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Bones in coeliac disease: diagnosis and treatment
Best Practice & Research Clinical Gastroenterology Vol. 19, No. 3, pp. 453–465, 2005 doi:10.1016/j.bpg.2005.01.002 available online at http://www.sciencedirect.com
12 Bones in coeliac disease: diagnosis and treatment Gino Roberto Corazza* Michele Di Stefano
MD
MD
Department of Medicine, University of Pavia, IRCCS “S.Matteo” Hospital, P.le C. Golgi 19, 27100 Pavia, Italy
Eduardo Maurin˜o
MD
Julio C. Bai* MD Department of Medicine, “Carlos Bonorino Udaondo” Gastroenterology Hospital, Univerdidad del Salvador, Av. Caseros 2061, (1264) Buenos Aires, Argentina Coeliac disease predisposes to metabolic osteopathy. The entity of bone loss is higher in patients with malabsorption at diagnosis but it is also present in asymptomatic or poorly symptomatic patients, occurring in roughly half of them. Calcium malabsorption and the release of proinflammatory cytokines, activating osteoclasts, represent the main mechanisms responsible for bone derangement. In coeliacs, the presence of an increased fracture risk was recently questioned and its importance on clinical grounds was reconsidered, in view of the fact that gluten-free diet generally improves bone mass and, consequently, reduces fracture risk. However, gluten-free diet rarely normalizes bone mass and the co-administration of mineral active drugs may be useful in a subgroup of coeliacs. Keywords: coeliac disease; bone mineral density; bone densitometry; gluten-free diet; osteopenia; osteoporosis.
Osteoporosis is ‘a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture’.1 That intestinal malabsorption may cause bone mass and mineral metabolism alteration and metabolic osteopathy in coeliac disease (CD) was recognized in the scientific literature almost 70 years ago. In several coeliac patients, marked bone deformities, rickets and fractures were described 2–4 whereas in more * Corresponding authors. Tel.: C39 382 502 973. E-mail address: [email protected] (G.R. Corazza). 1521-6918/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
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recent years the advent of non-invasive techniques such as bone densitometry, have made it possible to demonstrate that the vast majority of both adult and childhood coeliacs are affected by a loss of bone mass.5
PREVALENCE OF BONE DAMAGE Studies dealing with the prevalence of bone loss in CD should be considered with caution, as differences in terms of age of the population studied, duration of disease, diagnostic delay and skeletal site of measurement may affect the results. Several papers agree in reporting that more than 75% of untreated adult coeliacs suffer from a loss of bone mass.6–12 Therefore, CD should be considered one of the most frequent predisposing conditions to metabolic osteopathy. The presence of an overt malabsorption leads to greater bone loss, but even in patients with subclinical CD, diagnosed because of minimal, transient or apparently unrelated symptoms 6,12 or asymptomatic patients diagnosed because of their first degree kinship,7 bone mineral density is significantly lower than in healthy volunteers. Patients on gluten-free diet 6,7,10,13–16 show a lower prevalence of bone loss suggesting that in a number of patients dietary therapy may normalize bone mineral density. Longitudinal studies confirm 6,9,11,17–19 this trend. The prevalence of bone loss after one year of gluten-free diet 6,17 is similar to the prevalence after three years 20 suggesting that the extent of bone mass gain in the first year of dietary treatment is indicative of the short-term bone mineral density improvement. It is not yet completely clear why a subgroup of patients respond only marginally to gluten-free diet. Practice points † bone loss is extremely frequent in coeliacs † patients with overt malabsorption show a more severe bone mass derangement than patients with subclinical disease † gluten-free diet improves bone mineral density but does not normalize it in all patients PATHOPHYSIOLOGICAL ASPECTS The pathogenesis of bone damage in CD is multifactorial and both systemic and local mechanisms may play a role. Intestinal malabsorption secondary to mucosal lesions leads to calcium malabsorption and subnormal levels of serum calcium.8,21 In fact, studies that evaluated calcium absorption in CD have confirmed the importance of this pathophysiological step.21–23 Moreover, several other mechanism may contribute to render calcium unavailable for intestinal absorption, such as a decreased dietary calcium intake secondary to concomitant lactase deficiency,24,25 precipitation of endogenous calcium in the intestinal lumen as calcium soaps,26 increased intestinal secretion 22 or decreased reabsorption.27 The subsequent pathogenetic step is represented by the hypersecretion of parathyroid hormone (PTH), as a response to hypocalcemia.6–8,10,11,28 PTH promotes
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bone resorption and contributes to the increased activity of the renal enzyme 1-ahydroxylase, which converts 25-vitamin D into 1,25-vitamin D:6,8,10,17 this step aims to allow an increased intestinal absorption of calcium through an increased vitamin D-dependent active transport. However, even if enterocytes express a normal number of vitamin D receptors,29 they contain negligible amounts of vitamin D-dependent calcium binding protein (calbindin)30 due to their immaturity, making this effort ineffective. Moreover, high levels of 1,25-vitamin D may, paradoxically, have a negative effect at bone level, being themselves a cause of bone resorption.31 The evaluation of serum markers of bone remodelling shows that metabolic osteopathy of CD is characterized by an enhancement of the markers of both bone synthesis (osteocalcin, propeptide of type I procollagen, bone-specific alkaline posphatase) and resorption (telopeptide of type I collagen, urinary crosslinks, urinary hydroxyproline). However, bone resorption is faster than bone neoformation, resulting in a net bone loss.6,8,10,17 The increase in serum PTH is responsible for this acceleration of bone turnover, as demonstrated by the significant correlation between PTH and osteocalcin and PTH and telopeptide of type I collagen.8 Bone derangement in CD should, therefore, be considered a high turnover osteoporosis, as increased resorption is not balanced by enhanced neoformation. Recently, local mechanisms of bone derangement have received attention. In particular, inflammatory and immunological alterations, by means of cytokine production, may contribute to bone mass reduction. Cytokines are involved in the mechanisms of cell-to-cell communication and some of them are implicated in both normal and abnormal bone remodeling.32,33 Production of proinflammatory cytokines, such as IL-1, IL-6, TNF-a, has been detected in the intestinal mucosa of coeliacs 34 and increased serum levels of these cytokines (IL-1, IL-6) have also been observed.35,36 IL-1 and IL-6 proved to have a role in the activation of bone cells.33 IL-6 plays an important role in bone resorption through the recruitment of osteoclast precursors in blood and the induction of their differentiation and functioning, resulting in an increased osteoclast activity.37,38 It is therefore an interesting point that in untreated coeliacs serum IL-6 correlates inversely with lumbar BMD values 35 and directly with serum parathyroid hormone and telopeptide of type I collagen levels.36 Very recently 39 bone loss in CD was shown to be also caused by a cytokine imbalance directly affecting osteoclastogenesis and osteoblast activity. The incubation of peripheral blood mononuclear cells of healthy donors with sera of untreated coeliacs resulted in a persistently increased osteoclast number, significantly higher than that obtained after incubation with sera of patients on gluten-free diet and with sera of healthy volunteers. This finding was associated with increased levels of IL-6. Moreover, a role of inhibitory cytokines, such as IL-12 and IL-18 was hypothesized since low levels of this cytokines were also found.39 In fact, low serum levels of IL-12 and IL-18 suggest the presence of an inhibition of their release and the lack of their inhibitory effect on osteoclastogenesis 40,41 may play a pathogenetic role. The RANKL/RANK/Osteoprotegerin (OPG) pathway is now considered the most potent regulatory system, coupling osteoclast and osteoblast activities.42 OPG is a regulatory protein with an inhibitory effect on osteoclast differentiation and activity.43,44 Its function is carried out through its link with its ligand, RANKL, whose main role in bone is the stimulation of osteoclast differentiation,45,46 activity,46 and inhibition of osteoclast apoptosis.47 The receptor for OPG/RANKL complex was identified in RANK.48 Knowledge of the activity at bone level of this complex system made it possible to understand the precise mechanism by which preosteoblastic/stromal cells control osteoclast development. Bone is constantly resorbed and formed at specific
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sites in the skeleton, known as basic multicellular units. The process begins by migration of osteoclast to these sites (activation), resorption of a portion of bone by these cells, a reversal phase characterized by apoptosis of the osteoclasts, followed by a phase of bone formation by newly formed osteoblasts. The critical, initial step in this process is the development of osteoclasts and is under the control of preosteoblastic/stromal cells, in order to ensure the coupling of the bone resorption and formation process, maintaining skeletal integrity. RANKL, expressed on the surface of preosteoblastic/stromal cells, binds to RANK on the osteoclastic precursor cells. RANKL is critical for the differentiation, fusion into multinucleated cells, activation and survival of osteoclastic cells. On the contrary, OPG inhibits the system by blocking the effect of RANKL. An increased RANKL/OPG ratio was found in untreated coeliacs.39 In female coeliacs the role of associated gynaecological disorders should also be considered. Amenorrhoea is a frequent finding in female coeliacs 49 and sex hormone imbalance represents an important pathogenetic factor for osteoporosis development.50 In male coeliacs, a peripheral resistance to testosterone activity was described 51 but no correlation between testosterone and bone mass and mineral metabolism was found.36 Another intriguing observation is represented by the detection of bone-specific antibodies in sera from coeliacs.52 Around one half of untreated coeliacs have antibodies that recognize antigenic structures in chondrocytes and the extracellular matrix along mature cartilage, bone interface and perichondrium of fetal rat bone. These antibodies localize in areas where an active mineralization process has occurred and the distribution of these areas is similar to the distribution of native bone transglutaminase. These results suggest that bone-specific antibodies might be at least a co-factor in the pathophysiology of CD-associated bone damage. Practice points † the pathogenesis of bone loss depends on both systemic and local factors † calcium malabsorption has a pivotal role to induce a complex network of events leading to bone demineralization † production of proinflammatory cytokines, responsible for osteoclast activation, is the key point for a local-acting mechanism † bone derangement in coeliacs should be considered as a high turnover osteoporosis as increased resorption is not compensated by enhanced neoformation
CLINICAL ASPECTS The diagnostic accuracy of symptoms related to the presence of bone damage in CD is very poor. In fact, in the absence of clinical symptoms or signs, a significant bone defect may be present in subclinical patients or even in patients diagnosed during screening programs.6,7 Therefore, to diagnose metabolic osteopathy in CD, a test which directly measures bone mineral density should be performed. The greater number of scientific publications in the last 15 years has demonstrated the increased interest in bone metabolic abnormalities of CD. These studies were performed by the use of an appropriate technology, allowing the quantitative measurement of bone impairment.
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In particular, bone densitometry by dual energy X-ray absorptiometry,53 a non-invasive and accurate test to evaluate bone mass, on one hand represented an important stimulus to the study of skeletal disorders, while on the other it provided a more accurate evaluation of fracture risk, certainly the main complication of bone loss on both clinical and economic grounds. Bone mass measurements may be expressed in two different ways: (a) Z score represents the number of standard deviations by which the patient value differs from the mean value of an age- and sex-matched reference population; this index reflects bone mass modifications in relation to the behaviour of such a reference population; in other words, considering the physiologic reduction of bone mass with advancing age, it shows whether the patient’s decline follows the average behaviour or is accelerated. (b) T score represents the number of standard deviations by which the patient value differs from the mean of a young adult reference population; this index, on the contrary, refers to the difference between patient value and the peak bone mass, which is the highest level that can be reached with height–weight growth, now considered the most important factor conditioning the onset of post-menopausal osteoporosis.50,54,55 Densitometric criteria for diagnosis of osteopenia are K2!Z score !K1 and K2.5!T score !K1; criteria for osteoporosis are Z score !K2 and T score !K2.5. It is known that the relative risk of fracture increases by a factor of about 2 for each SD decrease in BMD.56,57 However, bone density measurement does not seem to be a strong predictor of fracture in CD, as a wide overlap in bone mass levels is evident comparing individuals with and without fractures in this condition.58,59 Studies did not find any significant difference between mean T score or Z score of patients with and without a fracture history 59 and bone mineral density seems to be only one of several unknown factors in explaining the increased risk of fractures in coeliacs. It is, however, likely that among other possible factors playing a role in bone weakening affecting coeliacs we need to include to bone quality and strength (considering plasticity, fatigue and damage), the architectural design (spatial organization of bones), but also regional muscles and neuromuscular coordination. A recent paper 60 addressed this issue and showed that bone weakening in CD might result from both a metabolic disturbance of bone remodelling affecting trabecular and cortical bone mass and the mechanical quality of the bone material and a reduction of muscle strength impairing the modellingdependent optimization of bone architectural design and mass of cortical bone. The prevalence of osteoporotic fractures increases with age and women are more affected than men. Fractures occur in sites where trabecular bone predominates and are associated with minimal or moderate trauma. Although, as already stated, bone involvement in CD was first reported several years ago, the true clinical magnitude of the problem was ignored for a long time and epidemiological information on fractures in coeliacs has only recently been acquired. In a case-control, cross-sectional study 58 the occurrence of fractures in 165 treated coeliacs was analyzed by bone mineral density measurement, spinal X-ray and a retrospective historical review. Coeliacs diagnosed in a referral centre had a significantly increased prevalence of fractures in the peripheral skeleton (25% of cases) compared with sex- and age-matched healthy controls (8%). In contrast, the excess of fracture prevalence was not extended to the axial skeleton. Unfortunately, the reported prevalence was mainly established among patients diagnosed on the basis of the presence of malabsorption symptoms and, therefore, not representative of the whole CD population where the number of subclinical and silent patients may be 8–10 fold greater than the number of patients with malabsorption. To overcome this problem, a subsequent study analyzed the relationship between bone
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fractures and CD exploring a cohort of 148 consecutive patients, 53% of whom were patients with overt malabsorption and 47% subclinical or silent patients, compared with 296 healthy controls. This study showed that the prevalence of fractures in the peripheral skeleton was significantly higher in symptomatic coeliacs (42%) compared both with controls (14%) and subclinical/silent cases (20%). In this latter group the prevalence of fractures did not differ from that of healthy controls.59 A recent study on a small cohort of coeliacs failed to show abnormalities of serum parathyroid hormone, serum vitamin D or calcium intake as responsible for bone fractures.61 Two recent population-based reports showed a slight increase of fracture prevalence in coeliacs.62,63 The study from England showed an overall age and sex adjusted odds ratio of 1.05 (95% CI 0.66–2.25). A trend towards an increased risk, but not statistically significant, was shown for forearm and wrist fractures.62 A larger study from Denmark 63 showed incidence rate ratios of 1.15 (1.00–1.32) before diagnosis and 1.19 (1.06–1.33) after diagnosis of CD. Finally, a recent study by West et al 64 on more than 4700 coeliacs, extracted from the General Practice Research Database, showed that CD is associated with a small increase in the risk of fracture and suggested that concerns regarding a marked increase of fracture risk in CD are unwarranted. The results of these studies were recently criticized.65 In fact, the failure to demonstrate a significant increase of fracture risk may be due to limitations in the study design rather than to the true absence of association. The size of the study and the method used to diagnose fractures are pivotal factors, but even more important is the fracture rate in the control population. However, since an increased risk was shown in coeliacs with overt malabsorption and not in asymptomatic patients, apart from correct considerations regarding the difference in study design, the power of the study, the method of defining or diagnosing fractures, what probably affects the results of previous studies seems to be the composition of the various case studies, i.e. the actual number of subjects with overt malabsorption and, therefore, a higher risk of fracture. On the other hand, in the study by West et al,64 the slight overall increased risk of fractures in CD could also be explained on the basis of the presence of a higher number of underweight patients that together with a higher number of medical consultations in the CD group than in the control group suggest the presence of a high proportion of patients with overt malabsorption or more severe disease. In short, the importance of bone derangement in coeliacs has to date been attributed to the possible induction of an increased risk of fractures. While on one hand, several data suggest that this problem may be overestimated, on the other it is also true that osteoporosis, by itself, may represent a clinical and practical problem for patients. In post-menopausal osteoporosis, as expected, patients with fractures show a significantly reduced health-related quality of life than patients without fractures, but the mere presence of low values of bone mineral density induces a reduction of quality of life.66 Thus, even in absence of the extreme manifestation represented by the development of a fracture, bone loss interferes with health status in post-menopausal women. We have no data about health-related quality of life in coeliacs concerning the presence of osteoporosis or bone fractures, but we cannot avoid thinking that low bone mass may have similar consequences in these patients. In a recent paper,67 the level of physical activity was lower in symptomatic than in asymptomatic patients, suggesting that, in the subgroup exposed to a higher risk of bone damage, recreational
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activities are significantly reduced. Moreover, if we consider that most CD diagnoses are made in the 3rd–4th decade,68 the presence of low bone mass may assume greater importance as it affects the activities of daily living, causes bone pain and reduces physical functioning and mobility. Particularly in young subjects, this problem may induce a sense of inadequacy and be felt in a negative way, causing social isolation and depression. These considerations must, therefore, lead us to consider osteoporosis as a target for therapy to improve the quality of life, even in the absence of a definite increase in the risk of fracture. Practice Points † in adult patients on gluten-free diet since childhood, bone mineral density is normal † gluten-free diet improves but rarely normalizes bone mineral density in patients diagnosed in adulthood
BONE MASS MEASUREMENT: WHO, WHEN, WHY As far as the need to measure bone mineral density in coeliacs is concerned, several doubts are present. It is not clear which patients should undergo bone mass measurement, when the first and subsequent measurements should be performed, but also why measurement should be performed. A general agreement on the positive effect of the treatment with a gluten-free diet is evident, as reported by prospective studies. However, while treated patients increase bone mass significantly, such restoration rarely reaches sex- and age-matched values for the control population in patients diagnosed in adulthood.8,13,17 In contrast, there is evidence that very early treatment of CD in childhood prevents bone loss and most patients reach normal peak densitometric values.69 This discrepancy can be explained by the fact that bone loss may have both an irreversible component (disappearance of trabeculae and thinning of the cortex) and a reversible component (increased intracortical tunnelling, thinning of trabeculae). While late treatment (in adulthood) may revert only the reversible bone loss, there is evidence 70 that very early treatment, started during infancy, could prevent both the irreversible and reversible bone loss. Consequently, there is no need to perform bone mass measurement in children if fully compliant with gluten-free diet. The availability for adult patients of a treatment able to restore bone mineral density values at normal levels, like gluten-free diet for children, would allow the same statement to be made for adults. In the meantime, in coeliacs diagnosed in adulthood, a different approach according to clinical presentation should be followed. The presence of an overt malabsorption, but not of subclinical or silent disease, makes it possible to select a subgroup of patients at higher risk for osteoporosis and bone fractures.59 Consequently, in these patients bone mineral density measurement may be indicated at diagnosis in order to evaluate the need for co-administration of mineral-active drugs. The ability of the propeptide of type I procollagen to predict the bone mass gain after a two-year period of gluten-free diet 18 seems useful for this purpose.
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On the contrary, the presence of subclinical or silent disease could allow elimination of the need for bone measurement at diagnosis. On clinical grounds the evaluation of bone mass after the first year of strict adherence to gluten-free diet does in fact seem of much greater use: the decision to begin therapy with mineral-active drugs would thus be taken on the basis of dietary regimen efficacy. The lack of knowledge about the efficacy of mineral-active drugs in coeliacs does not make it possible to draw up a strategy for managing post-menopausal coeliacs. This subgroup has a higher risk of suffering from osteoporosis and bone mass measurement will, therefore, be more sensitive in detecting a bone defect. We have to consider that the efficacy of anti-resorptive therapy started later in life is lower than early treatment and screening at presentation allows diagnosis of bone loss at early stage. As the efficacy of mineral-active drug treatment on fracture risk is unknown in this subgroup of patients, it was suggested that bone mass should be measured at diagnosis, as patients will have suffered malabsorption for many years.71 Then, in a fully compliant patient, measurement should be repeated in the perimenopausal period and repeated after 18–24 months if normal. For men, an age cut-off of 55 years could represent a valid option.71 These guide-lines were recently criticized 64,65 and an approach based on bone mass measurement restricted to the minority of individuals in whom short term (5–10 years) fracture risk is high was suggested. Risk factors for fractures have not been specifically identified in CD, but are likely to include, in addition to noncompliance with gluten-free diet, failure to respond fully to a gluten-free diet, steroid treatment, untreated hypogonadism, age, low body mass index and previous fragility fracture.65 Once a diagnosis of osteoporosis has been made or if the specific treatment with a gluten-free diet is ineffective for promoting remineralization, additional secondary causes of osteoporosis (hypogonadism, thyroid dysfunction, hyperprolactinemia, medications [anticonvulsivants, corticosteroids]) should be ruled out. The role of lifestyle factors should be not underestimated in the prevention of osteoporosis: in a recent paper,67 sun exposure and prevalence of smokers were similar in symptomatic and asymptomatic coeliacs, but physical activity was significantly lower in symptomatic than asymptomatic patients. Patients should be encouraged to follow a calcium rich diet, to maintain a high level of exercise and to stop smoking.
Practice Points † in coeliacs with malabsorption symptoms bone mineral density should be measured at diagnosis and after a year of strict gluten-free diet. Then, mineralactive drugs should be associated with dietary treatment if bone mass gain is not satisfactory † in asymptomatic coeliacs bone mineral density should be measured after a year of strict gluten-free diet † CD women should undergo bone mineral density measurement in the perimenopausal period † coeliacs on gluten-free diet from childhood should not undergo bone mineral density measurement
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GLUTEN-FREE DIET: ALONE OR ASSOCIATED WITH MINERAL-ACTIVE DRUGS? Little attention has been dedicated to other therapy regimens in CD. In an early longitudinal study, the co-administration of 25-hydroxycholecalciferol did not induce any significant modifications in BMD of the distal two-thirds of the forearm after 12 months of GFD.72 Another study showed a significant improvement in BMD at all sites after a year of GFD, supplemented only in some patients with oral calcium and 25-hydroxycholecalciferol.11 The list of drugs for treatment of osteoporosis is growing and although they have been demonstrated to have a place in the treatment of postmenopausal osteoporosis there are no studies of comparability in coeliacs. We therefore have no information on which subgroup of patients should follow this therapeutic approach, nor on which is the best therapeutic strategy, in terms of drug, dosage and duration. It seems appropriate to prescribe an association with mineral-active drugs in cases presenting a severe densitometric alteration or when a past clinical history of osteoporotic fractures is reported. There is no agreement on the BMD treatment threshold and a Z-score value below K1 was suggested.71 As far as drug choice is concerned, hormone replacement therapy or bisphosphonates represent the best options for post-menopausal osteoporosis 73 and similarly, these two approaches seem the best options also for coeliacs. However, results from therapeutic trials are anxiously awaited in order to define precise guide-lines. Research agenda † the effect of mineral-active drugs on bone mineral density and fracture risk in adult coeliacs is not known † there is no agreement on the bone mineral density treatment threshold GENERAL RECOMMENDATIONS Osteoporosis is a complex chronic disorder that may progress without producing symptoms until a fracture occurs. Moreover, relatively few people are diagnosed in time for effective therapy to be administered. Diagnosis of CD gives an opportunity for suspicion of osteoporosis and, therefore, for preventive action. General advice to coeliacs in order to protect and maintain bone health is necessary. Among recommendations, explanations to the patient about the risk of osteoporosis, the necessity of strictly adhering to a gluten-free diet and the effect of treatment on bone remineralization in the event of established bone involvement are particularly important. Although all general measurements have proved to be effective in the general population and in postmenopausal osteoporosis, none of them have been proved in patients with CD. Education on the importance of lifestyle changes such as regular exercise and stopping smoking should be given. Regular calcium intake needs to be recommended (1.2 g/day for women), ideally through calcium-rich foods. If dietary calcium is insufficient, malabsorption is suspected or patients present low calcium serum levels, calcium supplementation is mandatory (1 g/day).
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Renal hyperconversion of 25-hydroxyvitamin D to 1,25-hydrohyvitamin D secondary to increased PTH levels 8 often make oral supplementation with Vitamin D unnecessary.
CONCLUSIONS Despite the more recent advents in the knowledge on CD osteopathy, the story is far from over. We now have information on the prevalence and how to diagnose and prevent the problem. We still need to improve our knowledge on the pathophysiological mechanisms, as the aspects connected with malabsorption must be associated with those linked to local factors. Bone mineral density measurement seems unnecessary in all patients, although a better evaluation of cost compared with benefits is required. Despite the fact that treatment seems to be largely dependent on gluten restriction from the diet, more information on therapeutic alternatives is needed.
SUMMARY Bone homeostasis is frequently affected in coeliac disease. More insight into the pathophysiology of bone damage will allow us to understand the relative importance of local and systemic factors, at present partially unknown. Diagnosis of metabolic osteopathy makes use of bone densitometry, but when to perform the measurement and which patients should undergo to measurement is a matter for discussion. A suitable strategy envisages bone mass measurement at diagnosis in symptomatic patients and, in fully compliant patients, a second measurement after one year of glutenfree diet. In asymptomatic patients, bone mass measurement may be delayed until after one year of gluten-free diet; women should be tested in the perimenopausal period. In childhood coeliac disease bone mass measurement seems of little use, since gluten-free diet normalizes bone mineral density. Doubts have been expressed as to the presence of an increased risk of bone fracture. Bone mineral density values do not discriminate between patients with and without fractures, suggesting that other parameters are also important in fracture occurrence, such as bone architectural modifications. Mineralactive drug co-administration may represent an effective measure, but no data are yet available on the effect on bone mineral density and fracture risk modification.
REFERENCES 1. Wood AJJ. Treatment of postmenopausal osteoporosis. N Engl J Med 1998; 336: 736–746. 2. Bennett TI, Hunter D & Vaugham JM. Idiopathic steatorrhea. A nutritional disturbance associated with tetany, osteomalacia and anaemia. Q J Med 1932; 1: 603–677. 3. Holms WH & Starr P. A nutritional disturbance in adults resembling coeliac disease and sprue: emaciation, anemia, tetany, chronic diarrhea and malabsorption of fat. JAMA 1929; 92: 975–980. 4. Salvesen HA & Boe J. Osteomalacia in sprue. Acta M Scand 1953; 146: 290–299. 5. Corazza GR, Di Stefano M & Veneto G. Bone and coeliac disease. In Auricchio S, Greco L, Maiuri L & Troncone R (eds.) Proceedings 8th International Symposium on Coeliac Disease. Naples, Italy; 1999, 1999, pp. 125–132.
Bones in coeliac disease: diagnosis and treatment 463 6. Corazza GR, Di Sario A, Cecchetti L et al. Influence of pattern of clinical presentation and of gluten-free diet on bone mass and metabolism in adult coeliac disease. Bone 1996; 18: 525–530. 7. Mazure R, Va´zquez H, Gonzalez D et al. Bone mineral affectation in asymptomatic adult patients with coeliac disease. Am J Gastroenterol 1994; 89: 2130–2134. 8. Corazza GR, Di Sario A, Cecchetti L et al. Bone mass and metabolism in patients with coeliac disease. Gastroenterology 1995; 109: 122–128. 9. McFarlane X, Bhalla AK & Robertson DAF. Effect of gluten-free diet on osteopenia in adults with newly diagnosed coeliac disease. Gut 1996; 39: 180–184. 10. Keaveny AP, Freaney R, McKenna MJ et al. Bone remodeling indices and secondary hyperparathyroidism in coeliac disease. Am J Gastroenterol 1996; 91: 1226–1231. 11. Valdimarsson T, Lofman O, Toss G & Strom M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996; 38: 322–327. 12. Mustalahti K, Collin P, Sieva¨nen H et al. Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet 1999; 354: 744–745. 13. Bode` S, Hassager C, Gudmand-Hoyer E & Christiansen C. Body composition and calcium metabolism in adult treated coeliac disease. Gut 1991; 32: 1342–1345. 14. Valdimarsson T, Toss G, Ross I et al. Bone mineral density in coeliac disease. Scand J Gastroenterol 1994; 29: 457–461. 15. Walters JRF, Banks LM, Butcher GP & Fowler CR. Detection of low bone mineral density by dual energy x ray absorptiometry in unsuspected suboptimally treated coeliac disease. Gut 1995; 37: 220. 16. Mc Farlane X, Bhalla AK, Reeves D et al. Osteoporosis in treated adults coeliac disease. Gut 1995; 36: 710–714. 17. Mautalen C, Gonzalez D, Mazure R et al. Effect of treatment on bone mass, mineral metabolism, and body composition in untreated coeliac disease patients. Am J Gastroenterol 1997; 92: 313–318. *18. Corazza GR, Di Stefano M, Jorizzo RA et al. Propeptide of type I procollagen is predictive of posttreatment bone mass gain in adult coeliac disease. Gastroenterology 1997; 113: 67–71. 19. Ciacci C, Maurelli L, Klain M et al. Effects of dietary treatment on bone mineral density in adults with coeliac disease: factors predicting response. Am J Gastroenterol 1997; 92: 992–996. *20. Bai JC, Gonzalez D, Mautalen C et al. Long-term effect of gluten restriction on bone mineral density of patients with coeliac disease. Aliment Pharmacol Ther 1997; 11: 157–164. 21. Ciacci C, Cirillo M, Mellone M et al. Hypocalciuria in overt and subclinical coeliac disease. Am J Gastroenterol 1995; 90: 1480–1484. 22. Harrison JE, Hitchman AJW, Finlay JM & McNeill KG. Calcium kinetic studies in patients with malabsorption syndrome. Gastroenterology 1969; 56: 751–757. 23. Molteni N, Bardella MT, Vezzoli G et al. Intestinal calcium absorption as shown by stable strontium test in coeliac disease before and after gluten-free diet. Am J Gastroenterol 1995; 90: 2025–2028. 24. Plotkin GR & Isselbacher KJ. Secondary disaccharidase deficiency in adult coeliac disease (nontropical sprue) and other malabsorption states. N Engl J Med 1964; 271: 1033–1037. 25. Di Stefano M, Veneto G, Malservisi S et al. Lactose malabsorption and intolerance and peak bone mass. Gastroenterology 2002; 122: 1793–1799. 26. Harris OD, Philip HM, Cooke WT & Power WFR. 47Ca studies in adult coeliac disease and other gastrointestinal conditions with particular reference to osteomalacia. Scand J Gastroenterol 1970; 5: 169–175. 27. Melvin KEW, Hepner GW, Bordier P et al. Calcium metabolism and bone pathology in adult coeliac disease. Q J Med 1970; 39: 83–113. 28. Caraceni MP, Molteni N, Bardella MT et al. Bone mineral density in adult coeliac disease. Am J Gastroenterol 1988; 83: 274–277. 29. Colston KW, McKay AG, Finlayson C et al. Localisation of vitamin D receptor in normal human duodenum and in patients with coeliac disease. Gut 1994; 35: 1219–1225. 30. Staun M & Jarnum S. Measurement of the 10.000-molecular weight calcium-binding protein in small intestinal biopsy specimens from patients with malabsorption syndrome. Scand J Gastroenterol 1988; 23: 827–832. 31. Maierhofer WJ, Gray RW, Cheung HS & Lemann Jr. J. Bone resorption stimulated by elevated serum levels of 1,25-(OH)2-vitamin D concentrations in healthy men. Kidney Int 1983; 24: 555–560. *32. Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem 1999; 45: 1353–1358.
464 G. R. Corazza et al 33. Goldring SR. Mechanisms of pathologic bone loss. Calcif Tissue Int 2003; 73: 97–100. 34. Kontakou M, Przemioslo RT, Sturgess RP et al. Expression of tumor necrosis factor-alpha, interleuchin-6 and interleukin-2 mRNA in the jejunum of patients with coeliac disease. Scand J Gastroentrol 1996; 30: 456–463. 35. Fornari MC, Pedreira S, Niveloni S et al. Pre- and post-treatment serum levels of cytokines IL-1b, IL-6 and IL-1 receptor antagonist in coeliac disease. Are they related to the associated osteopenia? Am J Gastroenterol 1998; 93: 413–418. 36. Di Stefano M, Sciarra G, Jorizzo RA et al. Local and gonadal factors in the pathogenesis of coeliac bone loss. Ital J Gastroenterol Hepatol 1997; 29(supplement 2): 31. *37. Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med 1988; 318: 818–828. 38. Devlin RD, Bone III. HG & Roodman GD. Interleukin-6: a potential mediator of the massive osteolysis in patients with Gorham-Stout disease. J Clin Endocrinol Metab 1996; 81: 1893–1897. 39. Taranta A, Fortunati D, Longo M et al. Imbalance of osteoclastogenesis-regulating factors in patients with coeliac disease. J Bone Miner Res 2004; 19: 1112–1121. 40. Horwood NJ, Elliot J, Martin TJ & Gillespie MT. IL-12 alone and in synergy with IL-18 inhibits osteocalst formation in vitro. J Immunol 2001; 15: 4915–4921. 41. Yamada N, Niwa S, Tsujimura T et al. Interleukin 18 and interleukin 12 synergistically inhibit osteocalstic bone-resorbing activity. Bone 2002; 30: 901–908. *42. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001; 142: 5050–5055. 43. Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309–319. 44. Yasuda H, Shima N, Nakagawa N et al. Identity of osteoclastogenesis inhibitor factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 1998; 39: 1329–1337. 45. Malyankar UM, Scatena M, Suchland KL et al. Osteoprotegerin is an a v b3-induced, NF-kB-dependent survival factor for endothelial cells. J Biol Chem 2000; 275: 20959–20962. 46. Lacey DL, Timms E, Tan H-L et al. Osteoprotegerin (OPG) ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165–176. 47. Fuller K, Wong B, Fox S et al. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 1998; 188: 997–1001. 48. Anderson MA, Maraskovski E, Billingsley WL et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1997; 390: 175–179. 49. Smecuol E, Maurino E, Vazquez H et al. Gynaecological and obstetric disorders in coeliac disease: frequent clinical onset during pregnancy or the puerperium. Eur J Gastroenterol Hepatol 1996; 8: 63–89. 50. Riggs BL & Melton III. LJ, Osteoporosis Etiology, diagnosis and management. New York: Raven Press; 1988. 51. Farthing MJ, Rees LH, Edwards CR & Dawson AM. Male gonadal function in coeliac disease: 2. Sex hormones. Gut 1983; 24: 127–135. 52. Sugai E, Chernavsky A, Pedreira S et al. Bone-specific antibodies in sera from patients with coeliac disease: characterization and implications in osteoporosis. J Clin Immunol 2002; 22: 353–362. 53. Hansen MA, Hassager C, Overgaard K et al. Dual-energy x-ray absorptiometry: a precise method of measuring bone mineral density in the lumbar spine. J Nucl Med 1990; 31: 1156–1162. 54. Hui SL, Slemenda CW & Johnston Jr. CC. The contribution of bone loss to postmenopausal osteoporosis. Osteoporosis Int 1990; 1: 30–34. 55. Johnston Jr. CC. Longcope C: postmenopausal bone loss-a risk factor for osteoporosis. N Engl J Med 1990; 323: 1271–1272. *56. Johnston CC, Melton III. LJ, Lindsay R & Eddy DM. Clinical indications for bone mass measurement. J Bone Miner Res 1989; 4(supplement 2): 1–28. 57. Melton III. LJ, Eddy DM & Johnston CC. Screening for osteoporosis. Ann Intern Med 1990; 112: 516–528. 58. Vazquez H, Mazure R, Gonzalez D et al. Risk of fractures in coeliac disease: a cross-sectional, case-control study. Am J Gastroenterol 2000; 95: 184–189. 59. Moreno ML, Vazquez H, Mazure R et al. Stratification of bone fracture risk in patients with coeliac disease. Clin Gastroenterol Hepatol 2004; 2: 127–134. 60. Ferretti J, Mazure R, Tanoue P et al. Analysis of the structure and strength of bonesa in coeliac disease patients. Am J Gastroenterol 2003; 98: 382–390.
Bones in coeliac disease: diagnosis and treatment 465 61. Fickling WE, McFarlen XA, Bhalla AK & Robertson DAF. The clinical impact of metabolic bone disease in coeliac disease. Postgrad Med J 2001; 77: 33–36. *62. Thomason K, West J, Logan RFA et al. Fracture experience of patients with coeliac disease: a population based survey. Gut 2003; 52: 518–522. *63. Vesteergaard V & Mosekilde L. Fracture risk in patients with coeliac disease, Crohn’s disease and ulcerative colitis: a nation wide follow-up study of 16,416 patients in Denmark. Am J Epidemiol 2002; 156: 1–10. *64. West J, Logan RFA, Card TR et al. Fracture risk in people with coeliac disease: a population-based cohort study. Gastroenterology 2003; 125: 429–436. 65. Compston J. Is fracture risk increased in patients with coeliac disease? Gut 2003; 52: 459–460. 66. Oleksik A, Lips P, Dawson A et al. Health-related quality of life in postmenopausal women with low BMD with and without prevalent vertebral fractures. J Bone Miner Res 2000; 15: 1384–1392. 67. Di Stefano M, Veneto G, Corrao G & Corazza GR. Role of lifestyle factors in the pathogenesis of osteopenia in adult coeliac disease: a multivariate analysis. Eur J Gastroenterol Hepatol 2000; 12: 1195–1199. 68. Corazza GR & Gasbarrini G. Coeliac disease in adults. Baillieres Clin Gastroenterol 1995; 9: 329–350. 69. Mora S, Weber G, Barera G et al. Effect of gluten-free diet on bone mineral content in growing patients with coeliac disease. Am J Clin Nutr 1993; 57: 224–228. 70. Mora S, Barera G, Ricotti A et al. Reversal of low bone mineral density with a gluten-free diet in children and adolescents with coeliac disease. Am J Clin Nutr 1998; 67: 477–481. *71. Scott EM, Gaywood I & Scott BB for the British Society of Gastroenterology. Guidelines for osteoporosis in coeliac disease and inflammatory bowel disease. Gut 2000; 46(supplement I): i1–i8. 72. Caraceni MP, Molteni N, Bardella MT et al. Bone mineral metabolism in adult coeliac disease. Am J Gastroenterol 1988; 83: 274–277. 73. Cranney A. Treatment of postmenopausal osteoporosis. BMJ 2003; 327: 355–356.
12 Bones in coeliac disease: diagnosis and treatment Gino Roberto Corazza* Michele Di Stefano
MD
MD
Department of Medicine, University of Pavia, IRCCS “S.Matteo” Hospital, P.le C. Golgi 19, 27100 Pavia, Italy
Eduardo Maurin˜o
MD
Julio C. Bai* MD Department of Medicine, “Carlos Bonorino Udaondo” Gastroenterology Hospital, Univerdidad del Salvador, Av. Caseros 2061, (1264) Buenos Aires, Argentina Coeliac disease predisposes to metabolic osteopathy. The entity of bone loss is higher in patients with malabsorption at diagnosis but it is also present in asymptomatic or poorly symptomatic patients, occurring in roughly half of them. Calcium malabsorption and the release of proinflammatory cytokines, activating osteoclasts, represent the main mechanisms responsible for bone derangement. In coeliacs, the presence of an increased fracture risk was recently questioned and its importance on clinical grounds was reconsidered, in view of the fact that gluten-free diet generally improves bone mass and, consequently, reduces fracture risk. However, gluten-free diet rarely normalizes bone mass and the co-administration of mineral active drugs may be useful in a subgroup of coeliacs. Keywords: coeliac disease; bone mineral density; bone densitometry; gluten-free diet; osteopenia; osteoporosis.
Osteoporosis is ‘a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration with a consequent increase in bone fragility and susceptibility to fracture’.1 That intestinal malabsorption may cause bone mass and mineral metabolism alteration and metabolic osteopathy in coeliac disease (CD) was recognized in the scientific literature almost 70 years ago. In several coeliac patients, marked bone deformities, rickets and fractures were described 2–4 whereas in more * Corresponding authors. Tel.: C39 382 502 973. E-mail address: [email protected] (G.R. Corazza). 1521-6918/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
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recent years the advent of non-invasive techniques such as bone densitometry, have made it possible to demonstrate that the vast majority of both adult and childhood coeliacs are affected by a loss of bone mass.5
PREVALENCE OF BONE DAMAGE Studies dealing with the prevalence of bone loss in CD should be considered with caution, as differences in terms of age of the population studied, duration of disease, diagnostic delay and skeletal site of measurement may affect the results. Several papers agree in reporting that more than 75% of untreated adult coeliacs suffer from a loss of bone mass.6–12 Therefore, CD should be considered one of the most frequent predisposing conditions to metabolic osteopathy. The presence of an overt malabsorption leads to greater bone loss, but even in patients with subclinical CD, diagnosed because of minimal, transient or apparently unrelated symptoms 6,12 or asymptomatic patients diagnosed because of their first degree kinship,7 bone mineral density is significantly lower than in healthy volunteers. Patients on gluten-free diet 6,7,10,13–16 show a lower prevalence of bone loss suggesting that in a number of patients dietary therapy may normalize bone mineral density. Longitudinal studies confirm 6,9,11,17–19 this trend. The prevalence of bone loss after one year of gluten-free diet 6,17 is similar to the prevalence after three years 20 suggesting that the extent of bone mass gain in the first year of dietary treatment is indicative of the short-term bone mineral density improvement. It is not yet completely clear why a subgroup of patients respond only marginally to gluten-free diet. Practice points † bone loss is extremely frequent in coeliacs † patients with overt malabsorption show a more severe bone mass derangement than patients with subclinical disease † gluten-free diet improves bone mineral density but does not normalize it in all patients PATHOPHYSIOLOGICAL ASPECTS The pathogenesis of bone damage in CD is multifactorial and both systemic and local mechanisms may play a role. Intestinal malabsorption secondary to mucosal lesions leads to calcium malabsorption and subnormal levels of serum calcium.8,21 In fact, studies that evaluated calcium absorption in CD have confirmed the importance of this pathophysiological step.21–23 Moreover, several other mechanism may contribute to render calcium unavailable for intestinal absorption, such as a decreased dietary calcium intake secondary to concomitant lactase deficiency,24,25 precipitation of endogenous calcium in the intestinal lumen as calcium soaps,26 increased intestinal secretion 22 or decreased reabsorption.27 The subsequent pathogenetic step is represented by the hypersecretion of parathyroid hormone (PTH), as a response to hypocalcemia.6–8,10,11,28 PTH promotes
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bone resorption and contributes to the increased activity of the renal enzyme 1-ahydroxylase, which converts 25-vitamin D into 1,25-vitamin D:6,8,10,17 this step aims to allow an increased intestinal absorption of calcium through an increased vitamin D-dependent active transport. However, even if enterocytes express a normal number of vitamin D receptors,29 they contain negligible amounts of vitamin D-dependent calcium binding protein (calbindin)30 due to their immaturity, making this effort ineffective. Moreover, high levels of 1,25-vitamin D may, paradoxically, have a negative effect at bone level, being themselves a cause of bone resorption.31 The evaluation of serum markers of bone remodelling shows that metabolic osteopathy of CD is characterized by an enhancement of the markers of both bone synthesis (osteocalcin, propeptide of type I procollagen, bone-specific alkaline posphatase) and resorption (telopeptide of type I collagen, urinary crosslinks, urinary hydroxyproline). However, bone resorption is faster than bone neoformation, resulting in a net bone loss.6,8,10,17 The increase in serum PTH is responsible for this acceleration of bone turnover, as demonstrated by the significant correlation between PTH and osteocalcin and PTH and telopeptide of type I collagen.8 Bone derangement in CD should, therefore, be considered a high turnover osteoporosis, as increased resorption is not balanced by enhanced neoformation. Recently, local mechanisms of bone derangement have received attention. In particular, inflammatory and immunological alterations, by means of cytokine production, may contribute to bone mass reduction. Cytokines are involved in the mechanisms of cell-to-cell communication and some of them are implicated in both normal and abnormal bone remodeling.32,33 Production of proinflammatory cytokines, such as IL-1, IL-6, TNF-a, has been detected in the intestinal mucosa of coeliacs 34 and increased serum levels of these cytokines (IL-1, IL-6) have also been observed.35,36 IL-1 and IL-6 proved to have a role in the activation of bone cells.33 IL-6 plays an important role in bone resorption through the recruitment of osteoclast precursors in blood and the induction of their differentiation and functioning, resulting in an increased osteoclast activity.37,38 It is therefore an interesting point that in untreated coeliacs serum IL-6 correlates inversely with lumbar BMD values 35 and directly with serum parathyroid hormone and telopeptide of type I collagen levels.36 Very recently 39 bone loss in CD was shown to be also caused by a cytokine imbalance directly affecting osteoclastogenesis and osteoblast activity. The incubation of peripheral blood mononuclear cells of healthy donors with sera of untreated coeliacs resulted in a persistently increased osteoclast number, significantly higher than that obtained after incubation with sera of patients on gluten-free diet and with sera of healthy volunteers. This finding was associated with increased levels of IL-6. Moreover, a role of inhibitory cytokines, such as IL-12 and IL-18 was hypothesized since low levels of this cytokines were also found.39 In fact, low serum levels of IL-12 and IL-18 suggest the presence of an inhibition of their release and the lack of their inhibitory effect on osteoclastogenesis 40,41 may play a pathogenetic role. The RANKL/RANK/Osteoprotegerin (OPG) pathway is now considered the most potent regulatory system, coupling osteoclast and osteoblast activities.42 OPG is a regulatory protein with an inhibitory effect on osteoclast differentiation and activity.43,44 Its function is carried out through its link with its ligand, RANKL, whose main role in bone is the stimulation of osteoclast differentiation,45,46 activity,46 and inhibition of osteoclast apoptosis.47 The receptor for OPG/RANKL complex was identified in RANK.48 Knowledge of the activity at bone level of this complex system made it possible to understand the precise mechanism by which preosteoblastic/stromal cells control osteoclast development. Bone is constantly resorbed and formed at specific
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sites in the skeleton, known as basic multicellular units. The process begins by migration of osteoclast to these sites (activation), resorption of a portion of bone by these cells, a reversal phase characterized by apoptosis of the osteoclasts, followed by a phase of bone formation by newly formed osteoblasts. The critical, initial step in this process is the development of osteoclasts and is under the control of preosteoblastic/stromal cells, in order to ensure the coupling of the bone resorption and formation process, maintaining skeletal integrity. RANKL, expressed on the surface of preosteoblastic/stromal cells, binds to RANK on the osteoclastic precursor cells. RANKL is critical for the differentiation, fusion into multinucleated cells, activation and survival of osteoclastic cells. On the contrary, OPG inhibits the system by blocking the effect of RANKL. An increased RANKL/OPG ratio was found in untreated coeliacs.39 In female coeliacs the role of associated gynaecological disorders should also be considered. Amenorrhoea is a frequent finding in female coeliacs 49 and sex hormone imbalance represents an important pathogenetic factor for osteoporosis development.50 In male coeliacs, a peripheral resistance to testosterone activity was described 51 but no correlation between testosterone and bone mass and mineral metabolism was found.36 Another intriguing observation is represented by the detection of bone-specific antibodies in sera from coeliacs.52 Around one half of untreated coeliacs have antibodies that recognize antigenic structures in chondrocytes and the extracellular matrix along mature cartilage, bone interface and perichondrium of fetal rat bone. These antibodies localize in areas where an active mineralization process has occurred and the distribution of these areas is similar to the distribution of native bone transglutaminase. These results suggest that bone-specific antibodies might be at least a co-factor in the pathophysiology of CD-associated bone damage. Practice points † the pathogenesis of bone loss depends on both systemic and local factors † calcium malabsorption has a pivotal role to induce a complex network of events leading to bone demineralization † production of proinflammatory cytokines, responsible for osteoclast activation, is the key point for a local-acting mechanism † bone derangement in coeliacs should be considered as a high turnover osteoporosis as increased resorption is not compensated by enhanced neoformation
CLINICAL ASPECTS The diagnostic accuracy of symptoms related to the presence of bone damage in CD is very poor. In fact, in the absence of clinical symptoms or signs, a significant bone defect may be present in subclinical patients or even in patients diagnosed during screening programs.6,7 Therefore, to diagnose metabolic osteopathy in CD, a test which directly measures bone mineral density should be performed. The greater number of scientific publications in the last 15 years has demonstrated the increased interest in bone metabolic abnormalities of CD. These studies were performed by the use of an appropriate technology, allowing the quantitative measurement of bone impairment.
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In particular, bone densitometry by dual energy X-ray absorptiometry,53 a non-invasive and accurate test to evaluate bone mass, on one hand represented an important stimulus to the study of skeletal disorders, while on the other it provided a more accurate evaluation of fracture risk, certainly the main complication of bone loss on both clinical and economic grounds. Bone mass measurements may be expressed in two different ways: (a) Z score represents the number of standard deviations by which the patient value differs from the mean value of an age- and sex-matched reference population; this index reflects bone mass modifications in relation to the behaviour of such a reference population; in other words, considering the physiologic reduction of bone mass with advancing age, it shows whether the patient’s decline follows the average behaviour or is accelerated. (b) T score represents the number of standard deviations by which the patient value differs from the mean of a young adult reference population; this index, on the contrary, refers to the difference between patient value and the peak bone mass, which is the highest level that can be reached with height–weight growth, now considered the most important factor conditioning the onset of post-menopausal osteoporosis.50,54,55 Densitometric criteria for diagnosis of osteopenia are K2!Z score !K1 and K2.5!T score !K1; criteria for osteoporosis are Z score !K2 and T score !K2.5. It is known that the relative risk of fracture increases by a factor of about 2 for each SD decrease in BMD.56,57 However, bone density measurement does not seem to be a strong predictor of fracture in CD, as a wide overlap in bone mass levels is evident comparing individuals with and without fractures in this condition.58,59 Studies did not find any significant difference between mean T score or Z score of patients with and without a fracture history 59 and bone mineral density seems to be only one of several unknown factors in explaining the increased risk of fractures in coeliacs. It is, however, likely that among other possible factors playing a role in bone weakening affecting coeliacs we need to include to bone quality and strength (considering plasticity, fatigue and damage), the architectural design (spatial organization of bones), but also regional muscles and neuromuscular coordination. A recent paper 60 addressed this issue and showed that bone weakening in CD might result from both a metabolic disturbance of bone remodelling affecting trabecular and cortical bone mass and the mechanical quality of the bone material and a reduction of muscle strength impairing the modellingdependent optimization of bone architectural design and mass of cortical bone. The prevalence of osteoporotic fractures increases with age and women are more affected than men. Fractures occur in sites where trabecular bone predominates and are associated with minimal or moderate trauma. Although, as already stated, bone involvement in CD was first reported several years ago, the true clinical magnitude of the problem was ignored for a long time and epidemiological information on fractures in coeliacs has only recently been acquired. In a case-control, cross-sectional study 58 the occurrence of fractures in 165 treated coeliacs was analyzed by bone mineral density measurement, spinal X-ray and a retrospective historical review. Coeliacs diagnosed in a referral centre had a significantly increased prevalence of fractures in the peripheral skeleton (25% of cases) compared with sex- and age-matched healthy controls (8%). In contrast, the excess of fracture prevalence was not extended to the axial skeleton. Unfortunately, the reported prevalence was mainly established among patients diagnosed on the basis of the presence of malabsorption symptoms and, therefore, not representative of the whole CD population where the number of subclinical and silent patients may be 8–10 fold greater than the number of patients with malabsorption. To overcome this problem, a subsequent study analyzed the relationship between bone
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fractures and CD exploring a cohort of 148 consecutive patients, 53% of whom were patients with overt malabsorption and 47% subclinical or silent patients, compared with 296 healthy controls. This study showed that the prevalence of fractures in the peripheral skeleton was significantly higher in symptomatic coeliacs (42%) compared both with controls (14%) and subclinical/silent cases (20%). In this latter group the prevalence of fractures did not differ from that of healthy controls.59 A recent study on a small cohort of coeliacs failed to show abnormalities of serum parathyroid hormone, serum vitamin D or calcium intake as responsible for bone fractures.61 Two recent population-based reports showed a slight increase of fracture prevalence in coeliacs.62,63 The study from England showed an overall age and sex adjusted odds ratio of 1.05 (95% CI 0.66–2.25). A trend towards an increased risk, but not statistically significant, was shown for forearm and wrist fractures.62 A larger study from Denmark 63 showed incidence rate ratios of 1.15 (1.00–1.32) before diagnosis and 1.19 (1.06–1.33) after diagnosis of CD. Finally, a recent study by West et al 64 on more than 4700 coeliacs, extracted from the General Practice Research Database, showed that CD is associated with a small increase in the risk of fracture and suggested that concerns regarding a marked increase of fracture risk in CD are unwarranted. The results of these studies were recently criticized.65 In fact, the failure to demonstrate a significant increase of fracture risk may be due to limitations in the study design rather than to the true absence of association. The size of the study and the method used to diagnose fractures are pivotal factors, but even more important is the fracture rate in the control population. However, since an increased risk was shown in coeliacs with overt malabsorption and not in asymptomatic patients, apart from correct considerations regarding the difference in study design, the power of the study, the method of defining or diagnosing fractures, what probably affects the results of previous studies seems to be the composition of the various case studies, i.e. the actual number of subjects with overt malabsorption and, therefore, a higher risk of fracture. On the other hand, in the study by West et al,64 the slight overall increased risk of fractures in CD could also be explained on the basis of the presence of a higher number of underweight patients that together with a higher number of medical consultations in the CD group than in the control group suggest the presence of a high proportion of patients with overt malabsorption or more severe disease. In short, the importance of bone derangement in coeliacs has to date been attributed to the possible induction of an increased risk of fractures. While on one hand, several data suggest that this problem may be overestimated, on the other it is also true that osteoporosis, by itself, may represent a clinical and practical problem for patients. In post-menopausal osteoporosis, as expected, patients with fractures show a significantly reduced health-related quality of life than patients without fractures, but the mere presence of low values of bone mineral density induces a reduction of quality of life.66 Thus, even in absence of the extreme manifestation represented by the development of a fracture, bone loss interferes with health status in post-menopausal women. We have no data about health-related quality of life in coeliacs concerning the presence of osteoporosis or bone fractures, but we cannot avoid thinking that low bone mass may have similar consequences in these patients. In a recent paper,67 the level of physical activity was lower in symptomatic than in asymptomatic patients, suggesting that, in the subgroup exposed to a higher risk of bone damage, recreational
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activities are significantly reduced. Moreover, if we consider that most CD diagnoses are made in the 3rd–4th decade,68 the presence of low bone mass may assume greater importance as it affects the activities of daily living, causes bone pain and reduces physical functioning and mobility. Particularly in young subjects, this problem may induce a sense of inadequacy and be felt in a negative way, causing social isolation and depression. These considerations must, therefore, lead us to consider osteoporosis as a target for therapy to improve the quality of life, even in the absence of a definite increase in the risk of fracture. Practice Points † in adult patients on gluten-free diet since childhood, bone mineral density is normal † gluten-free diet improves but rarely normalizes bone mineral density in patients diagnosed in adulthood
BONE MASS MEASUREMENT: WHO, WHEN, WHY As far as the need to measure bone mineral density in coeliacs is concerned, several doubts are present. It is not clear which patients should undergo bone mass measurement, when the first and subsequent measurements should be performed, but also why measurement should be performed. A general agreement on the positive effect of the treatment with a gluten-free diet is evident, as reported by prospective studies. However, while treated patients increase bone mass significantly, such restoration rarely reaches sex- and age-matched values for the control population in patients diagnosed in adulthood.8,13,17 In contrast, there is evidence that very early treatment of CD in childhood prevents bone loss and most patients reach normal peak densitometric values.69 This discrepancy can be explained by the fact that bone loss may have both an irreversible component (disappearance of trabeculae and thinning of the cortex) and a reversible component (increased intracortical tunnelling, thinning of trabeculae). While late treatment (in adulthood) may revert only the reversible bone loss, there is evidence 70 that very early treatment, started during infancy, could prevent both the irreversible and reversible bone loss. Consequently, there is no need to perform bone mass measurement in children if fully compliant with gluten-free diet. The availability for adult patients of a treatment able to restore bone mineral density values at normal levels, like gluten-free diet for children, would allow the same statement to be made for adults. In the meantime, in coeliacs diagnosed in adulthood, a different approach according to clinical presentation should be followed. The presence of an overt malabsorption, but not of subclinical or silent disease, makes it possible to select a subgroup of patients at higher risk for osteoporosis and bone fractures.59 Consequently, in these patients bone mineral density measurement may be indicated at diagnosis in order to evaluate the need for co-administration of mineral-active drugs. The ability of the propeptide of type I procollagen to predict the bone mass gain after a two-year period of gluten-free diet 18 seems useful for this purpose.
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On the contrary, the presence of subclinical or silent disease could allow elimination of the need for bone measurement at diagnosis. On clinical grounds the evaluation of bone mass after the first year of strict adherence to gluten-free diet does in fact seem of much greater use: the decision to begin therapy with mineral-active drugs would thus be taken on the basis of dietary regimen efficacy. The lack of knowledge about the efficacy of mineral-active drugs in coeliacs does not make it possible to draw up a strategy for managing post-menopausal coeliacs. This subgroup has a higher risk of suffering from osteoporosis and bone mass measurement will, therefore, be more sensitive in detecting a bone defect. We have to consider that the efficacy of anti-resorptive therapy started later in life is lower than early treatment and screening at presentation allows diagnosis of bone loss at early stage. As the efficacy of mineral-active drug treatment on fracture risk is unknown in this subgroup of patients, it was suggested that bone mass should be measured at diagnosis, as patients will have suffered malabsorption for many years.71 Then, in a fully compliant patient, measurement should be repeated in the perimenopausal period and repeated after 18–24 months if normal. For men, an age cut-off of 55 years could represent a valid option.71 These guide-lines were recently criticized 64,65 and an approach based on bone mass measurement restricted to the minority of individuals in whom short term (5–10 years) fracture risk is high was suggested. Risk factors for fractures have not been specifically identified in CD, but are likely to include, in addition to noncompliance with gluten-free diet, failure to respond fully to a gluten-free diet, steroid treatment, untreated hypogonadism, age, low body mass index and previous fragility fracture.65 Once a diagnosis of osteoporosis has been made or if the specific treatment with a gluten-free diet is ineffective for promoting remineralization, additional secondary causes of osteoporosis (hypogonadism, thyroid dysfunction, hyperprolactinemia, medications [anticonvulsivants, corticosteroids]) should be ruled out. The role of lifestyle factors should be not underestimated in the prevention of osteoporosis: in a recent paper,67 sun exposure and prevalence of smokers were similar in symptomatic and asymptomatic coeliacs, but physical activity was significantly lower in symptomatic than asymptomatic patients. Patients should be encouraged to follow a calcium rich diet, to maintain a high level of exercise and to stop smoking.
Practice Points † in coeliacs with malabsorption symptoms bone mineral density should be measured at diagnosis and after a year of strict gluten-free diet. Then, mineralactive drugs should be associated with dietary treatment if bone mass gain is not satisfactory † in asymptomatic coeliacs bone mineral density should be measured after a year of strict gluten-free diet † CD women should undergo bone mineral density measurement in the perimenopausal period † coeliacs on gluten-free diet from childhood should not undergo bone mineral density measurement
Bones in coeliac disease: diagnosis and treatment 461
GLUTEN-FREE DIET: ALONE OR ASSOCIATED WITH MINERAL-ACTIVE DRUGS? Little attention has been dedicated to other therapy regimens in CD. In an early longitudinal study, the co-administration of 25-hydroxycholecalciferol did not induce any significant modifications in BMD of the distal two-thirds of the forearm after 12 months of GFD.72 Another study showed a significant improvement in BMD at all sites after a year of GFD, supplemented only in some patients with oral calcium and 25-hydroxycholecalciferol.11 The list of drugs for treatment of osteoporosis is growing and although they have been demonstrated to have a place in the treatment of postmenopausal osteoporosis there are no studies of comparability in coeliacs. We therefore have no information on which subgroup of patients should follow this therapeutic approach, nor on which is the best therapeutic strategy, in terms of drug, dosage and duration. It seems appropriate to prescribe an association with mineral-active drugs in cases presenting a severe densitometric alteration or when a past clinical history of osteoporotic fractures is reported. There is no agreement on the BMD treatment threshold and a Z-score value below K1 was suggested.71 As far as drug choice is concerned, hormone replacement therapy or bisphosphonates represent the best options for post-menopausal osteoporosis 73 and similarly, these two approaches seem the best options also for coeliacs. However, results from therapeutic trials are anxiously awaited in order to define precise guide-lines. Research agenda † the effect of mineral-active drugs on bone mineral density and fracture risk in adult coeliacs is not known † there is no agreement on the bone mineral density treatment threshold GENERAL RECOMMENDATIONS Osteoporosis is a complex chronic disorder that may progress without producing symptoms until a fracture occurs. Moreover, relatively few people are diagnosed in time for effective therapy to be administered. Diagnosis of CD gives an opportunity for suspicion of osteoporosis and, therefore, for preventive action. General advice to coeliacs in order to protect and maintain bone health is necessary. Among recommendations, explanations to the patient about the risk of osteoporosis, the necessity of strictly adhering to a gluten-free diet and the effect of treatment on bone remineralization in the event of established bone involvement are particularly important. Although all general measurements have proved to be effective in the general population and in postmenopausal osteoporosis, none of them have been proved in patients with CD. Education on the importance of lifestyle changes such as regular exercise and stopping smoking should be given. Regular calcium intake needs to be recommended (1.2 g/day for women), ideally through calcium-rich foods. If dietary calcium is insufficient, malabsorption is suspected or patients present low calcium serum levels, calcium supplementation is mandatory (1 g/day).
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Renal hyperconversion of 25-hydroxyvitamin D to 1,25-hydrohyvitamin D secondary to increased PTH levels 8 often make oral supplementation with Vitamin D unnecessary.
CONCLUSIONS Despite the more recent advents in the knowledge on CD osteopathy, the story is far from over. We now have information on the prevalence and how to diagnose and prevent the problem. We still need to improve our knowledge on the pathophysiological mechanisms, as the aspects connected with malabsorption must be associated with those linked to local factors. Bone mineral density measurement seems unnecessary in all patients, although a better evaluation of cost compared with benefits is required. Despite the fact that treatment seems to be largely dependent on gluten restriction from the diet, more information on therapeutic alternatives is needed.
SUMMARY Bone homeostasis is frequently affected in coeliac disease. More insight into the pathophysiology of bone damage will allow us to understand the relative importance of local and systemic factors, at present partially unknown. Diagnosis of metabolic osteopathy makes use of bone densitometry, but when to perform the measurement and which patients should undergo to measurement is a matter for discussion. A suitable strategy envisages bone mass measurement at diagnosis in symptomatic patients and, in fully compliant patients, a second measurement after one year of glutenfree diet. In asymptomatic patients, bone mass measurement may be delayed until after one year of gluten-free diet; women should be tested in the perimenopausal period. In childhood coeliac disease bone mass measurement seems of little use, since gluten-free diet normalizes bone mineral density. Doubts have been expressed as to the presence of an increased risk of bone fracture. Bone mineral density values do not discriminate between patients with and without fractures, suggesting that other parameters are also important in fracture occurrence, such as bone architectural modifications. Mineralactive drug co-administration may represent an effective measure, but no data are yet available on the effect on bone mineral density and fracture risk modification.
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