Clinical research
Osteopenia and osteoporosis in patients with dermatitis herpetiformis. Effect of gluten-free diet

Introduction
In contrast to the physiological loss of bone density, in the course of some pathological conditions defects in skeletal mineralization occurred, which is called secondary osteoporosis. Bone mass defect may also accompany gluten-sensitive enteropathy (GSE), i.e., celiac disease (CD). This process is associated with decreased absorption of dietary factors that are necessary for maintaining adequate bone mass from abnormal intestines. Among the extra intestinal symptoms, loss of bone mass and bone metabolism disturbances are frequently present and can be the only signs of an otherwise silent celiac disease [1].
It has been demonstrated that gluten intolerance is a feature of dermatitis herpetiformis (DH) [2]. Common aetiology of both diseases is assumed, with the most important role attributed to gluten intolerance [3-5].
DH is a bullous skin disease with polymorphic lesions: papules, erythemas, vesicles [6]. The most common sites of involvement are the sacral region, buttocks, scapulae, nape, elbows, knees, face and scalp. The lesions are accompanied by a very intensive itching which results in forming erosions and crusts [7]. DH is diagnosed based on a typical clinical picture as well as histological and immunopathological examination of the skin (DIF). Granular deposits of IgA in dermal papillae are pathognomonic for the disease [8-11]. The presence of IgA class antibodies directed against smooth muscle endomysium (IgAEmA) in patient’s serum is also very important. These antibodies are viewed as a specific and sensitive marker of GSE, although they cannot be determined in about 30% of DH cases (latent enteropathy) and are revealed only after provocation with gluten [12-17].
New studies on the autoimmune pathogenesis of DH demonstrated that the key role in this process is the deamination reaction of a gluten metabolism product, which is carried out by tissue transglutaminase (tTG) [18, 19]. IgA EmA antibodies react with tTG, which acts as an autoantigen for those antibodies [20, 21]. Pathological changes in the small intestine, in the form of villous atrophy, are histologically identical with the ones observed in celiac disease, although they can be less pronounced [22, 23]. Both diseases affect the mucosa of small intestine. It results in development of a “flat mucosa” and subsequent disorders in intestinal absorption [24, 25].
Gluten-free diet (GFD) is essential in the treatment and has beneficial effects on both skin lesions and intestinal changes [26-29]. Malabsorption results in the deficiency of trace elements and insufficient absorption of calcium, magnesium, iron, folic acid and vitamin B complex. As a result deficiency anaemia and avitaminoses occur, especially concerning the fat-soluble vitamins such as vitamin D, with subsequent calcium deficiency [29-31]. Bone alternations were once thought to derive from calcium and vitamin D deficiency secondary to simple intestinal malabsorption [32].
Although villous atrophy is present in 70% of patients with DH, yet diarrhoeas, which are typical for celiac disease are observed only in some cases [29, 33]. However, there is no evidence as yet to suggest that symptom-free celiac disease or DH patients run an increased risk of osteoporosis or malignant intestinal lymphoma, the prevention of osteoporosis seems to be the strongest indicator for widespread screening today [34, 35]. It has been demonstrated that CD, including its latent form, may be accompanied by osteopenia and osteoporosis [36-38]. Literature data confirm significantly lower bone mineralization in patients with CD, evaluated in densitometry [39-42].
It is controversial whether gluten-free diet is sufficient enough to prevent the development of this complication [36, 37, 43]. According to some authors, gluten-free diet observed for some time contributes to the reconstruction of intestinal mucosa and restoration of crypts. Some investigators report that gluten-free diet can ameliorate, but not normalize the process of skeletal mineralization [44]. Others confirm the protective role of restrictive gluten-free diet in the development of reported complications [37, 45, 46]. Failure to achieve an optimal bone mass in childhood and adolescence as well as other risk factors, probably play a role in further changes [47-49].

Material and methods
The aim of the study was to determine whether bone mineralization defects, such as osteopenia and osteoporosis, are present in patients with DH. In addition, in this study we evaluate their frequencies in patients with and without gluten-free diet.
The examined group consisted of 37 patients who were treated in the Department of Dermatology and Venerology of Medical University of Lodz. These patients were previously diagnosed with DH based on the clinical picture and immunopathological examinations. The group was comprised of 18 women (13 before and 5 after menopause) and 19 men. Mean age of patients was approximately 45 years (range between 17 and 80 years); mean duration of the disease was 9.3 years.
The control group consisted of 27 subjects without any skin disease, age and sex matched. The control group comprised 17 women (10 before and 7 after menopause) and 10 men; mean age was 51 years (range between 23 and 80 years).
Dual-energy x-ray absorptiometry (DXA) of lumbar spine and determination of markers of bone reconstruction were performed in all patients from the examined and the control groups. We compared T-values (DXA) for the same bone in both groups.
In order to exclude impact of factors other than malabsorption on skeletal mineralization, evaluation of physical activity, calcium intake, cigarette smoking, and use of medications and coexistence of chronic disease influencing the condition of the skeleton was performed in both groups. The groups did not differ statistically with respect to physical activity, dietary calcium intake or value of the Body Mass Index. The incidence of cigarette smoking in the control group was significantly higher compared to the study group. No chronic diseases or use of medications was observed in both groups. Occasionally, our patients with DH were treated with topical steroids. We always use the first choice drug for DH – sulfone (Disulone/Dapson).
The studied group was divided according to GFD based on the established criteria [13]. Mean duration of gluten-free diet was 6.66 years (SEM=1.35):
• group I – 15 patients on GFD (excluding gluten form the diet or gluten intake lower than 10 g daily for at least 6 months);
• group II – 22 patients without any diet applied (gluten intake higher than 10 g daily). In both groups the following factors were determined in the peripheral blood serum: Ca²⁺, K⁺, Na⁺, Mg²⁺, Cl^– as well as the ionogram, blood cell count, sedimentation rate, levels of glucose, hepatic transaminases, urea and creatinine. General urine test and results of all laboratory tests were within the normal range. Daily calcium intake in the diet of patients with DH (mean =1104.05 mg/24 hours) and in control group (mean =972.5 mg/24 hours), as well as BMI, were not statistically different.
Densitometric examinations of L1-L4 spine section were made with dual photon X-ray absorptiometry using DPX instrument (Lunar, Madison, USA). The BMD (bone mineral density) value was expressed as g/cm² and interpreted against the T-score scale.
Markers of bone rebuilding, i.e., osteocalcine (ELISA-Osteo Kit CIS, Bio International, France) and β cross laps (CTX, cross laps, Osteometer AIS, Denmark) were determined in blood serum by immunoelectrochemiluminescence (ECLIA) with ELECSYS 1010 instrument (Roche) using sandwich-type method. Bone isoenzyme of alkaline phosphatase (Alkaphase B kit, Metra Biosystems, Mountain View, CA) was determined by ELISA method with Quidel Metra BAP assay.

Statistical analysis
The collected data were analyzed with the program Statgraphic version 6.0. The mean, standard deviation and the median were calculated for all the variables.
Obtained results as a number of observations were statistically analysed with χ² independence test for four- and two-field table. A value of p<0.05 was taken as the level of significance.

Results
Results of bone mineral density examination
In the examined group, mean BMD value was 1.04 g/cm². Mean BMD value in the control group was 1.20 g/cm². Mean BMD values were higher in the control group than in the examined group, however the differences were not statistically significant (p>0.05).
In the group of patients with DH, osteopenia was diagnosed based on BMD examination with the T-score scale (1.0SD>x<2.5SD) in 11 patients (fraction =0.3), while osteoporosis (>2.5SD) in 12 patients (f=0.32).
In the control group, values of the BMD index against the T-score scale were within the normal range in 25 subjects (f=0.92). Two, however, were women above 55 years of age who had values that were typical for osteoporosis (f=0.07). A statistically significant difference was observed for the BMD values on the T-score scale between the study and control groups (p<0.001) (Table I).
In the group of men with DH (mean age =42.47 years), osteopenia and osteoporosis were diagnosed in 12 out of 19 patients (f=0.63). There were no bone mineralization defects in any of the men from the control group. A statistically significant difference between those values in the sub-groups of men from the examined and control groups was revealed (p<0.00). In the group of women with DH (mean age =47.22 years), disturbances in skeletal mineralization constituted a fraction of 0.61, 7 out of 13 premenopausal women (f=0.54) and 4 out of 5 postmenopausal women. No statistically significant differences were observed for BMD in g/cm² between the sub-groups of women and men. Osteopenia and osteoporosis were not diagnosed in women before the age of 55 from the control group.
In the sub-group of women over the age of 55, osteopenia and osteoporosis were diagnosed in 2 cases (f=0.28). In the age group of patients younger than 35, osteopenia and osteoporosis was observed in 3 out of 12 cases (f=0.25) of patients with DH. Bone mineralization disturbances were not observed in subjects younger than 35 years of age.
In the groups divided according to application of the gluten-free diet, no statistically significant differences in the BMD values on the T-score were found (Table II).

Results of determination of bone rebuilding markers
Osteocalcine-normal ranges:
men 11-43 ng/ml
women premenopausal 12-41 ng/ml
women postmenopausal 20-48 ng/ml
In the examined group, mean osteocalcine value was 30.91 ng/ml. It was below normal in 2 patients (f=0.05), within normal range in 28 patients (f=0.76) and above normal in 7 patients (f=0.19). The value of this marker in the control group of healthy subjects was similar (mean 31.71 ng/ml); all values in this group were within normal range. There were no statistically significant differences in the examined group between mean values of osteocalcine in women and men (25.15 and 36.36 ng/ml) and between women before and after the age of 55 (24.50 and 26.85). In the groups divided according to gluten-free diet, fractions of patients with normal osteocalcine values were not significantly different. β-cross laps-normal ranges: men 0.01-0.30 ng/ml women premenopausal 0.01-0.28 ng/ml women postmenopausal 0.01-0.32 ng/ml

Marker of resorption, i.e., β-cross laps in the examined group was within the range from 0 to 1.46 ng/ml (mean 0.5 ng/ml). The β-cross laps below normal range were found in 1 patient (f=0.027), above normal in 22 patients (f=0.59) and normal in 14 cases (f=0.38).
In the control group, mean value of the bone resorption marker was 0.233 ng/ml, with the minimum at 0.114 and maximum at 0.414 ng/ml. Three subjects (f=0.11) had results above the normal range, while the remaining 24 persons (f=0.88) were within normal range. These results are mostly normal in contrast to the examined group and statistically significant difference was obtained for the distribution of this feature between the groups (p<0.05) (Table III). There was no statistically significant difference found in the level of this marker between women and men from the examined group (0.42 and 0.58 ng/ml).
A difference was observed for the value of b-cross laps between the group without the GFD and the group with gluten excluded form of diet. In the first group, increased values of β-cross laps concentrations were obtained in 15 out of 22 patients (f=0.68), while in patients on GFD such results were found in 7 out of 15 patients (f=0.47), with no statistically significant difference found (p>0.05) (Table III).
Both in the examined group and in the control group there were no deviations from the normal in the values of bone isoenzyme of alkaline phosphatase.

Discussion
Morphologic changes in the intestine that develop in CD and DH on the base of immunological processes lead in consequence to disturbances in intestinal absorption that may lead to secondary osteoporosis [16, 44]. Majority of studies reveal the presence of osteoporosis in approximately 50% of patients with CD even in latent form [37, 39]. However, little information is available on the biochemical bone turnover markers in patients treated with GFD [50]. So far, similar studies have not been performed in a group of patients with DH [51]. In contrast to postmenopausal osteoporosis, interventional studies in secondary osteoporosis are often limited by a small study population and data about the efficacy of any treatment in prevention of fractures are therefore lacking [52]. Our paper shows the study of bone changes in DH patients. According to other authors, a short systemic therapy with steroids and rare topical treatment with steroids seems to be of no significance [36, 37].
In DH, as compared with CD, the extent of morphological changes in the bowel is smaller [52]. Thus, one could expect a low degree of disturbed absorption or even absence. However, patients with DH periodically present with stomachaches, anaemia and/or diarrheas. Experimental studies confirm disturbed absorption of calcium, Vitamin D and trace elements.
Starting from middle age, both in men and in women gradual loss of bone mass occurs [53]. This process is quickened in women in early years after the menopause and after the age of 65 in men [54, 55]. In case of secondary disorders decrease in bone mass may occur in younger patients [49].
In the presented study, BMD measurements by densitometry of lumbar spine revealed reduced values, indicating loss of bone mass and osteoporosis in a significant percentage of patients with DH. It should be noted that in the T-score of DXA examination, the majority of women after menopause from the examined group had established osteopenia or osteoporosis. Results obtained in premenopausal women are also characteristic. Disturbances in skeletal mineralization on the DXA examination were found in more than half of these women and one of them had also a history of pathological fracture. Such results in patients with DH suggest a similar risk of osteoporosis in premenopausal as in postmenopausal women. Osteopenia and osteoporosis were found in more than half of the examined patients with DH. It seems that such a large number of defects revealed in skeletal mineralization could be associated with GSE. Influence of other possible risk factors for osteoporosis was similar in both examined and control groups as well as in general Polish population [56]. In the group of patients with DH, serum concentrations of Ca2+ were within the normal range. Studies on CD undertaken by other authors revealed both normal and decreased levels of the examined element [57, 58]. Normal concentration of Ca2+ in blood serum of the examined patients seems to be caused by secondary hyperparathyroidism. Bone mass acquired in the first years of life is probably the most important factor determining the condition of skeletal system for the whole life [59]. Patients with DH may achieve lower peak bone mass as a result of the pathological process in the small intestine which causes disturbances in absorption [54]. It is confirmed by results obtained in the examined group of patients with DH, who were characterized by a lower value of mean BMD as compared to the control group.
Persons who had not achieved the optimal bone mass in childhood and adolescence may develop osteoporosis without accelerated loss of bone mass [59]. Symptoms suggesting GSE should be quickly confirmed so that treatment could be introduced. Unfortunately, opposite to CD, whose symptoms appear in the first decade of life, first clinical symptoms of DH are present only in the older age, after the bone mass has been formed. In the examined group of patients, changes in concentration of osteocalcine, and mainly resorption marker – β-cross laps, were described. Elevated values of this marker, which were found in more than half of the patients, revealed increased resorption of the skeleton compared with the control group. This phenomenon was observed in a very small number of persons. This finding seems to confirm a special risk of osteoporosis in DH patients.
There are no homogenous data on the role of GFD in the development of osteoporosis in current literature. Some studies suggest that long-term (>5 years) of GFD is sufficient for maintaining adequate skeletal mineralization and its metabolism. It is confirmed by both results of densitometric studies and by determination of biochemical parameters in patients observing the GFD [37, 45]. Some authors report rebuilding of the bones even after first year of GFD on the base on increase in the parameter of BMD [37, 39].
Life-long GFD is established therapy for CD and DH it allows the intestinal mucosa to recover, improves nutrient malabsorption and osteoporosis [60, 61]. Gajewska et al. data show normal bone resorption and formation processes in most patients with celiac disease on gluten-free diet [62]. However, some cases had changes in the pattern of bone turnover markers. Similarly, no statistically significant effect of GFD on metabolic processes in the skeleton was demonstrated in the presented study.
In our densitometric examinations of patients not-observing the GFD osteoporosis was more frequent than in patients observing the diet, although the difference was not statistically significant. Corraza et al. [63] compared the BMD values in patients with gluten-sensitive enteropathy who were treated with GFD, not-observing the diet and healthy persons. These authors report higher values of BMD in diet-treated patients while the values are lower than in the group of healthy persons.
Effects of dietary improvement on bone metabolism in elderly underweight women with osteoporosis in a 12-month randomised controlled trial are as follows: reduction in bone resorption with a small beneficial effect on bone formation [64]. It’s a good example for calcium and vitamin supplementation gluten-free diet in celiac disease and DH patients.
The results of the present study confirm the thesis that sole observation of GFD does not prevent from the development of defects in bone mineralization. High percentage of DH patients with diagnosed osteopenia and osteoporosis in spite of the gluten-excluding diet may result from lower peak bone mass obtained earlier as a result of a pathological process in the intestine.
The authors confirmed that the current advice concerning dietary adherence is necessary to avoid long-term complications, which are principally osteoporosis and small bowel lymphoma. However, risk of these complications diminishes very considerably in patients who are on GFD [65].

Conclusions
Osteopenia and osteoporosis are complications of DH and are encountered more frequently in patients with this disease than in healthy persons.
The fact that osteopenia and osteoporosis are observed in the course of DH even in young persons and in women before menopause reveals the necessity of routine bone mineral density measurements in all patients with DH.
The frequency of bone mineralization defects in patients observing and not-observing the GFD is similar, thus all patients with DH should receive supplementation of calcium and vitamin D.

Acknowledgments
This study was supported by the research projects of Medical University of Lodz, Poland: 503-1019-1 and 503-8019-1.

References
1. Bianchi ML, Bardella MT. Bone and celiac disease. Calcif Tissue Int 2002; 71: 465-71.
2. Marks J, Shuster S, Watson AJ. Small-bowel changes in dermatitis herpetiformis. Lancet 1966; 2: 1280-2.
3. Alexander JO. Dermatitis herpetiformis. In: Major Problems in Dermatology. Rook A (ed.) WB Saunders, London 1975.
4. Ferguson A. New perspectives of the pathogenesis of the coeliac disease: evolution of a working clinical definition. J Intern Med 1996; 240: 315-8.
5. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40: 1-19.
6. Beutner EH, Chorzelski TP, Bean SF. Immunopathology of the skin. Wiley Publication, New York 1979.
7. Reunala TL. Dermatitis herpetiformis. Clin Dermatol 2001; 19: 728-36.
8. Beutner EH, Chorzelski TP, Reunala TL, Kumar V. Immunopathology of dermatitis herpetiformis. Clin Dermatol 1991; 9: 295-311.
9. Chorzelski TP, Beutner EH, Jablonska S, Blaszczyk M, Triftshauser C. Immunofluorescence studies in the diagnosis of dermatitis herpetiformis and its differentiation from bullous pemphigoid. J Invest Dermatol 1971; 56: 373-80.
10. Fry L. Dermatitis herpetiformis: problems, progress and prospects. Eur J Dermatol 2002; 12: 523-31.
11. Zone JJ, Meyer LJ, Petersen MJ. Deposition of granular IgA relative to clinical lesions in dermatitis herpetiformis. Arch Dermatol 1996; 132: 912-8.
12. Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease: a guide for dermatologists. Am J Clin Dermatol 2003; 4: 13-20.
13. Ferreira M, Davies SL, Butler M, Scott D, Clark M, Kumar P. Endomysial antibody: is the best screening test for coeliac disease? Gut 1992; 33: 1633-7.
14. Kolho KL, Färkkilä MA, Savilahti E. Undiagnosed coeliac disease is common in Finnish adults. Scand J Gastroentrol 1998; 33: 1280-3.
15. Kumar V, Jarzabek-Chorzelska M, Sulej J, Rajadhyaksha M, Jablonska S. Tissue transglutaminase and endomysial antibodies-diagnostic markers of gluten-sensitive enteropathy in dermatitis herpetiformis. Clin Immunol 2001; 98: 378-82.
16. Maki M, Collin P. Coeliac disease. Lancet 1997; 349: 1755-9.
17. Managment of Blistering Diseases. Wojnarowska F, Briggaman RA (eds). Raven Press, New York 1990.
18. Molberg O, Mcadam SN, Körner R, et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 1998; 4: 713-7.
19. van de Wal Y, Kooy Y, van Veelen P, et al. Cutting Edge: Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 1998; 161: 1585-8.
20. Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997; 3: 797-801.
21. Zanchetta J, Plotkin H, Alvarez Filgueira ML. Bone mass in children: normative values for the 2-20-year-old population. Bone 1995; 16 (4 Suppl): 393S-9S.
22. Holm K, Maki M, Savilahti E, Lipsanen V, Laippala P, Koskimies S. Intraepithelial gamma delta T-cell-receptor lymphocytes and genetic susceptibility to coeliac disease. Lancet 1992; 339: 1500-3.
23. Vecchi M, Crosti L, Berti E, Agape D, Cerri A, De Franchis R. Increased jejunal intraepitelial lymphocytes bearning gamma/delta T-cell receptor in dermatitis herpetiformis. Gastroenterology 1992; 102: 1499-505.
24. Caproni M, Feliciani C, Fuligni A, et al. Th2-like cytokine activity in dermatitis herpetiformis. Br J Dermatol 1998; 138: 242-7.
25. Weinstein WM, Brow JR, Parker F, Rubin CE. The small intestinal mucosa in dermatitis herpetiformis. Relationship of the small intestinall lesion to gluten. Gastroenterology 1971; 60: 362-9.
26. Ermacora E, Prampolini L, Tribbia G. Long-term follow-up of dermatitis herpetiformis in children. J Am Acad Dermatol 1986; 15: 24-30.
27. Fry L, McMinn RM, Cowan JD, Hoffbrand AV. Effect of gluten-free diet on dermatological, intestinal, and haematological manifestations of dermatitis herpetiformis. Lancet 1968; 1: 557-61.
28. Fry L, Seath PP, Riches DJ, Hoffbrand AV. Clearance of skin lesions in dermatitis herpetiformis after gluten withdrawal. Lancet 1973; 1: 288-91.
29. Gammon W (eds). Dermatologic Immunology and Allergy. Julius Stone (ed). St. Louis Mosby, 1985.
30. Kemppainen T, Kroger H, Janatuinen E, et al. Osteoporosis in adult patients with celiac disease. Bone 1999; 24: 249-55.
31. Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child 1990; 65: 909-11.
32. Rossini M, Bianchi G, Di Munno O, et al. Determinants of adherence to osteoporosis treatment in clinical practice. Osteoporos Int 2006; 17: 914-21.
33. Griffiths CE, Menzies IS, Barrison IG, Leonard JN, Fry L. Intestinal permeability in dermatitis herpetiformis. J Invest Dermatol 1988; 91: 147-9.
34. Collin P. Should adults be screened for celiac disease? What are the benefits and harms of screening? Gastroenterology 2005; 128: S104-8.
35. Valdimarsson T, Löfman O, Toss G, Ström M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996; 38: 322-7.
36. Mora S, Barera G, Ricotti A, Weber G, Bianchi C, Chiumello G. Reversal of low bone density with a gluten-free diet in children and adolescents with celiac disease. Am J Clin Nutr 1998; 67: 477-81.
37. Mora S, Barera G, Beccio S, et al. Bone density and bone metabolism are normal after long-term gluten-free diet in young celiac patients. Am J Gastroenterol 1999; 94: 398-403.
38. Selby PL, Davies M, Adams JE, Mawer EB. Bone loss in celiac disease is related to secondary hyperparathyroidism. J Bone Miner Res 1999; 14: 652-7.
39. Kemppainen T, Kröger H, Janatuinen E, et al. Bone recovery after a gluten-free diet: a 5-year follow-up study. Bone 1999; 25: 355-60.
40. Pistorius LR, Sweidan WH, Purdie DW. Coeliac disease and bone mineral density in adult female patients. Gut 1995; 37: 639-42.
41. Di Stefano M, Jorizzo RA, Veneto G, Cecchetti L, Gasbarrini G, Corazza GR. Bone mass and metabolism in dermatitis herpetiformis. Dig Dis Sci 1999; 44: 2139-43.
42. Zebrowska A, Torzecka JD, Waszczykowski M, Dziankowska-Bartkowiak B. Bone mineral density in patients with dermatitis herpetiformis – pilot study. JEADV 2001; 2: 807-10.
43. Leiva L, Burrows R, Rios G, et al. Bone mass in celiac patients [Spanish]. Arch Latinoam Nutr 1996; 46: 128-31.
44. Szathmári M, Tulassay T, Arató A, Bodánszky H, Szabó A, Tulassay Z. Mineral content in bones of children with symptomless celiac disease and gluten-free diet [Hungarian]. Orv Hetil 1997; 138: 3233-8.
45. Caraceni MP, Molteni N, Bardella MT, Ortolani S, Nogara A, Bianchi PA. Bone and mineral metabolism in adult celiac disease. Am J Gastroenterol 1988; 83: 274-7.
46. Taranta A, Fortunati D, Longo M, et al. Imbalance of osteoclastogenesis-regulating factors in patients with celiac disease. J Bone Miner Res 2004; 19: 1112-21.
47. Koop I, Ilchmann R, Izzi L, Adragna A, Koop H, Barthelmes H. Detection of autoantibodies against tissue transglutaminase in patients with celiac disease and dermatitis herpetiformis. Am J Gastroenterol 2000; 95: 2009-14.
48. Sárdy M, Odenthal U, Kárpáti S, Paulsson M, Smyth N. Recombinant human tissue transglutaminase ELISA for the diagnosis of gluten-sensitive enteropathy. Clin Chem 1999; 45: 2142-9.
49. Broll H. Consensus statement: osteoporosis, classification and clinical features. Rheum in Europe 1996; 25: 33-6.
50. Sategna-Guidetti C, Grosso SB, Grosso S, et al. The effects of 1-year gluten withdrawal on bone mass, bone metabolism and nutritional status in newly-diagnosed adult coeliac disease patients. Aliment Pharmacol Ther 2000; 14: 35-43.
51. von Tripitz C, Reinshagen M. Management of osteoporosis in patients with gastrointestinal diseases. Eur J Gastroenterol Hepatol 2003; 15: 869-76.
52. Brow JR, Parker F, Weinstein WM, Rubin CE. The small intestinal mucosa in dermatitis herpetiformis. I. Severity and distribution of the small intestinal lesion and associated malabsorption. Gastroenterology 1971; 60: 355-61.
53. Pocock NA, Eisman JA, Hopper JL, Yeates MG, Sambrook PN, Eberl S. Genetic determinants of bone mass in adults. A twin study. J Clin Invest 1987; 80: 706-10.
54. Dempster DW, Lindsay R. Pathogenesis of osteoporosis. Lancet 1993; 341: 797-801.
55. Nasu M, Sugimoto T, Chihara M, Hiraumi M, Kurimoto F, Chihara K. Effect of natural menopause on serum levels of IGF-I and IGF-binding proteins: relationship with bone mineral density and lipid metabolism in perimenopausal women. Eur J Endocrinol 1997; 136: 608-16.
56. Miazgowski T, Hoszowski K, Gawron J. Częstość występowania i czynniki ryzyka osteoporozy w badaniach epidemiologicznych w populacji warszawskiej i szczecińskiej. Medycyna 2000 1993; 35/36: 6-11.
57. Mc Farlane XA, Bhalla AK, Reeves DE, Morgan LM, Robertson DAF. Osteoporosis in treated adult coeliac disease. Gut 1995; 36: 710-14.
58. Harrison JE, Hitchman AJ, Finlay JM, McNeill KG. Calcium kinetic studies in patients with malabsorption syndrome. Gastroenterology 1969; 56: 751-7.
59. Klibanski A, Adams Cambell L, Bassford T. Osteoporosis prevention, diagnosis and therapy. JAMA 2001; 285: 785-95.
60. Løvik A, Lundin KE. Dietary treatment of celiac disease and dermatitis herpetiformis [Norwegian]. Tidsskr Nor Laegeforen 2003; 123: 3237-40.
61. Gregory J, Foster K, Tyler H, Wiseman M. The dietary and nutritional survey of British adults. HMSO, London 1990.
62. Gajewska J, Ambroszkiewicz J, Hozyasz K. Biochemical marker sof bone turnover in children with celiac disease on gluten free-diet. Med Wieku Rozwoj 2005; 9: 675-83.
63. Corazza GR, Di Sario A, Cecchetti L, et al. Bone mass and metabolism in patients with celiac disease. Gastroenterology 1995; 109: 122-8.
64. Hampson G, Martin FC, Moffat K, Vaja S. Effects of dietary improvement on bone metabolism in elderly underweight women with osteoporosis: a randomised controlled study. Osteoporos Int 2003; 14: 750-6.
65. Mc Gough N, Cummings JH. Coeliac disease: a diverse clinical syndrome caused by intolerance of wheat, barley and rye. Proc Nutr Soc 2005; 64: 434-50.