Introduction 1 4 5 6 8 7 5 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. Subjects and methods Subjects 5 1 5 Table 1 Baseline and follow-up demographic, clinical, and treatment variables ( = 66) Variable Baseline (n=66) Follow-up (n=66) P Demographic variables Female sex 33 (50%)   Postmenopausal 11 (17%) 14 (21%) ns Age, years 43 (20–66)   Body mass index, kg/m2 26.9 ± 5.7 27.2 ± 5.3 ns Smoking 7 (11%)   Daily dietary calcium intake, mg 740 (110–2360) 758 (150–1340) ns Clinical variables Disease duration, years 3 (1–22) 7 (5–26)  Chest X-ray stage (0-I-II-III-IV) 24/11/12/16/3 27/5/12/15/7 ns FEV1,% of predicted 87 ± 28 91 ± 26 ns DLCO,% of predicted 87 ± 16 92 ± 18 ns Physical activity 8.6 ± 3.7 8.1 ± 3.7 ns Laboratory values (in serum) Calcium, mmol/l (2.1–2.6) 2.4 ± 0.1 2.4 ± 0.08 ns 1,25(OH)2D3, nmol/l (0.040–0.200) 0.14 ± 0.03   ACE, U/l (9–25) 22.5 ± 9.8 15.3 ± 7.9 0.001 sIL-2R, kU/l (241–846) 654 (188–4315)   Hs-CRP, mg/l (<10) 3.2 (0.2–191) 2.0 (1–16) <0.05 Z-score ICTP 0.7 ± 1.4   Z-score PINP −0.1 ± 0.9   Treatment variables GC use never 31 (47) 26 (39) ns GC use previous 14 (21) 25 (38) <0.01 GC use current 21 (32) 15 (23) ns Lifetime GC dose, mg 9240 (200–48750) 11187 (200–56700) <0.001 Daily dose, mg 12.4 ± 6.2 10.5 ± 3.3 <0.05 Started on bisphosphonates after baseline measurement  6 (9)  Clinical risk factors for osteoporosis Fracture 2 (2/24 = 8%) 5 (5/28 = 18%) ns Low body weight (< 60 kg) 8 (12) 7 (11) ns Severe immobilization 0 0 ns Low physical activity index ≤ 5 18 (27) 18 (27) ns Mother with hip fracture 6 (9) 7 (11) ns Data are given as mean ± SD, median (range) or number (%); *=  value between baseline and follow-up measurement. Reference parameters in brackets Abbreviations: GC, glucocorticoid; FEV1, forced expiratory volume in one second; DLCO, diffusion capacity for carbon monoxide; 1,25(OH)2D3, 1,25 dihydroxyvitamin D; ACE, angiotensin converting enzyme; sIL-2R, soluble interleukin-2 receptor; Hs-CRP, high-sensitivity C-reactive protein; ICTP, carboxy-terminal cross-linked telopeptide of type I collagen; PINP, procollagen type I amino-terminal propeptide Pulmonary evaluation 11 12 13 Laboratory assays Serum 1,25-dihydroxyvitamin D concentration was determined by radioimmuno-assay using a commercially available kit [(IDS Ltd, Boldon, England, interassay coefficient of variation (IE-CV) 18%, intra-assay CV (IA-CV) 15%)]. High-sensitivity C-reactive protein (hs-CRP) was measured by particle-enhanced immunonephelometry on the BN Prospec (Dade Behring). The detection limit is 0.175 mg/L and the measuring range is 0.175–1100 mg/L. Soluble IL-2 receptor (sIL-2R) was determined on the IMMULITE automated analyzer, by means of a two-site chemiluminescent enzyme immunometric assay with a measuring range of 50–7500 kU/L (Diagnostic Product Corporation, Los Angeles, CA, cat no LKIP1). Serum angiotensin converting enzyme (ACE) was measured using a colorimetric method. The precision of the ACE assay was < 5.6% and the reference interval for ACE was 9–25 U/L. 14 15 Bone mineral density and vertebral morphometry Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DXA, Hologic QDR 4500). In 2002 only the BMD of the hip was measured. In 2006 the BMD of both the hip and of the lumbar spine were determined. As reference group for the hip the NHANES III database (sex- and age-matched) was used. A standard protocol as described previously was used for measurement of BMD. To adjust for age and gender, Z-scores were used. To examine changes in Z-scores between baseline and follow-up measurements a Δ Z-score was calculated reflecting the difference between the Z-score at follow-up and the Z-score at baseline. 16 17 17 17 Questionnaires 18 Statistics 19 Results Bone mineral density and bone turnover parameters 2 Table 2 BMD variables at baseline and follow-up for the total group (n = 66, median follow-up duration 45 months (range 35–49 months) Variable Baseline measurement Follow-up measurement P BMD, mean ± SD gm/cm2 Femoral neck 0.84 ± 0.12 0.83 ± 0.12 ns Trochanter 0.74 ± 0.13 0.74 ± 0.12 ns Total hip 0.97 ± 0.13 0.98 ± 0.14 ns Lumbar spine  1.04 ± 0.14  Z-score, mean ± SD Femoral neck 0.17 ± 1.0 0.23 ± 1.1 ns Trochanter 0.27 ± 1.1 0.32 ± 1.1 ns Total hip 0.18 ± 1.0 0.32 ± 1.0 0.001 Lumbar spine  0.03 ± 1.4  T-score, mean ± SD Femoral neck −0.42 ± 1.0 −0.46 ± 1.0 ns Trochanter −0.02 ± 1.1 −0.03 ± 1.0 ns Total hip −0.14 ± 1.0 −0.10 ± 1.0 ns Lumbar spine  −0.50 ± 1.3  Abbreviations: BMD, bone mineral density P Clinical fractures and vertebral deformities Three new non-vertebral fractures occurred during the follow-up period. These included a hip fracture (twice in the same patient), an ankle fracture and a fracture of the thumb. All these fractures were related to trauma and occurred in subjects older than 50 years. 3 17 3 Table 3 Number and grade of deformities   Baseline Follow-up No. of subjects with deformity 13 (20%) 21 (32%)* No. of deformities  Mild 17 28  Moderate 2 8  Severe 0 0 Total 19 36 *P Comparing the groups with and without new or progressive vertebral deformities at follow-up, no differences in Δ Z-scores of BMD of the trochanter or femoral neck (FN) were found (Δ Z-score trochanter −0.02 ± 0.41 and 0.08 ± 0.38 respectively and Δ Z-score FN 0.01 ± 0.32 and 0.08 ± 0.35). In addition no differences in baseline Z-scores of ICTP and PINP were seen between these groups. Multivariable logistic regression analysis, including factors that correlated in the univariate analysis, revealed that a T-score of the femoral neck at baseline (OR per 1 SD T-score reduction = 2.5 (CI: 1.0–5.9),  = 0.04), and a mother with a hip fracture (OR = 14.1 (CI:1.4–142,6),  = 0.02) were determinants of a new and/or progressive morphometric vertebral deformity at follow-up measurement. Factors such as age, gender, calcium in take, GC use, daily GC dose, lifetime GC dose, disease activity, bone markers, radiographic stage and disease duration at baseline did not predict new and/or progressive vertebral deformities. 1 Fig. 1 Arrow  Discussion 17 20 21 22 23 24 25 26 27 17 28 29 17 30 31 32 1 2 33 34 35 36 37 38 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. 40 41 17 42 43 44 25 25 28 45 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.