Evidence indicates a well-established relationship between low bone mineral density (BMD) and celiac disease (CD), but data on the pathogenesis of bone derangement in this setting are still inconclusive. In patients with symptomatic CD, low BMD appears to be directly related to the intestinal malabsorption. Adherence to a strict gluten-free diet (GFD) will reverse the histological changes in the intestine and also the biochemical evidence of calcium malabsorption, resulting in rapid increase of BMD. Nevertheless, GFD improves BMD but does not normalize it in all patients, even after the recovery of intestinal mucosa. Other mechanisms of bone injury than calcium and vitamin D malabsorption are thought to be involved, such as proinflammatory cytokines, parathyroid function abnormalities, and misbalanced bone remodeling factors, most of all represented by the receptor activator of nuclear factor B/receptor activator of nuclear factor B-ligand/osteoprotegerin system. By means of dual-energy X-ray absorptiometry (DXA), it is now rapid and easy to obtain semiquantitative values of BMD. However, the question is still open about who and when submit to DXA evaluation in CD, in order to estimate risk of fractures. Furthermore, additional information on the role of nutritional supplements and alternative therapies is needed.
Since 1980s, the most widely used tool in osteoporosis detection, treatment, and follow-up has been dual-energy X-ray absorptiometry (DXA) which showed a strong correlation between detection of bone mineral density (BMD) and fracture risk. Other procedures used to assess BMD include dual-photon absorptiometry (DPA), quantitative computed tomography (QTC), and ultrasound [
Several studies evaluated bone status in celiac disease (CD), both at diagnosis and after gluten-free diet (GFD), and to date, it has been recognized that bone involvement may be a frequent finding during CD. Nevertheless, studies focusing on the prevalence of bone derangement in celiac patients are still inconclusive since both old and recent findings fall in a wide range ([
Prevalence of low bone mineral density in patients with celiac disease as assessed by dual-energy X-ray absorptiometry scan at spine.
Authors | Patients characteristics | Low BMD |
---|---|---|
*McFarlane et al., 1995 [ | No. 65, on GFD | 47% |
Walters et al., 1995 [ | No. 34, on GFD | 38% |
Valdimarsson et al., 1996 [ | No. 63, untreated | 38% |
Bai et al., 1997 [ | No. 25, untreated | 72% |
*Kemppainen et al., 1999 [ | No. 77, on GFD and untreated | 26% |
Sategna-Guidetti et al., 2000 [ | No. 86, untreated | 66% |
Meyer et al., 2001 [ | No. 128, on GFD and untreated | 72% |
Motta et al., 2009 [ | No. 31, on GFD | 9% |
Vilppula et al., 2011 [ | No. 35, untreated | 62% |
BMD: bone mineral density; GFD: gluten-free diet.
*Established as osteoporosis.
On the other hand, the prevalence of CD in idiopathic osteoporotic patients has been investigated in many studies, but controversy still does exist about the value of screening for CD in this setting. Duerksen and Leslie [
Prevalence of positive serology for celiac disease in patients with low bone mineral density.
Authors | Positive serology for celiac disease |
---|---|
Lindh et al., 1992 [ | 11 out of 92 (12%) |
Mather et al., 2001 [ | 7 out of 96 (7.3%) |
Stenson et al., 2005 [ | 12 out of 266 (4.5%) |
Karakan et al., 2007 [ | 13 out of 135 (9.6%) |
Individual’s gender, constitution, and age as well as variations in endocrine systems associated with factors such as menopause and presence of comorbidities can all interact with lifestyle factors, including smoking, lack of exercise, and low dietary calcium intake to determine the onset of osteoporosis [
Bone is a dynamic tissue continuously renewed in a process called bone remodeling which is highly regulated by means of a complicated mechanism. However, the peculiar molecular pathways that control its initiation, progression, and cessation remain poorly understood. A leading role relies on two types of cells: osteoclasts, which are differentiated monocyte-derived cells involved in the removal of bone matrix, and osteoblasts, which derive from mesenchymal stem cells and are capable to form new bone. In the third decade of life, the process of bone resorption begins to exceed bone formation, and this fact leads to a progressive bone loss [
Nutrition plays an important role in bone homeostasis, providing the necessary substrates for the metabolic functions of bone tissue, most at all vitamin D and minerals. Vitamin D regulates intestinal calcium absorption by stimulating the formation of specific proteins that transport calcium through enterocytes, called calbindin and calcium-binding proteins. There are two forms of vitamin D: D3 (cholecalciferol) and D2 (ergocalciferol). Both forms are biologically activated in humans by hydroxylation first in the liver, to form 25-hydroxyvitamin D (25-[OH]D), and then in the kidneys, to form 1,25-dihydroxyvitamin D (1,25-[OH]2D). Even with low biological activity, 25-(OH)D is the main circulating form of vitamin D; therefore, blood 25-(OH)D concentrations are generally thought to reflect nutritional status regarding vitamin D. Furthermore, reduced calcium intake or malabsorption leads to increased parathyroid hormone (PTH) secretion which promotes bone turnover and cortical bone loss. PTH and 1,25-(OH)2D are linked in a series of coordinated activities to maintain normal serum calcium levels. When circulating calcium is reduced, the parathyroid glands increase the secretion of PTH, which in turn increases the circulating levels of 1,25-(OH)2D, by stimulating the renal hydroxylation of 25-(OH)D. This is the reason why increased 1,25-(OH)2D levels may be observed in CD [
The impact of nutrient malabsorption caused from untreated CD is well documented. In patients with symptomatic CD, the main cause of low BMD is related to the state of malabsorption. Impaired absorption of calcium during CD is thought to result principally from loss of villous in the proximal intestine, where calcium is most actively absorbed. Adherence to a strict GFD will reverse the histological damage in the intestinal mucosa and also the biochemical evidence of calcium malabsorption, as demonstrated with the use of strontium test by Molteni et al. [
It is well recognized that an excess of PTH can be associated with bone loss. Selby et al. [
On the other hand, Lemieux et al. [
Celiac males are also at greater risk of infertility and hypogonadism. In this case, CD patients are more likely to develop osteoporosis. On the other hand, hypogonadism in men may be often associated with hyperprolactinemia; thus, the occurrence of bone loss can be due to secondary increased levels of estrogens. Controversial opinions do exist about testosterone therapy in men for the prevention and treatment of osteoporosis. Nevertheless, it has been shown that men with osteoporosis and concomitant hypogonadism, as well as those with CD associated, may obtain beneficial effects from this treatment [
Recent studies showed that chronic release of proinflammatory cytokines, hormonal components, and other misbalanced bone remodeling factors can predispose celiac patients, either or not on GFD, to mineral metabolism derangement. Fornari et al. [
Insights on the molecular mechanisms regulating osteoclast formation and activation progressed a lot in the past 15 years, with the identification of the receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B-ligand (RANK/RANKL) signaling system as well as the discovering of osteoprotegerin (OPG), a protein that appeared to protect from excessive bone reabsorption. Bone homeostasis is reached by a dynamic balance between bone reabsorbing activity performed by RANKL and the effects of its natural decoy receptor OPG. Fiore et al. [
In a brief paper by Riches et al. [
Naturally gluten-free products are often low in B vitamins, calcium, vitamin D, iron, zinc, magnesium, and fiber. On the other hand, few gluten-free products are enriched or fortified. Bardella et al. [
Kinsey et al. [
The real impact of vitamin D deficiency in CD is not well established at date. While Bai et al. [
During childhood and early adulthood, bone formation generally equals bone resorption, favouring the maintenance of a constant bone mass. The most rapid gain in bone mass occurs during adolescence with bone mineral accretion accelerating dramatically along with the onset of puberty, while a less consistent fraction is subsequently acquired between the ages of 20 and 30 years. If normal peak bone mass is not achieved during those critical early years, subject is at higher risk for developing osteoporosis; thus, the amount of bone accrued during the pediatric years is an important predictor of an individual’s future resistance to fractures [
During childhood, villous atrophy due to mucosal damage sustained by CD impairs intestinal absorption of nutrients, including the amount of calcium needed for bone accruement. Abnormal bone formation in children is an important problem for paediatricians because skeletal derangement consequences on growth are often of great importance as well as irreversible. Tau et al. [
Recent data demonstrated that bone remodeling is under endocrine control; thus, a peculiar interest for pediatricians is represented by the role of hormones and specific growth factors in the mediation of bone turnover. Secondary hyperparathyroidism could be found also in celiac children in response to hypocalcemia. In a study by Zanchi et al. [
Another factor affecting bone remodeling in young celiac patients is the hormone leptin, the lack of which could be related to growth and puberty anomalies. Indeed, it is involved in a regulatory loop that appears to explain the protective effect of obesity on bone mass in humans. Leptinaemia levels were found to be low and to significantly increase after GFD in patients with severe intestinal atrophy [
Garrote et al. [
Monitoring dietary compliance is important to ensure appropriate bone mass accrual throughout childhood and puberty in CD patients. Adherence to a strict GFD worsens the already nutritionally unbalanced diet of adolescents, increasing elevated protein and lipid consumption despite a low carbohydrate intake [
Mechanisms involved in the pathogenesis of bone derangement in CD are reported in Figure
Mechanisms involved in the pathogenesis of bone derangement in celiac disease. GFD: gluten-free diet; IFN
Considering that an impaired bone mass is described in both symptomatic and asymptomatic CD patients, the question arises about which patients should undergo bone mass evaluation. Despite the high prevalence of bone demineralization in CD, there is still not a consensus about the timing to perform densitometric studies. In women, postmenopausal DXA is more sensitive for detecting osteoporosis, but it could lead to a delayed diagnosis in order to achieve a bone density gain with a proper treatment. At this regard, a screening DXA at diagnosis may detect an important bone involvement allowing an early management of the disease. However, Lewis and Scott [
According to some authors, the BMD screening question in CD patients must be addressed differently in childhood. Zanchi et al. [
An additional point to discuss refers to the method for assessing bone health in childhood. Indeed, there is a debate whether DXA is an appropriate tool for studying BMD in children. Gafni and Baron [
A special concern arises from the risk of fracture associated with bone demineralization in CD. Given that few studies addressed the actual fracture risk in this setting, the clinical impact of reduced BMD in CD is not well established. Furthermore, as assessed by Marshall et al. [
Sánchez et al. [
Risk of fracture in celiac disease.
Authors | Comments |
---|---|
Marshall et al., 1996 [ | DXA assessment does not accurately predict fracture risk |
Vestergaard and Mosekilde, 2002 [ | No differences before and after diagnosis of CD |
Thomason et al., 2003 [ | No difference in fracture history between CD and control patients |
Jafri et al., 2008 [ | Fracture risk is higher in CD patients, even on GFD |
Sanchez et al., 2011 [ | Fracture risk is comparable between CD and control patients |
DXA: dual-energy X-ray absorptiometry; CD: celiac disease; GFD: gluten-free diet.
On the basis of current data, a correct conclusion might be that an increased fracture risk in CD cannot be excluded, but the clinical impact of this occurrence is relatively minor in celiac patients considered as a whole population.
In children with CD, GFD is currently the first-choice therapy since it restores the intestinal malabsorption and therefore provides an improvement in bone mineralization process. This has been shown by Kavak et al. [
In CD patients diagnosed during adulthood, GFD is still considered to play a major role in bone health, even if it is not effective in completely reversing bone derangement by itself. McFarlane et al. [
Few studies tested calcium and vitamin D supplementation in adult celiac patients, and current data did not provide evidence for additional benefits to GFD. In some special situations, such as osteoporosis detected in celiac postmenopausal women, it could be useful to begin a treatment with hormone replacement therapy or bisphosphonates (antiresorption agents). In addition, education on the importance of lifestyle changes, such as regular exercise, smoking cessation, and excessive alcohol intake, should be provided [