformities in individuals with sarcoidosis despite preservation of BMD.
Although data on prevalent or incident fractures in younger healthy populations are lacking, data from other studies suggest that the incidence and prevalence of vertebral deformities in this population are indeed high. Prevalence rates of 30% asymptomatic vertebral fractures are demonstrated in elderly post-menopausal women on chronic GC therapy using the same techniques [
20]. In a previous study in 60 subjects (mean age 49 ± 13 years) with differentiated thyroid carcinoma we found vertebral deformities in 7% of patients [
21]. Data from the European Vertebral Osteoporosis Study (EVOS), a very large cross-sectional population based study on European subjects aged 50 to 79 years, showed a prevalence of vertebral deformities of 12% (range 6–21%) in males and females [
22]. In the Rotterdam study, in which 3469 men and women aged 55 years and older were studied, the prevalence of vertebral deformity suggestive of fracture was 6.9% in men and 7.5% in women [
23]. The epidemiology of vertebral fractures in women aged 50–54 years turned out to vary in different countries from 4.7% – 11.5% [
24]. All these studies indicate that the fracture risk in subjects with sarcoidosis is substantial, regardless the differences in populations studied and differences in methodology.
A new vertebral deformity was found in 15 subjects (23%). To identify incident deformities several approaches can be followed. Measurement of changes in vertebral heights of the same vertebral body from a baseline to a later radiograph in which a decrease in height of 15 or 20% or 4 mm is suggestive of fracture [
25,
26], changes in indices of vertebral area [
27] or changes in the number or presence of prevalent deformities [
17,
28]. Black and coworkers evaluated these different approaches and concluded that none of these were consistently better than any other method [
29]. As we aimed to assess the change of numbers of subjects with one or more vertebral deformities over time we used the last method [
17], in which changes in number of prevalent deformities are scored. A comparable approach was followed in the European Prospective Osteoporosis Study (EPOS) [
30], which revealed an incidence of new deformities of 3.4% after a similar follow-up period. As the mean age of subjects included in this study was substantially higher than that of our cohort, these data cannot be used as a reference, although it is likely that in younger age groups even lower incident deformities would be observed. The high prevalence of vertebral deformities at baseline, the significant increase of more than 50% of subjects after follow-up with one or more deformity and the increase of severity of prevalent deformities all imply that sarcoidosis is a relevant risk factor for vertebral deformity.
What is the underlying mechanism of this predisposition to vertebral deformities in view of the lack of effects on BMD in sarcoidosis? The load bearing capacity of bone, also referred to as ‘whole bone strength’, depends on the amount of bone, the spatial distribution of the bone mass, and the intrinsic properties of the materials that comprise the bone. Thus, properties at the cellular, matrix, micro- and macro-architectural levels may all impact the mechanical properties of bone [
31,
32]. Apparently, in sarcoidosis mechanisms are involved that influence bone strength without having a significant impact on bone mass. As we found in the total group an increased marker of bone resorption (Z-score ICTP) at baseline, one of the possible mechanisms could be increased bone remodelling with a negative effect on bone micro-architecture that is not reflected by a change in BMD. It is well known that chronic inflammatory diseases influence bone physiology by the production of cytokines stimulating bone turnover [
1,
2,
33]. Increased bone remodelling is associated with an increased bone fragility and thus fracture risk [
34,
35] and in postmenopausal women the level of bone turnover turned out to be an as strong and independent predictor of fractures as BMD [
36,
37]. These data may support the hypothesis that the chronic inflammatory state in sarcoidosis results in increased bone remodelling with a negative effect on bone strength and thus an increased fracture risk.
No changes in BMD in the group currently treated with GCs were found. This is unexpected as GCs are known to effect BMD via several mechanisms with consequent decrease of BMD. It may well be that this is due to intermittent GC use, as most of our patients were on intermittent glucocorticoids. Other studies have demonstrated that intermittent GC use has no major effects on BMD [
38]. A recent large retrospective cohort study on clinical fracture risk among patients from the UK General Practice Research Database showed that intermittent use of high dose of oral GCs was associated with only a small increase in the risk of osteoporotic fractures [
39].
Despite the on average normal BMD, we found T-score of the femoral neck and a family history of hip fractures to be predictors of a new and/or progressive vertebral deformity. This suggests that the combination of a lower BMD in combination with the increased bone turnover in sarcoidosis predisposes to progressive vertebral deformity. If so, this would mean that in these high risk individuals preventive treatment should be considered to reduce fracture risk. Controlled trials are needed, however, to substantiate this suggestion.
One of the limitations of our study is the lack of an age and sex matched control population. Unfortunately data on vertebral deformities in younger populations are at present not available. The aim of this study was, however, not to compare sarcoidosis patients with healthy subjects, but to follow a cohort of these patients and to compare follow-up with baseline measurements. Another limitation is the use of morphometric X-ray absorptiometry (MXA) instead of spine radiographs. MXA is less reliable for the detection of deformities at the upper thoracic spine, where deformities are less frequent as compared to the lumbar and mid-thoracic spine. A recent study comparing MXA with lateral spine X-ray found that vertebral morphometry using MXA allowed diagnosis of vertebral fracture in the lumbar and mid thoracic spine, where vertebral fractures are most common [
40]. The advantage of MXA is the low dose of radiation and the convenience of the technique for patients. The present quality of the images, with ongoing refinement of this technology, is considered sufficient to be used for the diagnosis of vertebral deformity consistent with fracture [
41]. Furthermore there is a lack of a “gold standard” for VFA. We followed the method of Genant [
17], which is based on a reduction of the ratios of anterior, middle or posterior heights and all measurements were performed twice to improve accuracy. This is the simplest and most practical method [
42] and an association with future fracture risk is documented [
43,
44]. The above mentioned EVOS study, however, applied the methodology described by McCloskey and Eastell and co-workers in which measurements are corrected for normal variations in vertebral shape [
25]. Relative to the method of Genant, the method of Eastell [
25] or McCloskey [
28] may have resulted in lower prevalences of vertebral deformities. This does not, however, explain the differences in prevalence of vertebral deformities reported elsewhere and in this paper. The restrictions of the methodology are also the limited ability to provide a differential diagnosis for the detected deformities, a lower sensitivity for milder fractures and the inability to evaluate the uppermost thoracic levels. Other disorders that may cause changes in vertebral shape involve congenital abnormalities and conditions as severe osteoarthritis [
45] and Scheuermann’s disease. We have, however, no indications that these relatively rare conditions may have interfered with our observations.
In conclusion, we have shown that in subjects with sarcoidosis the number of vertebral deformities, diagnosed with morphometric assessment, increases during the course of this disease despite preservation of BMD. Although this is an uncontrolled study, it appears that subjects with sarcoidosis have an increased fracture risk, even if BMD is normal. High risk individuals can be identified by a low-normal BMD and by a family history of hip fractures. Probably these individuals will benefit from therapies that increase bone strength. A T-score FN below −0.45 may be used to identify these individuals with a high sensitivity and an acceptable specificity. Studies evaluating the effects of such therapies in individuals with sarcoidosis are however clearly needed.