Abstract
Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The worldwide prevalence of CD is estimated to be 0.7–1.4% of the general population. Etiopathology of this disease is multifactorial, with genetic determinants being a major contributing player to CD susceptibility. Its manifestation embraces different organs, including the musculoskeletal apparat. Patients with CD have increased risk of bone disorders. According to data, bone disorders – osteopenia and osteoporosis – can affect up to 70% of patients with CD at diagnosis, and it decreases after the initiation of a gluten-free diet. Gluten consumption in patients with CD triggers an inflammatory reaction followed by tissue damage, and both; local and systemic inflammation can increase the risk of bone mass deterioration. Other theory assumes shortages of vitamin D and an impaired calcium absorption mechanism leading to secondary hyperparathyroidism. Taking into account the increasing prevalence of CD and osteoporosis, we broadly discuss genetic, immunological, dietary, gut microbiota, and environmental factors that could increase the risk of osteoporosis in CD. Furthermore, we discuss lifestyle and pharmacological preventing and treatment measures.
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Introduction
Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals [1]. In the submucosa of the small bowel, the enzyme called tissue transglutaminase (tTG) deamidates gluten peptides, leading to high-affinity binding to human leucocyte antigen (HLA) DQ2 and HLA DQ8 molecules. In patients with CD, this mechanism triggers an inflammatory reaction followed by tissue damage [2]. Factors predisposing to the development of CD are presented in Fig. 1.
The worldwide prevalence of CD is estimated to be 0.7–1.4% of the general population [3]. This prevalence can be different from continent to continent and country to country. In Europe, a higher prevalence has been reported in northern (1.6%) compared to eastern (0.98%), southern (0.69%), and western (0.60%) countries [4]. While the small bowel is the primary target of the immune response, CD is now known as a systemic disease as its manifestation embraces different organs, including the musculoskeletal apparat [5].
Definition and Epidemiology of Osteoporosis in the Course of Celiac Disease
According to the American College of Physicians, osteoporosis is a skeletal disorder resulting in low bone mass and micro-architectural deterioration in bone tissue, which further leads to increased bone fragility and a higher risk of bone fractures. Celiac disease—both classic and asymptomatic—is one of the risk factors for development of secondary osteoporosis [6].
In 1994 World Health Organization (WHO) proposed general categories of osteoporosis for women based on measurements by dual-energy X-ray absorptiometry (DEXA) [7]. Osteoporosis is diagnosed when bone mineral density (BMD) is 2.5 SD or more below the average value for young healthy women and osteopenia when BMD is more than 1 SD below the young adult mean, but less than 2.5 SD below this value.
A modern view of osteoporosis includes in its definition the occurrence of previous fractures and other risk factors [8, 9]. Therefore risk assessment algorithms like FRAX [10] include in their calculation conditions of secondary osteoporosis including celiac disease. Although pathophysiological mechanisms underlying bone disorders in CD are not fully understood, possible mechanism include malabsorption of calcium, vitamin D, and other crucial for bone health nutrients as a result of villous atrophy and inflammation in small intestine. Also inflammation and production of proinflammatory cytokines drive bone tissue degradation. These mechanisms are fully discussed below.
The prevalence of osteoporosis seems to be 18.3% worldwide with the higher prevalence in Africa (39.5%) affecting both women and men—23.1% and 11.7%, respectively [9]. The consequence of osteoporosis are fractures with countless impact on healthcare spending. Osteoporosis affects up to 70% of CD patients at the diagnosis but generally is reported to be under 20% and osteopenia under 40%, although test results very often vary [6]. The limitation and probably the reason for these differences is the fact that in most studies these estimations do not take into account the presence of other risk factors like age or endocrine disorders. On a group of 563 premenopausal women and men, after excluding other factors predisposing to the development of osteoporosis, such as smoking, it was estimated that osteoporosis occurs in 14.4% and osteopenia in 39.6% of patients [6].
In the latest systematic literature review, Mosca et al. observed a high prevalence of low BMD in newly diagnosed patients between 20 and 35 years [11]. Moreover, peak bone mass is reached between age 20–30 years, so it can impact risk of later osteoporosis. A progressive bone loss starts at age 35 and reaches peak after 50 years of life. It affects mainly women [12].
CD-related osteoporosis can lead up to 20–25% of peripheral bone fractures in those patients, especially involving the wrist [13], and can variably involve the hip, lumbar spine, and distal radius [14]. Most bone fractures occur before the diagnosis of CD confirming that osteoporotic fractures can be a sign of an undiagnosed CD.
Importantly, BMD improves after introducing a strict GFD [15]. While CD patients are known to have a high prevalence of osteoporosis, the actual dimension of bone fracture risk is more controversial, especially after diagnosis [16,17,18]. A higher risk of fractures of any type seems to be more than plausible in CD patients both before and after the diagnosis, but difficult to estimate precisely [19]. Given those premises, the advances in diagnosis of CD may have mitigated the prevalence of fractures in CD patients in the XXI century [20]. Factors predisposing to the development of osteoporosis in patients with celiac disease are presented in Fig. 2.
It is worth to mention that studies on groups of women with CD show that their physical activity rates are at very low levels, presumably as a result of symptoms and complications of the disease what may also translate into a risk of decreased bone mineral density [21, 22].
Genetic and Immunological Conditions of Osteoporosis in the Course of Celiac Disease
The correlation between bone disorders and celiac disease was noticed decades ago [23]. Osteoporosis deserves special attention as a non-celiac symptom of CD; in fact, abnormal bone metabolism and decreased BMD may be the only signs of “silent” CD [24]. Newly diagnosed patients or those inadequately treated for celiac disease often suffer from bone disorders, reduced bone mass, and BMD, consequently leading to increased bone fragility [24, 25]. Interestingly, studies have shown that osteoporosis has a worse course in those affected by CD [26] and presents as a extraintestinal manifestation of the disease. Scientific reports also indicate that osteoporosis is more common in people with celiac disease (3.4%) than in those without celiac disease (0.2%). In addition, severe cases of CD are accompanied by more severe osteoporosis [27], and people with celiac disease, who also suffer from reproductive disorders, are affected even more severely [26]. To date, it has been shown that about 75% of celiac patients also suffer from bone mass loss associated with osteopenia or osteoporosis [28,29,30,31,32]. Despite this strong association between low BMD values and CD, there are currently no guidelines on whether every patient with newly diagnosed CD should undergo DEXA scanning [33].
One of the theories of the development of osteoporosis in the course of celiac disease is due to a characteristic pathophysiological feature of celiac disease—an increased number of intraepithelial lymphocytes with gamma-delta T-cell receptors compared to healthy individuals [11]. These lymphocytes show significantly higher expression of interferon-gamma (INF-ϒ), which is the predominant cytokine in the damaged intestinal mucosa, and interleukin-10 (IL-10) [34]. Thus, it follows that both local and systemic inflammation plays a key role in bone mass loss in CD, characterized by an increase of pro-inflammatory cytokines in mucosa and serum, particularly tumor necrosis factor-alpha (TNFα), interleukin-1 (IL-1), and interleukin-6 (IL- 6), which has been confirmed [35, 36]. TNFα and IL-1 stimulate osteoclastogenesis and cause bone resorption and IL-6 recruits osteoclasts and promotes their differentiation [37]. Another study showed that increased production and release of TNFα and INF-ϒ is associated with increased bone mass loss. Higher levels of the cytokines TNFα and also IL-1, IL-6 stimulating osteoclasts were also observed in CD patients, with concomitant low levels of the cytokines interleukin- 18 (IL-18) and interleukin-12 (IL-12) [38, 39]. These events can directly affect bone density, independent of vitamin D levels and parathyroid hormone (PTH) levels.
The second theory assumes a lack of vitamin D and an impaired calcium absorption mechanism, leading to secondary hyperparathyroidism. Patients with celiac disease have lower vitamin D levels correlating with an increase in PTH levels [40] consequently leading to increased bone resorption (raises alkaline phosphatase levels), which explains the patient's symptoms.
In recent years, much attention has been paid to the receptor activator of NF-κB ligand(RANKL)/receptor activator of nuclear factor-κB (RANK)/osteoprotegerin (OPG) [RANKL/RANK/OPG] pathway, which is now considered as a major signaling system in bone metabolism. The expression level of the OPG gene is affected by many factors: cytokines (TNF-α, IL-1α, IL-18, TNF-β), bone morphogenetic proteins (BMP), 17β-estradiol, tensional forces; glucocorticosteroids, immunosuppressants, PTH, prostaglandin E2, or fibroblast growth factor (FGF). RANKL is produced by mature osteoblasts and their precursors, as well as by activated T lymphocytes [41]. Its expression is influenced by cytokines (IL-1, IL-6, IL-11, TNF-α), glucocorticosteroids, as well as PTH and 1,25(OH)vitamin D3, among others (8). It is a factor that activates the entire process of mature osteoclast formation: through differentiation, fusion, function, and survival of resorption cells bone (6). The genesis of such pathological bone changes in celiac disease originates in the mucosa of the small intestine, most severely affected by the disease. Inflammation of the mucosa from the duodenum to the distal part of the ileum lead to malabsorption and hepatic steatosis, which consequently translates into bone disorders. However, the mechanism is not entirely so straightforward. The consequences of bone disorders lie primarily in interactions between cytokines and factors affecting bone formation and resorption.
In patients with the asymptomatic form of celiac disease, factors correlated with chronic CD (i.e., growth factor deficiency, increased cytokine production, and autoimmune changes) may be the main factors leading to decreased BMD [37, 42]. A study by Moreno et al. suggests that low BMD in the total skeleton of CD patients is associated with an allelic variant of the IL1B gene. This implies that carrying IL1B-511 T is associated with lower bone mass in the peripheral skeleton of adult CD patients [43] and an increased prevalence of osteopenia/osteoporosis, which could explain one of the causes of bone weakness in CD [37].
Nutritional Determinants of Osteoporosis in the Course of Celiac Disease
Loss of villous cells in the proximal intestine leads to deterioration of intestinal absorption efficiency. As a result, patients who do not adhere to a GFD have a high risk of nutrient and vitamin deficiencies, including calcium and vitamin D essential for proper bone metabolism [44]. Hypocalcemia and vitamin D malabsorption lead to compensatory increases in serum levels of PTH, which is observed in newly diagnosed individuals with CD. After the implementation of a strict GFD which results in the reconstruction of intestinal villi, PTH serum levels normalize [45].
In addition, in patients with the classic form of celiac disease, manifested by intestinal symptoms, observed is the reduction of intestinal calcium absorption due to its binding to unabsorbed fatty acids, and as a result, increased fecal calcium losses and decreased urinary excretion of calcium [44, 46].
Also, deficiencies in other minerals and vitamins can adversely affect bone metabolism. Common nutritional deficiencies in the newly diagnosed and untreated CD are iron, magnesium, B12, calcium, vitamin D, zinc, and copper [47]. For example, zinc deficits correlate with low levels of insulin-like growth factors, that are responsible for alterations in bone metabolism [48, 49]. After the introduction of a gluten-free diet, the values return to normal in most patients, however, approximately 30% of patients with CD nutritional deficiencies can persist [47].
Magnesium, as intracellular cation, is necessary for calcium metabolism. Its 50–60% of the total body content is accumulated in the bone where its ions bind at the surface of the hydroxyapatite crystals, improve the solubility of phosphorous and calcium hydroxyapatite. Magnesium induces osteoblast proliferation and is also necessary for the activation of vitamin D because most of the enzymes involved in vitamin D metabolism require magnesium [50].
Nevertheless, introducing a gluten-free diet has a positive effect on BMD in patients with CD [28, 30, 32, 51,52,53,54,55]—although not all of them manage to restore BMD adequate for healthy people. Zanchetta et al. conducted an interesting study in this area. Researchers assessed BMI, bone microarchitectural parameters including BMD, and biochemical measurements—IgA tTG, IgA DGP, IgG DGP, hemoglobin, calcium, C-telopeptide, PTH, 25OHD in patients at diagnosis and after 1 year on GFD and supplementation of vitamin D and calcium. The study showed that after 1 year of treatment, the bone microarchitecture improved, yet there were still significant differences with a control group of women of similar age and BMI [56].
Thus, on the one hand, strict exclusion of gluten from the diet is the only possible form of CD treatment, and strict adherence to it allows for the reconstruction of damaged intestinal villi and, as a result, improvement of intestinal absorption [49]. On the other hand, a gluten-free diet is very often a diet deficient in minerals and vitamins that are essential for bone health. Additionally, despite strict adherence to diet, patients are at risk of cross-contamination with gluten [49].
In addition, patients with CD very often focus on excluding gluten from their diet, forgetting the importance of a proper balance of the menu in terms of the content of minerals and vitamins. Research indicates that the diet of patients with CD is low in cereals, fruits, and vegetables and excessive in meat and derivatives. Furthermore, it is very often based on processed, gluten-free, low-nutritional products [57,58,59]. Gluten-free products are characterized by a higher content of saturated fats, simple sugars and a lower content of vitamins and minerals than their traditional counterparts [49]. Processed foods and an improperly balanced, high-fat diet also promote the development of low-grade chronic inflammation [60]. As we know that BMD of patients is largely determined by the ongoing inflammation, it is also worth paying attention to the quality of the patient's diet in terms of its inflammatory nature [61].
It should also be noted that many celiac patients limit or even exclude the consumption of dairy products. Most of the CD patients with villi atrophy experience secondary lactose malabsorption due to decreased lactase activity on the enterocyte brush border. In a study by Ojetti et al. 24% of patients with lactose intolerance determined by HBT were diagnosed as CD and in many, lactase deficiency was the only manifestation of CD [62]. However, it should be noted that after introducing a gluten-free diet in CD patients, intestinal villi begin to rebuild, and after 1–2 months in most patients, lactose begins to be well tolerated again [47].
The elimination of milk and milk products from the diet, which are one of the richest sources of calcium, is considered one of the possible causes of the frequent occurrence of reduced BMD in patients with CD [63]. Unfortunately, many CD patients, as well as the general population, avoid dairy in their diet – in the study by Zingone et al. 22.2% of patients with CD and 19.9% of healthy patients constituting the control group claimed not drinking fluid milk regularly [64]. Therefore, the nutritional education of patients is of key importance, including not only guidelines for the elimination of gluten from the diet, but also the correct composition and balancing of the diet depending on the coexisting symptoms.
Gut Microbiota and Osteoporosis in the Course of celiac disease
The gut microbiota has a pivotal role in determining immune self-tolerance and, over the years, it has become clear its importance in the complex pathogenesis of autoimmune diseases [65]. Through microbial translocation and molecular mimicry, the microbiota regulates both innate and adaptive immune homeostasis of the local and systemic immune system [66]. Immune dysregulation due to altered gut microbiota and infections have been advocated as possible explanation for the increasing prevalence of autoimmune diseases during XX and XXI centuries but other interpretations are possible [67].
Recent evidence suggest an important role of the gut microbiota in bone-mineral metabolism and osteoporosis [68, 69]. Once more, this influence of gut microbiota seems to be played through its regulation of the immune system [70]. The altered immune-inflammatory axis due to the impaired gut microbiota could partially explain the higher prevalence of osteoporosis in autoimmune diseases regardless of corticosteroids and immunosuppressants. The connection between autoimmunity, gut microbiota, and BMD it is only partially justified by the activity of T lymphocytes helper Th17 and regulatory T (Treg) [71]. Vitamin D would play a bivalent role in the connection between the gut microbiome and bone metabolism [70]: vitamin D has a role in regulating the microbiome and the immune-inflammatory axis (Treg) but, at the same time, an altered microbiome and inflammatory diseases (i.e., IBDs and CD) can lead to a reduced vitamin D absorption. For all these reasons, gut microbiota is thought to be a possible future target of osteoporosis treatment [69].
In particular, CD and IBDs share many common patterns of the gut microbiome [72]. The taxa included in those gut microbiomes were found to be associated with low BMD, strengthening the association between autoimmune diseases, and osteoporosis. The gut microbiome is thought to be crucial in the normalization of BMD after the initiation of a GFD [15]. More studies are needed to better understand the precise role of the microbiome in autoimmunity and osteoporosis and its implications on therapy.
Environmental Determinants of Osteoporosis in the Course of Celiac Disease
Physical activity (PA) has a positive effect on bone metabolism and has a preventive effect on the development of osteoporosis [73]. Peak bone mass is achieved by late adolescence, therefore, promoting physical activity is particularly important among children and adolescents [74]. The National Osteoporosis Foundation and International Osteoporosis Foundation recommend weight-bearing exercises in the prevention of osteoporosis—especially high-intensity PA such as jumping, hopping, but, mostly in adults, also lower-intensity PA as walking and weight training is recommended [73].
An interesting study was conducted by Nestares et al. to evaluate of influence of Mediterranean Diet adherence and PA on body composition and bone health in young patients with CD. They observed in a group of 59 children with CD and 40 healthy controls that patients with CD have lower body weight, lean mass, and bone mass than non-celiac children, regardless of the length of time on a GFD [75]. Furthermore, they observed that lean mass is independently associated with BMD in these patients, explaining 11% of its variability [75]. Studies suggest that BMI can be considered as a predictor of bone density in children with CD since lower BMI is associated with lower BMD [76, 77].
Attention should be also paid to toxins and environmental pollution, since studies show that environmental substances may be related to osteoporosis [78]. In a population-based, cross-sectional study analysis was made of data collected from the National Health and Nutrition Examination Survey. The authors observed that 115 persons following a GFD had significantly higher urine levels of total arsenic and blood levels of mercury, lead, and cadmium than 11 239 persons not avoiding gluten. These results suggest that a gluten-free diet that may contribute to the accumulation of potentially toxic metals [79, 80]. In the meta-analysis, the authors found that exposure to cadmium and lead, but not mercury, is associated with an increased risk of osteopenia or osteoporosis in adults [81].
Therapeutic Strategies
Lifestyle and Dietary Modifications
Osteoporosis treatment for patients with CD includes non-pharmacological and pharmacological interventions. A strict gluten-free diet reduces systemic inflammation, heals intestinal mucosa, allows recovery of nutrient absorption and, as a result, improvement or normalization of BMD [82, 83]. However, it should be emphasized that, apart from the elimination of gluten from the diet, it is crucial to properly balance patient’s diet and rely on products with high nutritional density. It is worth educating patients and explaining the role of an appropriate diet and lifestyle in the prevention of osteoporosis—Quattrini et al. conducted a prospective observational study in a population of 200 women aged 30–80 years and observed that patients who follow MD, consume more dietary calcium. Furthermore, the authors underline that short nutritional conversation improves lifestyle habits that could have a preventive effect on osteoporosis development [84]. Numerous studies confirm the bone benefits of the MD in the prevention of osteoporosis in the general population. Data from 49 cross-sectional, case–control, longitudinal, and clinical trial studies suggest that a plant-based diet, rich in whole grains, poultry, fish, nuts, legume, and low-fat dairy products have a positive impact on bone health. It seems to be a positive outcome of the high nutritional density of these products—for example, fruits and vegetables are rich in potassium, magnesium, vitamin C, vitamin K, folate, carotenoids, fish and seafood abound in anti-inflammatory omega-3 fatty acids, and dairy products are the best dietary source of calcium and magnesium in the diet. On the contrary, the western-style diet—characterized as a high-caloric diet, rich in refined grains and sugar, e.g., soft drinks, sweets, and desserts, sodium, phosphorus, saturated fats, animal protein, e.g., meats and derivatives, and low in fiber, vitamins, and trace elements—have been proven to be a deleterious for bones [85].
It is crucial to consume adequate amounts of calcium—dairy products, e.g., milk, yogurt and cheese, fish—especially sardines with bones, pulses, nuts, and seeds [44]. If dietary calcium requirements cannot be met, adequate supplementation with calcium should be provided [82]. Furthermore, care should be taken to maintain the appropriate concentration of vitamin D. Since only 10–20% of vitamin D is obtained from a foods—such as oily fish, mushrooms, or fortified dairy products—the role of moderate sun exposure is emphasized, because the total of 80–90% of vitamin D is obtained from cutaneous synthesis [50]. Adequate vitamin D supplementation should be provided [86]. Special attention should also be paid to potassium and magnesium, vitamin K, C, omega-3 fatty acids, folate, vitamin B12, and zinc, as well as an adequate supply of wholesome protein [50].
A very interesting study in this area on a group of 57 children with CD and 40 healthy children was conducted by Nestares et al. The authors observed that higher MD adherence and more time performing vigorous physical activity were associated with higher Z-score and lean mass among CD children [75]. Therefore, it is also advisable to ensure an appropriate level of physical activity, which promotes better inflammatory and redox profiles in the general adult population. Patients should be encouraged to participate in weight-bearing exercises, but also limit alcohol intake, and avoid cigarette smoking [82].
It is also important to identify early risk factors for the development of osteoporosis, such as estrogen deficiency and hypoghonadism.
Clinical Treatment of Osteoporosis
There is no general agreement on the correct timing of bone densitometry in celiac patients. According to the European Society for the Study of Coeliac Disease (ESsCD), bone densitometry should be performed in every patient at the time of diagnosis and should be repeated after 2–3 years if abnormal—or in patients who have evidence of ongoing villus atrophy or do not adhere strict gluten free diet—or 5 years if normal [87]. Furthermore, it is recommended to measure calcium, alkaline phosphatase and vitamin D levels at diagnosis and replace as necessary [87]. Other guidelines suggest performing bone densitometry only in patients with a high risk of osteoporosis or those older than 55 years [83, 88, 89].
Pharmacological treatment of osteoporosis in patients with celiac disease includes taking bisphosphonates, denosumab, teriparatide, romosozumab. There are no longitudinal studies dealing with effect of particular form of osteoporosis treatment in patients with CD and there are no studies on which to base the choice in the individual subgroups of patients.
Bisphosphonates usually are first line treatment in treating ostoporosis. They act by inhibiting farnesyl pyrophosphate synthase which is an osteoclast enzyme. Bisphosphonates promote apoptosis of osteoclasts and, as a result, stop bone resorption and increase BMD. According to ESsCD, it is recommended to start calcium and vitamin D supplementation before treatment with bisphosphonates to decrease risk of tetany in patents with osteomalacia [87]. In celiac disease patients, parenteral treatment options such denosumab or intravenous bisphosphonates, e.g., zoledronic acid are preferred above oral medication due to poor absorption of oral bisphosphonates. Other options include follow-up bone markers such as CTX—bone resorption—and P1NP—bone formation—assessment after 3–6 months of therapy to assess efficacy of absorption [90].
Denosumab is a monoclonal antibody to RANKL and romosozumab is a monoclonal antibody to sclerostin which blocks canonical Wnt signaling bone formation pathway. Obstacles associated with romosozumab use include the high cost and the need for monthly appointments to receive a dose of the drug [91]. Lastly, teriparatide is the first drug in category of osteoporosis called anabolic therapy [92]. It is recombinant parathyroid hormone, reserved for severe osteoporosis with high risk of fractures, that increase bone formation [90].
Summary and Conclusion
Celiac disease is characterized by inflammation of the small intestine and villous atrophy [1]. Small intestinal villous atrophy leads to impaired nutrient absorption, acute weight loss, and diarrhea, as well as fractures. A 2015 meta-analysis demonstrated that celiac patients have a 30% higher risk of any fracture and a 69% higher risk of femoral neck fracture [19]. Another meta-analysis from 2017 showed that patients with CD had an increased risk of osteoporosis [93]. Similar results were also obtained in large screening studies [94]. The conclusion of such studies would seem fairly straightforward; however, these studies did not examine the risk of CD in patients who were first diagnosed with osteoporosis, which is important for clinicians because of the decision to screen a patient with osteoporosis for celiac disease.
The paper by Laszkowska and colleagues, in which they analyzed articles published in PubMed, Medline, or EMBASE up to May 2017 to estimate the prevalence of celiac disease in patients with osteoporosis, identified eight studies, among which 3188 osteoporotic subjects were identified, 59 of whom (1.9%) had CD. Also weighted pooled analysis showed biopsy-confirmed celiac disease in 1.6% of people with osteoporosis. Importantly, with the inclusion of studies based on positive celiac serology—the absolute percentage increased from 1.9 to 2.6%, but the total weighted prevalence remained at 1.6% [95].
Various studies have shown that treatment with a gluten-free diet improves BMD in celiac patients suggesting that treating celiac disease would likely reduce the excess risk of fractures, but it is important to remember that the mechanism of osteoporosis in celiac patients is likely multifactorial. Individuals with celiac disease at the time of diagnosis often have low bone density, even in the absence of celiac disease symptoms, which may be due to impaired intestinal absorption efficiency, leading to hypocalcemia and vitamin D malabsorption [40]. This in turn results in secondary hyperparathyroidism, as well as chronic inflammation causing increased production of pro-inflammatory cytokines in the mucosa and serum, particularly TNFα, IL-1, and IL-6 [11] disrupting bone growth and autoimmune factors.
In addition, the quality of patients' diets is worth considering since research show that patients with CD consume low amounts of cereals, fruits, vegetables and excess of meat and derivatives [57,58,59]. Gluten-free products are often highly processed products characterized by a higher content of saturated fats, simple sugars and a lower content of vitamins and minerals than their traditional counterparts [49].
Recent evidence also suggests an important role for the gut microbiota in bone metabolism, but more research is needed to better understand the exact role of the microbiome in osteoporosis in CD [68, 69]. It appears that physical activity and environmental pollution may also influence the development of bone disorders in CD [75, 81].
Answering the question in the title, which factor—genetic, immunological, dietary, gut microbiota, or environmental—plays the first violin in the development of osteoporosis in the course of celiac disease, we emphasize that there is no unequivocal answer to the question. All the presented determinants are important elements that affect the development of bone disorders in patients with celiac disease, and abnormalities in one can disrupt the entire complex mechanism of action.
References
Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PHR, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KEA, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C (2013) The Oslo definitions for coeliac disease and related terms. Gut 62:43–52. https://doi.org/10.1136/gutjnl-2011-301346
Molberg O, Mcadam SN, Körner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Norén O, Roepstorff P, Lundin KE, Sjöström H, Sollid LM (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 4:713–717. https://doi.org/10.1038/nm0698-713
Makharia GK, Chauhan A, Singh P, Ahuja V (2022) Review article: epidemiology of coeliac disease. Aliment Pharmacol Ther 56:S3–S17. https://doi.org/10.1111/apt.16787
Roberts SE, Morrison-Rees S, Thapar N, Benninga MA, Borrelli O, Broekaert I, Dolinsek J, Martin-de-Carpi J, Mas E, Miele E, Pienar C, Ribes-Koninckx C, Thomassen RA, Thomson M, Tzivinikos C, Thorne K, John A, Williams JG (2021) Systematic review and meta-analysis: the incidence and prevalence of paediatric coeliac disease across Europe. Aliment Pharmacol Ther 54:109–128. https://doi.org/10.1111/apt.16337
Raiteri A, Granito A, Giamperoli A, Catenaro T, Negrini G, Tovoli F (2022) Current guidelines for the management of celiac disease: a systematic review with comparative analysis. WJG 28:154–176. https://doi.org/10.3748/wjg.v28.i1.154
Ganji R, Moghbeli M, Sadeghi R, Bayat G, Ganji A (2019) Prevalence of osteoporosis and osteopenia in men and premenopausal women with celiac disease: a systematic review. Nutr J 18:9. https://doi.org/10.1186/s12937-019-0434-6
Kanis JA (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group Osteoporos Int 4:368–381. https://doi.org/10.1007/BF01622200
Clynes MA, Harvey NC, Curtis EM, Fuggle NR, Dennison EM, Cooper C (2020) The epidemiology of osteoporosis. Br Med Bull. https://doi.org/10.1093/bmb/ldaa005
Salari N, Ghasemi H, Mohammadi L, Behzadi M, Rabieenia E, Shohaimi S, Mohammadi M (2021) The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res 16:609. https://doi.org/10.1186/s13018-021-02772-0
Kanis JA, McCloskey EV, Johansson H, Strom O, Borgstrom F, Oden A, National Osteoporosis Guideline Group (2008) Case finding for the management of osteoporosis with FRAX®—assessment and intervention thresholds for the UK. Osteoporos Int 19:1395–1408. https://doi.org/10.1007/s00198-008-0712-1
Mosca C, Thorsteinsdottir F, Abrahamsen B, Rumessen JJ, Händel MN (2022) Newly diagnosed celiac disease and bone health in young adults: a systematic literature review. Calcif Tissue Int 110:641–648. https://doi.org/10.1007/s00223-021-00938-w
Osteoporosis in celiac disease: An Update[v1] | Preprints. https://www.preprints.org/manuscript/202207.0344/v1. Accessed 22 Jan 2023
Hjelle AM, Apalset E, Mielnik P, Bollerslev J, Lundin KEA, Tell GS (2014) Celiac disease and risk of fracture in adults—a review. Osteoporos Int 25:1667–1676. https://doi.org/10.1007/s00198-014-2683-8
Walker MD, Williams J, Lewis SK, Bai JC, Lebwohl B, Green PHR (2020) Measurement of forearm bone density by dual energy x-ray absorptiometry increases the prevalence of osteoporosis in men with celiac disease. Clin Gastroenterol Hepatol 18:99–106. https://doi.org/10.1016/j.cgh.2019.03.049
Grace-Farfaglia P (2015) Bones of contention: bone mineral density recovery in celiac disease—a systematic review. Nutrients 7:3347–3369. https://doi.org/10.3390/nu7053347
Vestergaard P (2002) fracture risk in patients with celiac disease, Crohn’s disease, and ulcerative colitis: a nationwide follow-up study of 16,416 patients in Denmark. Am J Epidemiol 156:1–10. https://doi.org/10.1093/aje/kwf007
West J, Logan RFA, Card TR, Smith C, Hubbard R (2003) Fracture risk in people with celiac disease: a population-based cohort study. Gastroenterology 125:429–436. https://doi.org/10.1016/S0016-5085(03)00891-6
Ludvigsson JF, Michaelsson K, Ekbom A, Montgomery SM (2006) Coeliac disease and the risk of fractures - a general population-based cohort study: Coeliac Disease And Risk Of Fracture. Aliment Pharmacol Ther 25:273–285. https://doi.org/10.1111/j.1365-2036.2006.03203.x
Heikkilä K, Pearce J, Mäki M, Kaukinen K (2015) Celiac disease and bone fractures: a systematic review and meta-analysis. J Clin Endocrinol Metab 100:25–34. https://doi.org/10.1210/jc.2014-1858
Sánchez MIP (2011) Risk of fracture in celiac disease: gender, dietary compliance, or both? WJG 17:3035. https://doi.org/10.3748/wjg.v17.i25.3035
Passananti V, Santonicola A, Bucci C, Andreozzi P, Ranaudo A, Di Giacomo DV, Ciacci C (2012) Bone mass in women with celiac disease: role of exercise and gluten-free diet. Dig Liver Dis 44:379–383. https://doi.org/10.1016/j.dld.2011.12.012
Kujawowicz K, Mirończuk-Chodakowska I, Witkowska AM (2022) Dietary behavior and risk of orthorexia in women with celiac disease. Nutrients 14:904. https://doi.org/10.3390/nu14040904
Volta U, Villanacci V (2011) Celiac disease: diagnostic criteria in progress. Cell Mol Immunol 8:96–102. https://doi.org/10.1038/cmi.2010.64
Bianchi ML, Bardella MT (2002) Bone and celiac disease. Calcif Tissue Int 71:465–471. https://doi.org/10.1007/s00223-001-2131-6
Vasquez H, Mazure R, Gonzalez D, Flores D, Pedreira S, Niveloni S, Smecuol E, Mauriño E, Bai JC (2000) Risk of fractures in celiac disease patients: a cross-sectional, case-control study. Am J Gastroenterol 95:183–189. https://doi.org/10.1111/j.1572-0241.2000.01682.x
Stazi AV, Trinti B (2006) Reproduction, endocrine disorders and celiac disease: risk factors of osteoporosis. Minerva Med 97:191–203
Stenson WF, Newberry R, Lorenz R, Baldus C, Civitelli R (2005) Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis. Arch Intern Med 165:393–399. https://doi.org/10.1001/archinte.165.4.393
Corazza GR, Di Sario A, Cecchetti L, Jorizzo RA, Di Stefano M, Minguzzi L, Brusco G, Bernardi M, Gasbarrini G (1996) Influence of pattern of clinical presentation and of gluten-free diet on bone mass and metabolism in adult coeliac disease. Bone 18:525–530. https://doi.org/10.1016/8756-3282(96)00071-3
Mazure R, Vazquez H, Gonzalez D, Mautalen C, Pedreira S, Boerr L, Bai JC (1994) Bone mineral affection in asymptomatic adult patients with celiac disease. Am J Gastroenterol 89:2130–2134
McFarlane XA, Bhalla AK, Robertson DA (1996) Effect of a gluten free diet on osteopenia in adults with newly diagnosed coeliac disease. Gut 39:180–184. https://doi.org/10.1136/gut.39.2.180
Godfrey JD, Brantner TL, Brinjikji W, Christensen KN, Brogan DL, Van Dyke CT, Lahr BD, Larson JJ, Rubio-Tapia A, Melton LJ, Zinsmeister AR, Kyle RA, Murray JA (2010) Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology 139:763–769. https://doi.org/10.1053/j.gastro.2010.05.041
Kotze LMS, Skare T, Vinholi A, Jurkonis L, Nisihara R (2016) Impact of a gluten-free diet on bone mineral density in celiac patients. Rev Esp Enferm Dig 108:84–88. https://doi.org/10.17235/reed.2015.3953/2015
Galli G, Lahner E, Conti L, Esposito G, Sacchi MC, Annibale B (2018) Risk factors associated with osteoporosis in a cohort of prospectively diagnosed adult coeliac patients. United European Gastroenterol J 6:1161–1168. https://doi.org/10.1177/2050640618784340
Garrote JA, Gómez-González E, Bernardo D, Arranz E, Chirdo F (2008) Celiac disease pathogenesis: the proinflammatory cytokine network. J Pediatr Gastroenterol Nutr 47:S27. https://doi.org/10.1097/MPG.0b013e3181818fb9
Bommu VJL, Mirza L (2021) Osteoporosis can be the sole presentation in celiac disease. Cureus. https://doi.org/10.7759/cureus.20602
Di Stefano M, Mengoli C, Bergonzi M, Corazza GR (2013) Bone mass and mineral metabolism alterations in adult celiac disease: pathophysiology and clinical approach. Nutrients 5:4786–4799. https://doi.org/10.3390/nu5114786
Krupa-Kozak U (2014) Pathologic bone alterations in celiac disease: etiology, epidemiology, and treatment. Nutrition 30:16–24. https://doi.org/10.1016/j.nut.2013.05.027
Fornari MC, Pedreira S, Niveloni S, González D, Diez RA, Vázquez H, Mazure R, Sugai E, Smecuol E, Boerr L, Mauriño E, Bai JC (1998) Pre- and post-treatment serum levels of cytokines IL-1beta, IL-6, and IL-1 receptor antagonist in celiac disease. Are they related to the associated osteopenia? Am J Gastroenterol 93:413–418. https://doi.org/10.1111/j.1572-0241.1998.00413.x
Taranta A, Fortunati D, Longo M, Rucci N, Iacomino E, Aliberti F, Facciuto E, Migliaccio S, Bardella MT, Dubini A, Borghi MO, Saraifoger S, Teti A, Bianchi ML (2004) Imbalance of osteoclastogenesis-regulating factors in patients with celiac disease. J Bone Miner Res 19:1112–1121. https://doi.org/10.1359/JBMR.040319
Fernández A, González L, de la Fuente J (2010) Coeliac disease: clinical features in adult populations. Rev Esp Enferm Dig 102:466–471
Epsley S, Tadros S, Farid A, Kargilis D, Mehta S, Rajapakse CS (2021) The effect of inflammation on bone. Front Physiol 11:511799. https://doi.org/10.3389/fphys.2020.511799
Bardella MT, Bianchi ML, Teti A (2005) Chronic inflammatory intestinal diseases and bone loss. Gut 54:1508
Moreno ML, Crusius JBA, Cherñavsky A, Sugai E, Sambuelli A, Vazquez H, Mauriño E, Peña AS, Bai JC (2005) The IL-1 gene family and bone involvement in celiac disease. Immunogenetics 57:618–620. https://doi.org/10.1007/s00251-005-0033-x
Micic D, Rao VL, Semrad CE (2020) Celiac disease and its role in the development of metabolic bone disease. J Clin Densitom 23:190–199. https://doi.org/10.1016/j.jocd.2019.06.005
Krupa-Kozak U, Drabińska N (2016) Calcium in gluten-free life: health-related and nutritional implications. Foods 5:51. https://doi.org/10.3390/foods5030051
Harrison JE, Hitchman AJW, Finlay JM, Mcneill KG (1969) Calcium kinetic studies in patients with malabsorption syndrome. Gastroenterology 56:751–757. https://doi.org/10.1016/S0016-5085(69)80037-5
Alkalay MJ (2021) Nutrition in patients with lactose malabsorption, celiac disease, and related disorders. Nutrients 14:2. https://doi.org/10.3390/nu14010002
Jameson S (2000) Coeliac disease, insulin-like growth factor, bone mineral density, and zinc. Scand J Gastroenterol 35:894–896
Cardo A, Churruca I, Lasa A, Navarro V, Vázquez-Polo M, Perez-Junkera G, Larretxi I (2021) Nutritional imbalances in adult celiac patients following a gluten-free diet. Nutrients 13:2877. https://doi.org/10.3390/nu13082877
Muñoz-Garach A, García-Fontana B, Muñoz-Torres M (2020) Nutrients and dietary patterns related to osteoporosis. Nutrients 12:1986. https://doi.org/10.3390/nu12071986
Pantaleoni S, Luchino M, Adriani A, Pellicano R, Stradella D, Ribaldone DG, Sapone N, Isaia GC, Di Stefano M, Astegiano M (2014) Bone mineral density at diagnosis of celiac disease and after 1 year of gluten-free diet. Sci World J 2014:173082. https://doi.org/10.1155/2014/173082
Corazza GR, Di Sario A, Cecchetti L, Tarozzi C, Corrao G, Bernardi M, Gasbarrini G (1995) Bone mass and metabolism in patients with celiac disease. Gastroenterology 109:122–128. https://doi.org/10.1016/0016-5085(95)90276-7
Duerksen DR, Leslie WD (2010) Positive celiac disease serology and reduced bone mineral density in adult women. Can J Gastroenterol 24:103–107
Valdimarsson T, Löfman O, Toss G, Ström M (1996) Reversal of osteopenia with diet in adult coeliac disease. Gut 38:322–327. https://doi.org/10.1136/gut.38.3.322
Kemppainen T, Kröger H, Janatuinen E, Arnala I, Lamberg-Allardt C, Kärkkäinen M, Kosma VM, Julkunen R, Jurvelin J, Alhava E, Uusitupa M (1999) Bone recovery after a gluten-free diet: a 5-year follow-up study. Bone 25:355–360. https://doi.org/10.1016/s8756-3282(99)00171-4
Zanchetta MB, Longobardi V, Costa F, Longarini G, Mazure RM, Moreno ML, Vázquez H, Silveira F, Niveloni S, Smecuol E, de la Paz TM, Massari F, Sugai E, González A, Mauriño EC, Bogado C, Zanchetta JR, Bai JC (2017) Impaired bone microarchitecture improves after one year on gluten-free diet: a prospective longitudinal HRpQCT study in women with celiac disease. J Bone Miner Res 32:135–142. https://doi.org/10.1002/jbmr.2922
Vici G, Belli L, Biondi M, Polzonetti V (2016) Gluten free diet and nutrient deficiencies: a review. Clin Nutr 35:1236–1241. https://doi.org/10.1016/j.clnu.2016.05.002
Calvo-Lerma J, Crespo-Escobar P, Martínez-Barona S, Fornés-Ferrer V, Donat E, Ribes-Koninckx C (2019) Differences in the macronutrient and dietary fibre profile of gluten-free products as compared to their gluten-containing counterparts. Eur J Clin Nutr 73:930–936. https://doi.org/10.1038/s41430-018-0385-6
Miranda J, Lasa A, Bustamante MA, Churruca I, Simon E (2014) Nutritional differences between a gluten-free diet and a diet containing equivalent products with gluten. Plant Foods Hum Nutr 69:182–187. https://doi.org/10.1007/s11130-014-0410-4
Malesza IJ, Malesza M, Walkowiak J, Mussin N, Walkowiak D, Aringazina R, Bartkowiak-Wieczorek J, Mądry E (2021) High-fat, western-style diet, systemic inflammation, and gut microbiota: a narrative review. Cells 10:3164. https://doi.org/10.3390/cells10113164
Weitzmann MN (2017) Bone and the immune system. Toxicol Pathol 45:911–924. https://doi.org/10.1177/0192623317735316
Ojetti V, Nucera G, Migneco A, Gabrielli M, Lauritano C, Danese S, Zocco MA, Nista EC, Cammarota G, De Lorenzo A, Gasbarrini G, Gasbarrini A (2005) High prevalence of celiac disease in patients with lactose intolerance. Digestion 71:106–110. https://doi.org/10.1159/000084526
Aaron L, Patricia W, Ajay R, Torsten M (2019) Celiac disease and lactose intolerance. Int J Celiac Dis. https://doi.org/10.12691/ijcd-6-3-8
Zingone F, Iovino P, Bucci C, Ciacci C (2019) Coeliac disease: no difference in milk and dairy products consumption in comparison with controls. BMJ Nutr Prev Health 2:39–42. https://doi.org/10.1136/bmjnph-2018-000022
Wu H-J, Wu E (2012) The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 3:4–14. https://doi.org/10.4161/gmic.19320
Zhang X, Chen B, Zhao L, Li H (2020) The gut microbiota: emerging evidence in autoimmune diseases. Trends Mol Med 26:862–873. https://doi.org/10.1016/j.molmed.2020.04.001
Biagi F, Raiteri A, Schiepatti A, Klersy C, Corazza GR (2018) The relationship between child mortality rates and prevalence of celiac disease. J Pediatr Gastroenterol Nutr 66:289–294. https://doi.org/10.1097/MPG.0000000000001696
Wang J, Wang Y, Gao W, Wang B, Zhao H, Zeng Y, Ji Y, Hao D (2017) Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. PeerJ 5:e3450. https://doi.org/10.7717/peerj.3450
Ohlsson C, Sjögren K (2015) Effects of the gut microbiota on bone mass. Trends Endocrinol Metab 26:69–74. https://doi.org/10.1016/j.tem.2014.11.004
Locantore P, Del Gatto V, Gelli S, Paragliola RM, Pontecorvi A (2020) The interplay between immune system and microbiota in osteoporosis. Mediators Inflamm 2020:1–8. https://doi.org/10.1155/2020/3686749
Dar HY, Shukla P, Mishra PK, Anupam R, Mondal RK, Tomar GB, Sharma V, Srivastava RK (2018) Lactobacillus acidophilus inhibits bone loss and increases bone heterogeneity in osteoporotic mice via modulating Treg-Th17 cell balance. Bone Rep 8:46–56. https://doi.org/10.1016/j.bonr.2018.02.001
Cao R-R, He P, Lei S-F (2021) Novel microbiota-related gene set enrichment analysis identified osteoporosis associated gut microbiota from autoimmune diseases. J Bone Miner Metab 39:984–996. https://doi.org/10.1007/s00774-021-01247-w
Troy KL, Mancuso ME, Butler TA, Johnson JE (2018) Exercise early and often: effects of physical activity and exercise on women’s bone health. Int J Environ Res Public Health 15:878. https://doi.org/10.3390/ijerph15050878
Henry YM, Fatayerji D, Eastell R (2004) Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone mineral density. Osteoporos Int 15:263–273. https://doi.org/10.1007/s00198-003-1542-9
Nestares T, Martín-Masot R, de Teresa C, Bonillo R, Maldonado J, Flor-Alemany M, Aparicio VA (2021) Influence of Mediterranean diet adherence and physical activity on bone health in celiac children on a gluten-free diet. Nutrients 13:1636. https://doi.org/10.3390/nu13051636
Webster J, Vajravelu ME, Choi C, Zemel B, Verma R (2019) Prevalence of and risk factors for low bone mineral density in children with celiac disease. Clin Gastroenterol Hepatol 17:1509–1514. https://doi.org/10.1016/j.cgh.2018.10.035
Dehghani SM, Ilkhanipour H, Samipour L, Niknam R, Shahramian I, Parooie F, Salarzaei M, Tahani M (2022) Investigation of the factors affecting bone mineral density in children with celiac disease. Pediatr Gastroenterol Hepatol Nutr 25:138–146. https://doi.org/10.5223/pghn.2022.25.2.138
Elonheimo H, Lange R, Tolonen H, Kolossa-Gehring M (2021) Environmental substances associated with osteoporosis-a scoping review. Int J Environ Res Public Health 18:E738. https://doi.org/10.3390/ijerph18020738
Raehsler SL, Choung RS, Marietta EV, Murray JA (2018) Accumulation of heavy metals in people on a gluten-free diet. Clin Gastroenterol Hepatol 16:244–251. https://doi.org/10.1016/j.cgh.2017.01.034
Elli L, Pigatto PD, Guzzi G (2018) Evaluation of metals exposure in adults on a gluten-free diet. Clin Gastroenterol Hepatol 16:152. https://doi.org/10.1016/j.cgh.2017.07.035
Jalili C, Kazemi M, Taheri E, Mohammadi H, Boozari B, Hadi A, Moradi S (2020) Exposure to heavy metals and the risk of osteopenia or osteoporosis: a systematic review and meta-analysis. Osteoporos Int 31:1671–1682. https://doi.org/10.1007/s00198-020-05429-6
Duerksen D, Pinto-Sanchez MI, Anca A, Schnetzler J, Case S, Zelin J, Smallwood A, Turner J, Verdú E, Butzner JD, Rashid M (2018) Management of bone health in patients with celiac disease. Can Fam Phys 64:433–438
Fouda MA, Khan AA, Sultan MS, Rios LP, McAssey K, Armstrong D (2012) Evaluation and management of skeletal health in celiac disease: position statement. Can J Gastroenterol 26:819–829. https://doi.org/10.1155/2012/823648
Quattrini S, Pampaloni B, Gronchi G, Giusti F, Brandi ML (2021) The Mediterranean diet in osteoporosis prevention: an insight in a peri- and post-menopausal population. Nutrients 13:531. https://doi.org/10.3390/nu13020531
Movassagh EZ, Vatanparast H (2017) Current evidence on the association of dietary patterns and bone health: a scoping review. Adv Nutr 8:1–16. https://doi.org/10.3945/an.116.013326
Duerksen D, Pinto-Sanchez MI, Anca A, Schnetzler J, Case S, Zelin J, Smallwood A, Turner J, Verdú E, Butzner JD, Rashid M (2018) Management of bone health in patients with celiac disease: practical guide for clinicians. Can Fam Phys 64:433–438
Al-Toma A, Volta U, Auricchio R, Castillejo G, Sanders DS, Cellier C, Mulder CJ, Lundin KEA (2019) European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J 7:583–613. https://doi.org/10.1177/2050640619844125
Downey L, Houten R, Murch S, Longson D, Guideline Development Group (2015) Recognition, assessment, and management of coeliac disease: summary of updated NICE guidance. BMJ 351:h4513. https://doi.org/10.1136/bmj.h4513
Ludvigsson JF, Bai JC, Biagi F, Card TR, Ciacci C, Ciclitira PJ, Green PHR, Hadjivassiliou M, Holdoway A, van Heel DA, Kaukinen K, Leffler DA, Leonard JN, Lundin KEA, McGough N, Davidson M, Murray JA, Swift GL, Walker MM, Zingone F, Sanders DS (2014) Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 63:1210–1228. https://doi.org/10.1136/gutjnl-2013-306578
Al-Toma A, Herman A, Lems WF, Mulder CJJ (2022) The dietary and non-dietary management of osteoporosis in adult-onset celiac disease: current status and practical guidance. Nutrients 14:4554. https://doi.org/10.3390/nu14214554
Krupa K, Parmar M, Delo LF (2023) Romosozumab. In: StatPearls. StatPearls Publishing, Treasure Island (FL)
Vall H, Parmar M (2023) Teriparatide. In: StatPearls. StatPearls, Treasure Island
Daron C, Soubrier M, Mathieu S (2017) Occurrence of rheumatic symptoms in celiac disease: a meta-analysis: comment on the article “Osteoarticular manifestations of celiac disease and non-celiac gluten hypersensitivity” by Dos Santos and Lioté. Joint Bone Spine 2016, doi:10.1016/j.jbspin.2016.09.007. Joint Bone Spine 84:645–646. https://doi.org/10.1016/j.jbspin.2017.03.006
Hujoel IA, Van Dyke CT, Brantner T, Larson J, King KS, Sharma A, Murray JA, Rubio-Tapia A (2018) Natural history and clinical detection of undiagnosed coeliac disease in a North American community. Aliment Pharmacol Ther 47:1358–1366. https://doi.org/10.1111/apt.14625
Laszkowska M, Mahadev S, Sundström J, Lebwohl B, Green PHR, Michaelsson K, Ludvigsson JF (2018) Systematic review with meta-analysis: the prevalence of coeliac disease in patients with osteoporosis. Aliment Pharmacol Ther 48:590–597. https://doi.org/10.1111/apt.14911
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IKK—Conceptualization; AD—Funding acquisition; KS, SzH, FT, AR—writing—original draft; AMR—graphic design; IKK, SzH, KS, AMR, RS, AG, AD—revision and edition of the whole manuscript. All authors have read and agreed to the present version of the manuscript.
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Kinga Skoracka and Anna Maria Rychter are participants of STER Internationalisation of Doctoral Schools Programme from NAWA Polish National Agency for Academic Exchange No. PPI/STE/2020/1/00014/DEC/02. Kinga Skoracka, Szymon Hryhorowicz, Francesco Tovoli, Alberto Raiteri, Anna Maria Rychter, Ryszard Słomski, Agnieszka Dobrowolska, Alessandro Granito, and Iwona Krela-Kaźmierczak declare no conflict of interest.
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Skoracka, K., Hryhorowicz, S., Tovoli, F. et al. Genetic, Immunological, Dietary, Gut Microbiota, and Environmental Determinants of Osteoporosis in the Course of Celiac Disease: Which Factor Plays the First Violin in This Orchestra?. Calcif Tissue Int 114, 98–109 (2024). https://doi.org/10.1007/s00223-023-01155-3
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DOI: https://doi.org/10.1007/s00223-023-01155-3