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What is the long-term effectiveness of following a gluten-free dietary pattern on bone density?



Conclusion Statement

Clinical trials and cross-sectional studies have reported reduced bone mineral content and bone mineral density in untreated children, adolescents and adults with celiac disease; both of these parameters improve significantly with compliance to a gluten-free dietary pattern for at least 1 year. Compliance with dietary treatment initiated during childhood or adolescence allows achievement of a normal bone mineralization. However, studies in untreated adults have shown that a gluten-free dietary pattern improves but may not normalize bone mineral density; successful treatment depends on the age at diagnosis, as patients who do not receive treatment in childhood and adolescence may never reach peak bone mass. Further studies are needed regarding the effects of calcium and vitamin D supplementation on bone mineral content and bone mineral density, as well as hormone replacement therapy for postmenopausal women.

Evidence Summary

A total of 32 studies were reviewed, 18 nonrandomized clinical trials, case-control studies and longitudinal studies, and 14 cross-sectional studies. Measurements of BMC and BMD are generally expressed in g (BMC) or g/cm2 (BMD), however, many studies also report BMD findings in terms of Z scores, which represent the number of standard deviations by which an individual value is separated from the corresponding mean normal value, corrected for gender and age.

Nonrandomized Clinical Trials, Case-Control and Longitudinal Studies

Children and Adolescents

Three positive-quality and three neutral-quality nonrandomized clinical trials and one neutral-quality longitudinal study on children and adolescents show reduced BMC and BMD in untreated patients, however, adherence to a gluten-free dietary pattern resulted in BMC and BMD comparable to controls.

In a positive-quality nonrandomized clinical trial by Rea et al (1996) of 23 celiac children in Italy on a gluten-free diet and vitamin D supplementation for 1 year, with which compliance was measured through antibody levels, forearm BMC Z scores improved from –0.76 +/- 0.3 at diagnosis to –0.05 +/- 0.1, P = 0.007, which was not statistically different from controls (0.28 +/- 0.2).

In a positive-quality nonrandomized clinical trial in Turkey by Kalayci et al (2001), on 16 recently diagnosed children and adolescents, mean age 10.6 years, and 16 strict gluten-free diet followers, mean age 11.5 years, who had been on the diet for a mean duration of 40.4 months (3.4 years) with compliance monitored through antibody measurement, lumbar spine BMD and BMC values in patients with recent diagnosis were found to be significantly lower than the control group (p < 0.05). After 1 year of gluten-free diet without calcium or vitamin supplementation, Z scores improved in the recently diagnosed patients from –1.55 +/- 1.36 at baseline to –0.38 +/- 1.19, p = 0.041; and in the strict diet followers from –0.67 +/- 0.85 at baseline to –0.37 +/- 0.98, p = 0.011.

In a positive-quality nonrandomized clinical trial by Mora et al (2001) in Italy of 19 children and adolescents with celiac disease, mean age 14.2 +/- 2.6 years, bone mineral measurements were repeated after 1.1 +/- 0.3 years and 4.3 +/- 0.6 years of gluten free diet without supplementation, with which compliance was measured through antibodies, spinal BMD and BMC and total-body BMD and BMC at the time of diagnosis were lower than controls (P = 0.03 and P = 0.04, respectively) but after gluten-free diet, spinal and total-body values did not differ from controls. Spinal BMC and spinal BMD of patients were, respectively, 18.0 +/- 1.9 g and 0.713 +/- 0.042 g/cm2 at diagnosis, increased to 21.3 +/- 2.5 g and 0.769 +/- 0.042 g/cm2 after short term gluten-free diet, and increased to 29.5 +/- 2.8 g and 0.904 +/- 0.050 g/cm2 after long-term gluten free diet. Total body BMC and BMD were, respectively, 1077.5 +/- 96.5 g and 0.874 +/- 0.022 g/cm2 at diagnosis, increased to 1311.6 +/- 107.5 g and 0.913 +/- 0.026 g/cm2 after short-term gluten free diet, and increased to 1717.4 +/- 117.1 g and 1.007 +/- 0.028 g/cm2 after long-term gluten-free diet.

In a neutral-quality nonrandomized clinical trial by Barera et al (2004) in Italy of 22 children with celiac disease aged 10.5 +/- 1.0 year at time of diagnosis, BMC was significantly lower than that of healthy controls at the time of diagnosis but not after 1 year of gluten-free diet without supplementation, with which compliance was not monitored (spine BMC: 18.9 +/- 2.3 g at diagnosis vs 23.2 +/- 2.6 g after 1 year, compared to 29.6 +/- 1.3 g of controls, P = 0.032; total body BMC: 1179.5 +/- 107.2 g at diagnosis vs 1421.6 +/- 114.9 g after 1 year, compared to 1727.0 +/- 64.1 g of controls, P = 0.03).

In a neutral quality nonrandomized clinical trial by Mora et al (1998) of 25 Italian children and adolescents aged 2.58 – 20.42 years at diagnosis, mean lumbar spine BMD was 0.708 +/- 0.034 g/cm2 and mean whole-body BMD was 0.875 +/- 0.020 g/cm2, both significantly lower than in controls (P = 0.015 and P = 0.0001, respectively). However, after 1.4 +/- 0.4 years of gluten-free diet without supplementation, with which compliance was ascertained through the antibody measurement and intestinal biopsies, lumbar spine and whole-body BMD values were not significantly different from controls.

A neutral-quality nonrandomized clinical trial by Carbone et al (2003) in Italy of 48 adolescents with celiac disease, aged 14.5 +/- 2.8 years, showed that weight, height, fat mass, fat-free mass, BMC and BMD were lower compared to controls (BMC of patients: 2119 +/- 529 g vs 2807 +/- 667 g of controls, p < 0.001; BMD of patients: 1.06 +/- 0.106 g/cm2 vs 1.176 +/- 0.125 g/cm2 of controls, p < 0.001). 11 of these patients had returned for follow-up after following a gluten-free diet without supplementation for 4 years, with which compliance was monitored through antibody measurement and poor dietary compliance was noted, and the body compartments of celiac patients had normalized, with the exception of weight and fat-free mass which remained lower than controls (BMC of patients: 2917 +/- 1479 g vs 2548 +/- 252 g of controls, NS; BMD of patients: 1.131 +/- 0.087 g/cm2 vs 1.129 +/- 0.08 g/cm2 of controls, NS).

In a neutral-quality longitudinal study in Argentina by Tau et al (2006), 24 children, mean age 4.9 +/- 4.3 years, followed a gluten-free diet for a mean of 1.17 +/- 0.93 years (range 3 months - 3.9 years) and received 1000 IU per day of vitamin D for the first 3 months of treatment but no calcium supplementation. Dietary compliance was not described. Height and weight increased significantly after gluten-free diet (P < 0.001) and the increase correlated positively with the increase in bone mineral density (0.46 +/- 0.13 to 0.55 +/- 0.13 g/cm2, P < 0.001).

Adults

Nine nonrandomized clinical trials (four positive-quality, five neutral-quality) and two case-control studies (one positive-quality, one neutral-quality) in adults show reductions in BMC and BMD in untreated patients, significant improvement in BMC and BMD after following a gluten-free dietary pattern, but not normalization for all adult patients.

In the positive-quality nonrandomized clinical trial by Valdimarsson et al (1996) of 63 Swedish adults, age-adjusted BMD at diagnosis was reduced at the forearm, lumbar spine, femoral neck and trochanter (p < 0.001). After 1 year of gluten free diet with calcium and vitamin D supplementation, with which compliance was confirmed through biopsy, BMD increased at all sites (P < 0.01), but was still reduced at all sites by the end of the year (p < 0.05).

In a positive-quality nonrandomized clinical trial by Sategna-Guidetti et al (2000) on 72 newly diagnosed adults with celiac disease in Italy, 1 year of gluten-free diet without supplementation, with which compliance was monitored through internal biopsy at end of study and showing mucosal recovery in only 56.9%, indicating incomplete dietary compliance, led to significant improvement of lumbar spine and femoral neck mean BMD values (from 0.886 +/- 0.15 to 0.933 +/- 0.14 g/cm2, P < 0.0001, and from 0.754 +/- 0.21 to 0.813 +/- 0.15 g/cm2, P = 0.0009, respectively).

In the positive-quality nonrandomized clinical trial by Ciacci et al (1997) in 41 Italian adults following a calcium-rich gluten-free diet for 12.3 +/- 0.8 months, with which compliance was monitored by a dietitian, post-treatment BMD was greater than pretreatment BMD at the lumbar spine (0.907 +/- 0.028 and 0.795 +/- 0.028 g/cm2, respectively, p < 0.001), the femoral neck (0.818 +/- 0.023 and 0.741 +/- 0.030 g/cm2, respectively, p = 0.002), and the Ward’s triangle (0.703 +/- 0.025 and 0.654 +/- 0.025 g/cm2, respectively, p < 0.001).

In the positive-quality nonrandomized clinical trial by McFarlane et al (1995) of 55 British adults already consuming a gluten-free diet for a duration of 0.3 – 40 years, with which compliance was checked through dietary assessment, no overall loss of bone was shown over the 12 months of follow-up, and relative to the reference population there was significant improvement in BMD at the lumbar spine in women (p < 0.025) and at the femoral neck in men (p < 0.05).

In the positive-quality case-control study in the United States by Pazianas et al (2005), 24 adult females with celiac disease were compared with 20 age- and sex-matched healthy controls. Subjects with celiac disease had been following a gluten-free diet for over 4 years, with compliance checked by dietitian interview. Whole body, spine and trochanter bone mineral density were significantly lower in treated celiac patients compared with controls (P < 0.05). After adjusting for calcium intake, the estimated amount of daily calcium absorbed was similar in both groups.

In a neutral-quality case-control study in Finland, Viljamaa et al (2005) studied 53 screen-detected celiac patients, 44 symptom-detected treated celiac patients, 54 untreated celiac patients, 110 non-celiac subjects and 2060 subjects from the general population. Treated patients had followed a gluten-free diet for a median of 14 years, with dietary compliance assessed by interview, 4 day food records and serology. 96% of screen-detected and 93% of symptom-detected celiac patients adhered to a strict or fairly strict gluten-free diet; bone mineral density was found to be similar to that in the general population.

In the neutral-quality nonrandomized clinical trial by Molteni et al (1995) in 18 Italian women, mean age 36.8 years, mean BMD of the forearm at diagnosis was significantly decreased compared with controls (p < 0.001), but did not increase significantly after 1 year of gluten-free diet, which was not monitored (573.5 +/- 98.89 vs 589.4 +/- 97.45 g/cm2).

In a neutral-quality nonrandomized clinical trial by McFarlane et al (1996) in 21 British adults on a gluten free diet without supplementation for 1 year, with compliance monitored by a dietitian, patients had a significant gain in BMD at lumbar spine (0.047 g/cm2/year, p < 0.001) and femoral neck (0.033 g/cm2/year, p < 0.002). However, despite improvement in BMD, it was still significantly lower in patients compared to controls after 1 year at lumbar spine (0.863 vs 1.014 g/cm2, p < 0.001) and at femoral neck (0.693 vs 0.799 g/cm2, p < 0.002).

In a neutral-quality nonrandomized clinical trial by Valdimarsson et al (2000) in Sweden of 105 adults newly diagnosed with celiac disease, on a gluten free diet for 3 years with calcium and vitamin D supplementation, with which compliance was not well monitored, initial age-adjusted BMD was reduced at all sites in patients with untreated celiac disease compared to controls (median BMD Z scores of –0.79, -0.72 and –0.88 for hip, spine and distal forearm, respectively, P < 0.001). After 3 years of gluten-free diet, median BMD Z scores increased to –0.57, -0.15 and –0.60 for hip, spine and distal forearm, respectively (P< 0.001).

In a neutral-quality nonrandomized clinical trial in Argentina by Bai et al (1997) on 45 adults with newly diagnosed celiac disease following a gluten-free diet without supplementation for a mean duration of 38 months (3.2 years), with which compliance was confirmed through dietary assessment, subjects were allocated to 2 groups based on dietary adherence as strict or partial. For all patients, the institution of a gluten-free diet produced a highly significant bone remineralization in the lumbar spine measured as both absolute values and Z score (P < 0.0001). A greater mean annual Z score change in the total skeleton was noted in subjects who were fully compliant compared to partially compliant, but this difference was not statistically significant (0.4 +/- 0.1 vs 0.3 +/- 0.1).

In a neutral-quality nonrandomized clinical trial by Kemppainen et al (1999) in Finland of 27 adults with newly diagnosed celiac disease on a gluten-free diet at 1 year and 22 adults at 5 years, with which compliance was measured through a questionnaire and food records, and shown to be 96% at 1 year and 82% at 5 years. In women, lumbar spine BMD values were 1.077 +/- 0.167 g/cm2 at diagnosis, to 1.115 +/- 0.116 g/cm2 at 1 year (p < 0.001) and 1.105 +/- 0.175 g/cm2 at 5 years (NS); femoral neck BMD values were 0.879 +/- 0.126 g/cm2 at diagnosis, to 0.909 +/- 0.116 g/cm2 at 1 year (NS), to 0.887 +/- 0.128 g/cm2 at 5 years (NS); trochanter BMD values were 0.745 +/- 0.103 g/cm2 at diagnosis, to 0.798 +/- 0.102 g/cm2 at 1 year (p < 0.05) to 0.804 +/- 0.091 g/cm2 at 5 years (p < 0.05); Wards’ triangle BMD values were 0.780 +/- 0.149 g/cm2 at diagnosis, to 0.813 +/- 0.160 g/cm2 at 1 year (p < 0.001) to 0.794 +/- 0.167 g/cm2 at 5 years (NS). In men, lumbar spine BMD values were 1.034 +/- 0.276 g/cm2 at diagnosis, to 1.033 +/- 0.259 g/cm2 at 1 year (NS) and 1.057 +/- 0.261 g/cm2 at 5 years (NS); femoral neck BMD values were 0.872 +/- 0.156 g/cm2 at diagnosis, to 0.897 +/- 0.146 g/cm2 at 1 year (NS), to 0.893 +/- 0.155 g/cm2 at 5 years (NS); trochanter BMD values were 0.799 +/- 0.165 g/cm2 at diagnosis, to 0.838 +/- 0.153 g/cm2 at 1 year (NS) to 0.849 +/- 0.200 g/cm2 at 5 years (p < 0.05); Wards’ triangle BMD values were 0.739 +/- 0.216 g/cm2 at diagnosis, to 0.758 +/- 0.200 g/cm2 at 1 year (p < 0.05) to 0.758 +/- 0.192 g/cm2 at 5 years (NS).

Postmenopausal Women

Three nonrandomized clinical trials discuss results in postmenopausal women.

In the aforementioned positive-quality nonrandomized clinical trial by Sategna-Guidetti et al (2000), between fertile and postmenopausal women, BMD in the lumbar spine was 0.940 +/- 0.118 g/cm2 for premenopausal vs 0.670 +/- 0.104 g/cm2 for postmenopausal, P < 0.0001; BMD in the femoral neck was 0.783 +/- 0.121 g/cm2 for premenopausal vs 0.621 +/- 0.118 g/cm2 for postmenopausal, P = 0.001.

In the aforementioned positive-quality nonrandomized clinical trial by McFarlane et al (1995) of British adults already consuming a gluten-free diet for 0.3 – 40 years, no significant difference between premenopausal, perimenopausal or postmenopausal women at either the lumbar spine or the femoral neck was found; some of the women studied were or had been on hormone replacement therapy for more than 1 year.

In the aforementioned neutral-quality nonrandomized clinical trial by Bai et al (1997), premenopausal women had significantly higher remineralization than post-menopausals (P < 0.05).

Cross-Sectional Studies

Children and Adolescents

Two positive-quality and four neutral-quality cross-sectional studies on children and adolescents have shown reduced BMC and BMD in untreated patients, however, treatment with a gluten-free dietary pattern improves BMC and BMD.

In a positive-quality cross-sectional study by De Lorenzo et al (1999), 43 Italian adolescents with celiac disease, mean age 12 +/- 2.4 years, were divided into 2 groups based on dietary compliance with a gluten-free diet for more than 1 year ascertained through dietary assessment of food records, clinical evaluation and antibody measurements. 28 were considered fully compliant and 15 were considered partially compliant. The values of BMC and BMD at the lumbar spine and total skeleton were significantly lower in celiac patients than in age-matched controls (p < 0.001). 18 (42%) patients with longer symptomatic periods before diagnosis presented the most significant reduction in bone mass (-23% compared with normal controls, p < 0.001). No significant difference was found between patients strictly adherent to a gluten-free diet and patients partially compliant.

In a positive quality cross-sectional study in Brazil by Sdepanian et al (2003) in 30 children and adolescents, children aged 6 – 9 years and adolescents aged 13 – 16 years, following a gluten-free diet for at least 1 year without supplementation, with which compliance was monitored through antibody measurement, the mean lumbar spine BMD in adolescents was significantly lower than controls (0.917 +/- 0.116 g/cm2 vs 1.060 +/- 0.158 g/cm2, P = 0.015), whereas no significant difference was found between children and controls (P = 0.595).

In a neutral-quality cross-sectional study by Kavak et al (2003) in Turkey of 34 untreated children with celiac disease and 28 children on a gluten-free diet and no supplementation for 1 year, with which compliance was monitored through antibody measurement, the mean values of lumbar spine BMD and BMC of untreated patients were significantly lower than controls (BMD: 0.447 +/- 0.144 vs 0.537 +/- 0.080 g/cm2, p = 0.006 and BMC: 14.80 +/- 9.69 vs 21.02 +/- 4.14 g, p = 0.005). Treated patients had mean BMD and BMC values not significantly different than controls (BMD: 0.520 +/- 0.112 g/cm2 and BMC: 18.89 +/- 10.79 g).

In a neutral-quality cross-sectional study by Szathmari et al (2001) in 91 Hungarian children and adolescents, mean age 11.7 years, on a gluten-free diet without supplementation for at least 3 years, with which compliance was measured through biopsy, the radius midshaft mean BMC Z-score value in the female adolescent group only was significantly lower than normal (mean Z-score –1.04, P < 0.01). In contrast, the radius midshaft mean BMD Z-score was significantly higher compared to a healthy population in both girls (mean Z-score +1.36, P < 0.001) and boys (mean Z-score +1.01, P < 0.001).

In a neutral-quality cross-sectional study by Scotta et al (1997) in Italy of 66 children, mean age 117 months (9.75 years), on a gluten-free diet without supplementation for differing durations of less than 1 year, 1-2 years or over 2 years, with which compliance monitoring not mentioned, spine BMD values in late diagnosed celiac patients who had been on the diet less than 1 year were significantly lower than those on the diet for more than 2 years (0.676 +/- 0.096 vs 0.751 +/- 0.078 g/cm2, p < 0.01). No significant difference appeared between celiac patients on medium and long-term gluten-free diets.

In a neutral-quality cross-sectional study by Hartman et al (2004), 41 children in Israel, mean age 11.2 +/- 3.6 years, followed a gluten-free diet for a mean of 5.7 +/- 4.3 years, with which compliance was ascertained by clinical evaluation, parental inquiry and antibody testing. Only 19 of 41 children were strictly compliant with the gluten-free diet. Children non-compliant with the gluten-free diet had significantly worse tibia speed of sound z-scores compared with children compliant with the diet (-2.3 +/- 1.8 vs -1.2 +/- 1.5, P = 0.04).

Adults

Three positive-quality and four neutral-quality cross-sectional studies in adults show similar reductions in BMC and BMD in untreated patients. However, although BMC and BMD significantly improve after following a gluten-free dietary pattern, BMC and BMD may not normalize for all adult patients.

In a positive-quality cross-sectional study in Argentina by Vazquez et al (2000), 165 patients with celiac disease, median age 40 years, were divided into groups according to initial interview of untreated patients (n = 51), those following a strict gluten-free diet (n = 74) and those following a partial gluten-free diet (n = 40), without supplementation. Untreated patients had lumbar spine and total skeleton BMD Z-scores of –1.3 and –2.0, respectively; partially compliant subjects had lumbar spine and total skeleton BMD Z-scores of –1.0 and –0.9, respectively; and fully compliant subjects had lumbar spine and total skeleton BMD Z-scores of –1.2 and –1.6, respectively.

In a positive-quality cross-sectional study by Bardella et al (2000) of 71 adults in Italy consuming a strict gluten-free diet without supplementation for over 2 years, with which compliance was measured through food questionnaires and dietitian interview, BMD in men and women was not significantly different than controls (for men: 1.1 +/- 0.07 vs 1.2 +/- 0.12 g/cm2, for women: 1.03 +/- 0.06 vs 1.1 +/- 0.09 g/cm2). However, when the BMD values of the groups of patients whose disease was diagnosed in either childhood (1.1 +/- 0.06 g/cm2) or adulthood (0.9 +/- 0.09 g/cm2) were considered separately, the BMD of the latter group was significantly lower than the control group value of 1.1 +/- 0.09 g/cm2 (P < 0.01).

In a positive-quality cross-sectional study by Mora et al (1999) of 30 young Italian adults, mean age 21.9 +/- 4.4 years, following a gluten-free diet for over 5 years, with which compliance was measured through assessment of antibody levels, BMD measurements of patients (lumbar spine: 1.131 +/- 0.121 g/cm2, total body: 1.145 +/- 0.184 g/cm2) did not differ from controls (lumbar spine: 1.131 +/- 0.184 g/cm2, total body: 1.159 +/- 0.118 g/cm2).

In a neutral-quality cross-sectional study in Italy by Corazza et al (1996) of 14 untreated subclinical patients and 10 untreated classical patients, lumbar spine BMD Z-scores were significantly higher in the subclinical group than classical group (-1.3 +/- 0.8 vs –2.6 +/- 0.6, p < 0.001), but significantly lower than in healthy controls (+0.4 +/- 1.1, p < 0.001).

In a neutral quality cross-sectional study by Walters et al (1995) of 44 British adults, recently diagnosed and untreated patients had reduced BMD in all regions (p < 0.001 for total body, lumbar spine and femoral neck, p < 0.01 for Ward’s triangle). In the celiac disease patients treated with gluten-free diet for at least 2 years, with which compliance was assessed through questionnaire, overall mean values for age-adjusted BMD Z scores were normal although there were many patients with low values in the lumbar spine and total body.

In a neutral-quality cross-sectional study by Corazza et al (1995) of 17 Italian adults with untreated celiac disease and 14 adults following a gluten-free diet without supplementation for a median duration of 28.5 months, with compliance judged by a dietitian and post-treatment biopsies, total body mean BMD Z-scores were significantly lower both in untreated and treated patients with celiac disease (-2.1 +/- 0.9 and –1.5 +/- 0.6, respectively, P < 0.05) than in controls (0.2 +/- 0.6) and significantly higher in treated than untreated patients (P < 0.05). In the untreated patients, there was no significant correlation between BMD and age at diagnosis (r = 0.39), and in the treated patients, BMD did not correlate significantly with the duration in months of gluten-free diet (r = 0.10).

In a neutral-quality cross-sectional 28-year follow-up study in Ireland by O’Leary et al (2004) of 50 adults following a gluten-free diet, with which compliance was classified through interview, 50% were found to be fully compliant with the gluten-free diet, 18% partially compliant (<10 g gluten) and 32% were not adhering to the diet. Lumbar spine and femoral neck BMD was subnormal in 32% of subjects – 28.9% were osteopenic and 2.6% were osteoporotic.

Postmenopausal Women

Two cross-sectional studies discuss results found in postmenopausal women.

In a neutral-quality cross-sectional study by Pistorius et al (1995) of 135 adult female celiac patients in Kingston Upon Hull following a gluten-free diet for a median duration of 8 years, with which compliance was monitored through questionnaire, 58 (43%) reported that they had always adhered to a gluten-free diet, 17 (13%) usually adhered, and 6 (4%) never adhered. In celiac patients, BMD was significantly lower at the lumbar spine that in controls (1.076 +/- 0.186 vs 1.155 +/- 0.143 g/cm2, p < 0.001) and also at the femoral neck (0.887 +/- 0.142 vs 0.965 +/- 0.127 g/cm2, p < 0.001). When the celiac patients were stratified by menopausal status, it was found that postmenopausal patients (n = 29) had significantly lower spinal BMD than controls (0.924 +/- 0.14 vs 1.129 +/- 0.70 g/cm2, p < 0.001) and femoral neck BMD also (0.785+/- 0.72 vs 0.885 +/- 0.55 g/cm2, p < 0.001). Premenopausal patients (n = 52) did not show significantly different spinal BMD compared to controls, but at the femoral neck, differences were significant (0.943 +/- 0.129 vs 1.010 +/- 0.114 g/cm2, p < 0.01). However, the age at diagnosis of celiac disease and adherence to a gluten-free diet did not exert a significant influence on BMD on either hip or spine; the authors noted that the number of non-adherers was small.

In the aforementioned neutral-quality cross-sectional study by Walters et al (1995), significantly lower Z scores for total body and lumbar spine were found in the postmenopausal patients compared to the premenopausal patients (p = 0.02 and p = 0.03, respectively).

Summary of research regarding the effectiveness of a gluten-free dietary pattern on bone density

listed in order of class and rating

Author/Year

Rating

Study Type

Location

Intervention

Population

Outcomes

Limitations

Sategna-Guidetti et al, 2000 C, + Nonrandomized Clinical Trial Italy 1 year of GFD without supplementation 72 newly diagnosed adults with celiac disease Treatment led to significant improvement of lumbar spine and femoral neck mean BMD values (from 0.886 +/- 0.15 to 0.933 +/- 0.14 g/cm2, P < 0.0001, and from 0.754 +/- 0.21 to 0.813 +/- 0.15 g/cm2, P = 0.0009, respectively). BMD in the lumbar spine was 0.940 +/- 0.118 g/cm2 for premenopausal vs 0.670 +/- 0.104 g/cm2 for postmenopausal, P < 0.0001; BMD in the femoral neck was 0.783 +/- 0.121 g/cm2 for premenopausal vs 0.621 +/- 0.118 g/cm2 for postmenopausal, P = 0.001. None.
Valdimarsson et al, 1996 C, + Nonrandomized Clinical Trial Sweden 1 year of GFD with calcium and vitamin D supplementation 63 adults Age-adjusted BMD at diagnosis was reduced at the forearm, lumbar spine, femoral neck and trochanter (p < 0.001). After treatment, BMD increased at all sites (P < 0.01), but was still reduced at all sites by the end of the year (p < 0.05). Some patients given calcium and vitamin D supplementation.
McFarlane et al, 1995 C, + Nonrandomized Clinical Trial United Kingdom GFD for a duration of 0.3 – 40 years 55 adults No overall loss of bone was shown over the 12 months of follow-up, and relative to the reference population there was significant improvement in BMD at the lumbar spine in women (p < 0.025) and at the femoral neck in men (p < 0.05). No significant difference between premenopausal, perimenopausal or postmenopausal women at either the lumbar spine or the femoral neck was found; some of the women studied were or had been on hormone replacement therapy for more than 1 year. Some of the patients had been on a GFD for less than 1 year.
Ciacci et al, 1997 C, + Nonrandomized Clinical Trial Italy Calcium-rich GFD for 12.3 +/- 0.8 months 41 adults Post-treatment BMD was greater than pretreatment BMD at the lumbar spine (0.907 +/- 0.028 and 0.795 +/- 0.028 g/cm2, respectively, p < 0.001), the femoral neck (0.818 +/- 0.023 and 0.741 +/- 0.030 g/cm2, respectively, p = 0.002), and the Ward’s triangle (0.703 +/- 0.025 and 0.654 +/- 0.025 g/cm2, respectively, p < 0.001). None.
Kalayci et al, 2001 C, + Nonrandomized Clinical Trial Turkey Followers had been on GFD for a mean duration of 40.4 months (3.4 years). Recently diagnosed followed GFD for 1 year without calcium or vitamin supplementation 16 recently diagnosed children and adolescents, mean age 10.6 years, and 16 strict GFD followers, mean age 11.5 years After treatment, Z scores improved in the recently diagnosed patients from –1.55 +/- 1.36 at baseline to –0.38 +/- 1.19, p = 0.041; and in the strict diet followers from –0.67 +/- 0.85 at baseline to –0.37 +/- 0.98, p = 0.011. None.
Rea et al, 1996 C, + Nonrandomized Clinical Trial Italy GFD and vitamin D supplementation for 1 year 23 celiac children Forearm BMC Z scores improved from –0.76 +/- 0.3 at diagnosis to –0.05 +/- 0.1, P = 0.007, which was not statistically different from controls (0.28 +/- 0.2). Authors note that small sample size and lack of homogeneity in subject age may affect study results.
Mora et al, 2001 C, + Nonrandomized Clinical Trial Italy 1.1 +/- 0.3 years and 4.3 +/- 0.6 years of gluten free diet without supplementation 19 children and adolescents with celiac disease, mean age 14.2 +/- 2.6 years Spinal BMD and BMC and total-body BMD and BMC at the time of diagnosis were lower than controls (P = 0.03 and P = 0.04, respectively) but after GFD, spinal and total-body values did not differ from controls. None.
Pazianas et al, 2005 C, + Case-Control Study United States Subjects with celiac disease had been following a GFD for over 4 years. 24 adult females with celiac disease were compared with 20 age- and sex-matched healthy controls. Whole body, spine and trochanter bone mineral density were significantly lower in treated celiac patients compared with controls (P < 0.05). After adjusting for calcium intake, the estimated amount of daily calcium absorbed was similar in both groups. None.
Viljamaa et al, 2005 C, ø Case-Control Study Finland Treated patients had followed a GFD for a median of 14 years. 96% of screen-detected and 93% of symptom-detected celiac patients adhered to a strict or fairly strict GFD. 53 screen-detected celiac patients, 44 symptom-detected treated celiac patients, 54 untreated celiac patients, 110 non-celiac subjects and 2060 subjects from the general population. Bone mineral density was found to be similar to that in the general population. Recruitment methods and inclusion/exclusion criteria not well defined for control subjects. Groups similar in age but not in gender.
Valdimarsson et al, 2000 C, ø Nonrandomized Clinical Trial Sweden GFD for 3 years with calcium and vitamin D supplementation 105 adults newly diagnosed with celiac disease Initial age-adjusted BMD was reduced at all sites in patients with untreated celiac disease compared to controls (median BMD Z scores of –0.79, -0.72 and –0.88 for hip, spine and distal forearm, respectively, P < 0.001). After 3 years of GFD, median BMD Z scores increased to –0.57, -0.15 and –0.60 for hip, spine and distal forearm, respectively (P< 0.001). Compliance not monitored.
Carbone et al, 2003 C, ø Nonrandomized Clinical Trial Italy 11 of these patients had returned for follow-up after following a GFD without supplementation for 4 years 48 adolescents with celiac disease, aged 14.5 +/- 2.8 years After GFD, body compartments of celiac patients had normalized, with the exception of weight and fat-free mass which remained lower than controls (BMC of patients: 2917 +/- 1479 g vs 2548 +/- 252 g of controls, NS; BMD of patients: 1.131 +/- 0.087 g/cm2 vs 1.129 +/- 0.08 g/cm2 of controls, NS). Poor compliance with diet noted. Small number of subjects returning for follow-up after 4 years.
Bai et al, 1997 C, ø Nonrandomized Clinical Trial Argentina GFD without supplementation for a mean duration of 38 months (3.2 years 45 adults with newly diagnosed celiac disease GFD produced a highly significant bone remineralization in the lumbar spine measured as both absolute values and Z score (P < 0.0001). A greater mean annual Z score change in the total skeleton was noted in subjects who were fully compliant compared to partially compliant, but this difference was not statistically significant (0.4 +/- 0.1 vs 0.3 +/- 0.1). Premenopausal women had significantly higher remineralization than post-menopausals (P < 0.05). Only 25 out of 45 returned for follow-up.
Kemppainen et al, 1999 C, ø Nonrandomized Clinical Trial Finland Compliance with GFD was 96% at 1 year and 82% at 5 years 27 adults with newly diagnosed celiac disease on a GFD at 1 year and 22 adults at 5 years In women, lumbar spine BMD values were significantly increased at 1 year (p < 0.001) but not 5 years; femoral neck BMD values were not significantly increased at 1 or 5 years; trochanter BMD values were significantly increased at 1 year (p < 0.05) and 5 years (p < 0.05); and Wards’ triangle BMD values were significantly increased at 1 year (p < 0.001) but not at 5 years. In men, lumbar spine and femoral neck BMD values were not significantly increased at 1 or 5 years; trochanter BMD values significantly increased at 5 years (p < 0.05) but not 1 year; and Wards’ triangle BMD values were significantly increased at 1 year (p < 0.05) but not at 5 years. Subjects with villous atrophy were non-compliant with diet. After 5 years, only 79% of subjects remained enrolled in study.
Mora et al, 1998 C, ø Nonrandomized Clinical Trial Italy 1.4 +/- 0.4 years of GFD without supplementation 25 children and adolescents aged 2.58 – 20.42 years at diagnosis Mean lumbar spine BMD was 0.708 +/- 0.034 g/cm2 and mean whole-body BMD was 0.875 +/- 0.020 g/cm2, both significantly lower than in controls (P = 0.015 and P = 0.0001, respectively). However, after treatment, lumbar spine and whole-body BMD values were not significantly different from controls. Sample may not have been representative of population.
Tau et al, 2006 C, ø Longitudinal Study Argentina GFD for a mean of 1.17 +/- 0.93 years (range 3 months - 3.9 years) and 1000 IU per day of vitamin D for the first 3 months of treatment but no calcium supplementation. 24 children, mean age 4.9 +/- 4.3 years Height and weight increased significantly after GFD (P < 0.001) and the increase correlated positively with the increase in bone mineral density (0.46 +/- 0.13 to 0.55 +/- 0.13 g/cm2, P < 0.001). Dietary compliance not described, some subjects had only been on diet for 3 months. Authors note limitation of small number of subjects, lack of local normal BMD values and variation in final follow-up time points.
Barera et al, 2004 C, ø Nonrandomized Clinical Trial Italy 1 year of GFD without supplementation, 22 children with celiac disease aged 10.5 +/- 1.0 year at time of diagnosis BMC was significantly lower than that of healthy controls at the time of diagnosis but not after 1 year of treatment (spine BMC: 18.9 +/- 2.3 g at diagnosis vs 23.2 +/- 2.6 g after 1 year, compared to 29.6 +/- 1.3 g of controls, P = 0.032; total body BMC: 1179.5 +/- 107.2 g at diagnosis vs 1421.6 +/- 114.9 g after 1 year, compared to 1727.0 +/- 64.1 g of controls, P = 0.03). GFD not defined, compliance not monitored. Certain outcome variables not reported.
McFarlane et al, 1996 C, ø Nonrandomized Clinical Trial United Kingdom GFD without supplementation for 1 year 21 adults Patients had a significant gain in BMD at lumbar spine (0.047 g/cm2/year, p < 0.001) and femoral neck (0.033 g/cm2/year, p < 0.002). However, despite improvement in BMD, it was still significantly lower in patients compared to controls after 1 year at lumbar spine (0.863 vs 1.014 g/cm2, p < 0.001) and at femoral neck (0.693 vs 0.799 g/cm2, p < 0.002). Dietary compliance questioned.
Molteni et al, 1995 C, ø Nonrandomized Clinical Trial Italy 1 year of GFD 18 women, mean age 36.8 years Mean BMD of the forearm at diagnosis was significantly decreased compared with controls (p < 0.001), but did not increase significantly after treatment (573.5 +/- 98.89 vs 589.4 +/- 97.45 g/cm2). GFD not monitored.
Vazquez et al, 2000 D, + Cross-Sectional Study Argentina Untreated patients (n = 51), those following a strict GFD (n = 74) and those following a partial GFD (n = 40), without supplementation 165 patients with celiac disease, median age 40 years Untreated patients had lumbar spine and total skeleton BMD Z-scores of –1.3 and –2.0, respectively; partially compliant subjects had lumbar spine and total skeleton BMD Z-scores of –1.0 and –0.9, respectively; and fully compliant subjects had lumbar spine and total skeleton BMD Z-scores of –1.2 and –1.6, respectively. Data not available for all subjects.
Bardella et al, 2000 D, + Cross-Sectional Study Italy Strict GFD without supplementation for over 2 years 71 adults BMD in men and women was not significantly different than controls (for men: 1.1 +/- 0.07 vs 1.2 +/- 0.12 g/cm2, for women: 1.03 +/- 0.06 vs 1.1 +/- 0.09 g/cm2). However, when the BMD values of the groups of patients whose disease was diagnosed in either childhood (1.1 +/- 0.06 g/cm2) or adulthood (0.9 +/- 0.09 g/cm2) were considered separately, the BMD of the latter group was significantly lower than the control group value of 1.1 +/- 0.09 g/cm2 (P < 0.01). Author notes that observed differences in anthropometric measurements and body composition seem to be justified by lower daily energy intakes of celiac disease patients.
De Lorenzo et al, 1999 D, + Cross-Sectional Study Italy 28 were considered fully compliant and 15 were considered partially compliant with GFD for more than 1 year. 43 adolescents with celiac disease, mean age 12 +/- 2.4 years The values of BMC and BMD at the lumbar spine and total skeleton were significantly lower in celiac patients than in age-matched controls (p < 0.001). 18 (42%) patients with longer symptomatic periods before diagnosis presented the most significant reduction in bone mass (-23% compared with normal controls, p < 0.001). No significant difference was found between patients strictly adherent to a GFD and patients partially compliant. None.
Sdepanian et al, 2003 D, + Cross-Sectional Study Brazil GFD for at least 1 year without supplementation 30 children and adolescents, children aged 6 – 9 years and adolescents aged 13 – 16 years Mean lumbar spine BMD in adolescents was significantly lower than controls (0.917 +/- 0.116 g/cm2 vs 1.060 +/- 0.158 g/cm2, P = 0.015), whereas no significant difference was found between children and controls (P = 0.595). None.
Mora et al, 1999 D, + Cross-Sectional Study Italy GFD for over 5 years 30 young adults, mean age 21.9 +/- 4.4 years BMD measurements of patients (lumbar spine: 1.131 +/- 0.121 g/cm2, total body: 1.145 +/- 0.184 g/cm2) did not differ from controls (lumbar spine: 1.131 +/- 0.184 g/cm2, total body: 1.159 +/- 0.118 g/cm2). None.
Pistorius et al, 1995 D, ø Cross-Sectional Study Kingston Upon Hull GFD for a median duration of 8 years. 58 (43%) reported that they had always adhered to a GFD, 17 (13%) usually adhered, and 6 (4%) never adhered. 135 adult female celiac patients Postmenopausal patients (n = 29) had significantly lower spinal BMD than controls (0.924 +/- 0.14 vs 1.129 +/- 0.70 g/cm2, p < 0.001) and femoral neck BMD also (0.785+/- 0.72 vs 0.885 +/- 0.55 g/cm2, p < 0.001). Premenopausal patients (n = 52) did not show significantly different spinal BMD compared to controls, but at the femoral neck, differences were significant (0.943 +/- 0.129 vs 1.010 +/- 0.114 g/cm2, p < 0.01). 60% response rate. Relationships between adherence and bone density were not investigated.
Szathmari et al, 2001 D, ø Cross-Sectional Study Hungary GFD without supplementation for at least 3 years 91 children and adolescents, mean age 11.7 years Radius midshaft mean BMC Z-score value in the female adolescent group only was significantly lower than normal (mean Z-score –1.04, P < 0.01). In contrast, the radius midshaft mean BMD Z-score was significantly higher compared to a healthy population in both girls (mean Z-score +1.36, P < 0.001) and boys (mean Z-score +1.01, P < 0.001). Controls and their measurements not well described.
Scotta et al, 1997 D, ø Cross-Sectional Study Italy GFD without supplementation for differing durations of less than 1 year, 1-2 years or over 2 years 66 children, mean age 117 months (9.75 years) Spine BMD values in late diagnosed celiac patients who had been on the diet less than 1 year were significantly lower than those on the diet for more than 2 years (0.676 +/- 0.096 vs 0.751 +/- 0.078 g/cm2, p < 0.01). No significant difference appeared between celiac patients on medium and long-term GFDs. All short-term GFD subjects were also late diagnosed subjects. Compliance methodology not described.
Kavak et al, 2003 D, ø Cross-Sectional Study Turkey GFD and no supplementation for 1 year 34 untreated children and 28 treated children with celiac disease Mean values of lumbar spine BMD and BMC of untreated patients were significantly lower than controls (BMD: 0.447 +/- 0.144 vs 0.537 +/- 0.080 g/cm2, p = 0.006 and BMC: 14.80 +/- 9.69 vs 21.02 +/- 4.14 g, p = 0.005). Treated patients had mean BMD and BMC values not significantly different than controls (BMD: 0.520 +/- 0.112 g/cm2 and BMC: 18.89 +/- 10.79 g). Results would have been more meaningful if same subjects measured at diagnosis had been followed for 1 year.
O'Leary et al, 2004 D, ø Cro


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