Celiac Disease: A Bone Perspective

Osteoporosis is a global problem that is increasing in significance with the growing population of elderly people (1). Fractures represent the main clinical manifestation of osteoporosis and the main cause of morbidity and mortality. In the past, osteoporosis was regarded as a condition affecting only adults. With the advent of accurate noninvasive methods for bone mass quantification, it has been shown that the condition has its antecedents during childhood and adolescence. A variety of different techniques are available to assess the appendicular, axial, or entire skeleton (2). Technically, these methods do not measure directly the bone mass, but rather the bone mineral content or the bone mineral density of a specific site. Currently, the most commonly used quantitative method for studying bone mass is dual-energy x-ray absorptiometry (DEXA). Bone mineral measurements by DEXA rely on the attenuation (absorption) of energy that occurs as the x-ray beam scans across the region of interest (2). Two energy settings are used to optimize the separation of mineralized and soft tissue components in the area analyzed. DEXA bone determinations are based on a two-dimensional projection of a three-dimensional structure, and the values are a function of three skeletal parameters: the size of the bone being examined, the volume of the bone, and its mineral density. (2) These values are computed as bone mineral content (BMC). Scan radiographs provide only an approximation of the size of the bone, so BMC values are usually corrected for the projectional area of the bone, and are expressed as bone mineral content per surface area (g/cm2), a measure defined as bone mineral density (BMD). However, bone mineral measurements by DEXA are heavily influenced by the size of the bones analyzed and the amount of the surrounding soft tissue. These problems are particularly evident in pediatrics and when performing longitudinal studies (2). For these reasons, appropriate scan modes need to be used, and the influence of bone size on measurements has to be taken into consideration. Growth of the skeleton and increase of bone mass are achieved by the coordinated activity of two different bone cells: osteoblasts synthesize new bone matrix and thus promote bone formation, whereas osteoclasts are devoted to bone resorption. The coupled activity of these cells persists throughout life and during growth promotes the changes in length and shape of bones (bone modeling) (3). The bone metabolism rate can be precisely assessed by histomorphometry of the iliac crest, which represents the gold standard for estimating the status of bone turnover (4). However, bone biopsy is an invasive procedure that is not feasible for routine use in the evaluation of bone metabolism. More readily available to physicians are some biochemical tests performed on blood or urine samples that mirror the ongoing bone metabolic processes (5). These biochemical markers are based on the measurements of an enzymatic activity characteristic of the bone forming or resorbing cells, or the bone matrix components released into the circulation during bone apposition or resorption. The concentration of bone metabolism markers changes markedly during childhood and adolescence. Maximum concentrations are observed in infancy and during the pubertal period, when skeletal growth is more rapid (5). The amount of bone in the skeleton at any age is the result of the amount of bone gained during growth, starting from intra-uterine life, and the loss of bone that occurs with age. During childhood and adolescence, the bones grow in length and diameter, increasing remarkably the total bone mass. At the end of puberty, modeling ceases and the final bone mass reaches its peak (6). Peak bone mass (PBM) is regarded as the bone bank for the remainder of life: acquiring a good PBM contributes to counteracting the inevitable bone loss caused by aging, illness, and other insults. Many factors contribute to the achievement of peak bone mass (heredity, nutrition, exercise, environment, lifestyle), and consequently any condition that impairs the acquisition of an optimal PBM will result in an increased susceptibility for the development of osteoporosis and bone fragility (6). Secondary osteoporosis is a common finding in many pediatric disorders. Diseases of the gastrointestinal tract and disorders of nutrition often lead to the development of a impressive reduction of bone mass. The degree of bone mass depletion and its therapeutic approach vary depending on the primary disease. The involvement of bone in celiac disease has been known for a long time (7). The possibility of new techniques for the assessment of bone mineral and the discovery of the high frequency of celiac disease among the general population created a growing interest in the study of bone mass in young patients with celiac disease. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Kavak et al. (8) investigate the bone mineral density (BMD) of children with celiac disease. They measured BMD at the lumbar spine with DEXA in a group of young patients with untreated celiac disease and in another group of patients who have been on gluten-free diet for a year. Both groups of patients were compared with a small number of healthy subjects of comparable age. Bone density values were significantly lower in patients with newly diagnosed disease than in control subjects after controlling for confounding variables. Conversely, the BMD values of patients on a gluten-free diet were not different from those of healthy subjects. These results are in line with the findings of previous studies performed in different cohorts of children with celiac disease (9–17). Nevertheless, some important remarks can be made about the evidence accumulated. First, at diagnosis children with celiac disease have low bone mineral density. The degree of such depletion varies individually, but it is present regardless of the clinical presentation. Bone problems can be the first clinical sign of celiac disease. Second, it is clear that osteopenia (low bone density) is not influenced by different dietary and lifestyle habits. It has been reported in populations that differ markedly in nutrient intake, degree of physical activity, or sunlight exposure. Therefore, osteopenia seems to be related to the disease itself. Third, a gluten-free diet alone is able to restore the bone density of children with celiac disease. This finding contrasts with the conflicting results of diet on bone density in adults (the bone mineralization of adult patients often does not improve), and it is encouraging because it raises the possibility of achieving an optimal PBM at the end of the pubertal period. However, adherence to the diet must be strict. Patients who indulged in dietary derangement did not achieve normal PBM values (18). A question arises from these considerations: should bone densitometry be performed in every patient with newly diagnosed celiac disease, and more importantly, should such analysis be repeated during treatment? The evidence for a complete recovery after just 1 year of gluten-free diet would suggest the use of bone mass measurements be restricted to patients who are not compliant with the dietary treatment. Nevertheless, the difficulties in accurately determining compliance emphasize the need for periodic examinations of bone mineral status. Moreover, adolescent patients often refuse a strict diet, making them prone to the development of osteopenia. Another point in favor of the use of bone densitometry in patients with celiac disease is provided by the study of Kavak et al. (8). They measured serum concentrations of calcium, phosphate, alkaline phosphatase, 25-hydroxy-vitamin D, and parathyroid hormone. They report that none of their patients who experienced bone pain showed alterations in biochemical test results. They state that because a “patient's bone status cannot be predicted clinically,” bone densitometry becomes essential to assess bone health in children with celiac disease. An additional, but not alternative, way to monitor the bone status is the use of specific markers of bone metabolism. Changes of biochemical markers during treatment have been only minimally explored. They can be useful in observing the efficacy of the treatment, as demonstrated by a short longitudinal study (19). Serial measurements of bone formation and bone resorption markers may help to detect early impairment of bone metabolism that inevitably will lead to bone mineral deficit. The pathogenesis of osteopenia in children with celiac disease remains unclear. Malabsorption may be advocated as the primary cause of mineral deficit in children with celiac disease. Reduced calcium intake and impaired calcium absorption trigger events that lead to low bone mass. These events include hypersecretion of parathyroid hormone, enhanced 1,25-dyhydroxy-vitamin D, and decreased 25-hydroxy-vitamin D. However, the absence of hypocalcemia and the normal parathyroid concentrations found in patients in the study by Kavak et al. (8) seem to be in contrast to this hypothesis. In conclusion, the data available on bone mass in youth with celiac disease and here presented by Kavak et al. (8) clearly indicate that very low BMC and BMD values are always present in untreated patients. Dietary treatment initiated during childhood or adolescence is able to restore normal bone density. Evidence indicates that the achievement of normal bone mass depends on the patient age at the beginning of the gluten-free diet and adherence to the diet. Treatment rapidly normalizes bone metabolism. Because of the difficulties reported in achieving optimal bone mass in patients with celiac disease whose disease is diagnosed during adulthood, early diagnosis should be sought, even in patients with no symptoms.