Celiac disease is a chronic enteropathy in genetically predisposed individuals in response to gluten intake . Rather than being a rare and incurable disease, as was believed until the 1950, celiac disease is a quite common condition when analyzing epidemiological or screening studies. It is usually readily treatable, and the treatment consists most commonly of a gluten-free diet . Pathogenesis of celiac disease is complex and partially revealed. Genetically susceptible individuals form autoantibodies against tissue transglutaminase (TTG) upon challenge by dietary gluten proteins, leading to small bowel inflammation with eventually atrophy of the intestinal mucosa as the final result. Celiac disease is a serious medical condition that requires a long-term follow-up plan to maintain health and to prevent complications of disease. Maintaining a strict gluten-free diet is challenging due to hidden gluten contents of food, due to the potential financial burden of a gluten-free diet, due to nonadherence to such a diet as clinical symptoms may be indiscernible or unnoticed, or due to social consequences of the necessity to consume a specified diet. Nonadherence to a gluten-free diet is a well-known cause of ongoing intestinal inflammation and associated decrease of quality of life . An evidence-based follow-up plan for patients with celiac disease is lacking (in current literature).
Celiac disease is a disease and is a different entity than nonceliac gluten sensitivity. Nonceliac gluten sensitivity is clinically expressed as intolerance for wheat or gluten without any sign of malabsorption or intestinal inflammation . It is therefore more a descriptive term. Pathophysiology of nonceliac gluten sensitivity is unknown and the reported clinical response to a gluten-free diet remains enigmatic .
Pathogenesis of celiac disease and its associated impaired bone health
Generally, in individuals carrying a specific man leukocyte antigens (HLA)-haplotype, that is, DQ2 or DQ8, CD4+ T lymphocytes are activated by gluten proteins. The initiating event leading to this activation is unknown but may occur at any age, although commonly in the first two decades of life. Gluten proteins are abundantly present in grass belonging to the class triticeae, including wheat, barley, and rye. When activated, CD4+ T lymphocytes orchestrate an inflammatory (intestinal) response with generation of IgA autoantibodies directed at tissue transglutaminase 2, and clinical—intestinal—symptoms may follow.
Pathophysiology of impaired bone health in celiac disease is multifactorial and includes both local and systemic mechanisms . Mucosal atrophy causes decreased calcium absorption, which leads to hypocalcemia and secondary hyperparathyroidism. Increased levels of parathyroid hormone (PTH) stimulate bone turnover to release calcium by osteoclast-mediated bone resorption. The high remodeling state may lead to osteopenia and osteoporosis. Concomitant hypogonadism may also affect bone metabolism . Moreover, hypersecretion of proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha and increased receptor activator of nuclear factor kappa-B (NF-kappaB) ligand/osteoprotegerin (RANKL/OPG) ratio contributes to the loss of bone . TTG, another immunological component in celiac disease, seems to be an important enzyme in bone metabolism , as a regulator of RANKL and of osteoblast differentiation . In celiac disease, mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) are generated in response to exogenous antigenic gluten proteins in individuals who have HLA-DQ2 or HLA-DQ8. These antibodies may potentially impair bone metabolism, but further research is required to unravel this mechanism.
Symptomatology of celiac disease comprises a broad spectrum, varying from wasting, undernutrition, and fatty diarrhea, particularly in the young aged, to a variety of “hidden” nutritional deficiencies, also known as point or selective nutritional deficiencies, potentially resulting in an osteoporotic fracture as the first presentation of the disease.
The pediatrician Dicke, the founding father of a gluten-free diet as a treatment for celiac disease, described a classical triad of celiac disease (diarrhea, weight loss, and anemia) in young children around 1930 . Primarily, symptomatology is associated with the severity of intestinal dysfunction ascribed to the gluten-induced intestinal inflammation accompanied by several stages of mucosal atrophy. Concomitantly with the symptoms of celiac disease, symptoms attributable to lactose malabsorption may coexist. Symptoms of bloating, abdominal discomfort, and diarrhea may therefore continue upon a gluten-free diet, while lactose is still ingested in the ones with lactase deficiency. In addition to celiac disease, microscopic colitis may occur, a condition—again—leading to secretory diarrhea. Other associated conditions are dermatitis herpetiformis, neuroceliac disease (gluten-induced ataxia), autoimmune diseases, including hypothyroidism, adrenal insufficiency, diabetes mellitus, and, although specifically not a variant of celiac disease, nonceliac gluten sensitivity. Symptomatology of celiac disease may be thwarted by these concurrently occurring and associated autoimmune diseases. There is a great overlap in extragastrointestinal symptoms in celiac disease and other gastrointestinal disorders.
Since celiac disease may present with a variety of (nonspecific) symptoms, an estimated 80% of patients still remain undiagnosed .
Improvement of symptoms on a gluten-free diet or exacerbation of alleged celiac disease symptoms after reintroduction of gluten has a very low predictive value for the diagnosis of celiac disease and should therefore not be used as a diagnostic means in the absence of other supportive evidence.
Diagnostic testing is advocated in patients with classical symptoms such as diarrhea, failure to thrive, and with “spontaneous” nutritional deficiencies. Also, extensive testing for celiac disease is encouraged in monosymptomatic patients with a documented increased prevalence for celiac disease, such as idiopathic osteoporosis, patients with noncirrhotic portal hypertension, elevated activity of serum transaminases, or iron-deficiency anemia. Furthermore, patients with autoimmune disorders, such as type 1 diabetes mellitus, autoimmune thyroid disorders, or autoimmune liver disease, have an increased prevalence of celiac disease and should therefore be routinely tested. And, finally, genetic disorders, such as Down syndrome and Turner syndrome, are associated with an increased occurrence of celiac disease.
Diagnostics include serology and histopathological examination of a duodenal biopsy specimen. These tests are most sensitive when the patient is still on a gluten-containing diet. The treatment for celiac disease is a gluten-free diet, which requires substantial patient education, motivation, and follow-up. Slow clinical response upon initiation of a gluten-free diet occurs frequently, particularly in those individuals in whom celiac disease was being diagnosed in adulthood .
Celiac disease has been more well-recognized over the last several decades, though many patients remain undiagnosed . Conversely, there are centers in Europe, India, and the United States, where awareness of celiac disease has been drilled into pediatricians and general physicians. In some cases, they might be too eager to diagnose celiac disease based on only serology examinations showing a TTG antibody concentration, which is merely two to three times the upper limit of normal, and advise a gluten-free diet for life without a tissue diagnosis . Nevertheless, celiac disease is one of the most common autoimmune disorders, affecting approximately 1% of the worldwide population . Globally, the prevalence is increasing, probably associated with the widespread use of wheat as staple food . Previously thought to be primarily a disorder to be established in childhood or early adult life, celiac disease is increasingly diagnosed in older adults. Currently, 40% of celiac disease is diagnosed during childhood and the remaining 60% in adulthood. In children, 50% is diagnosed before the age of 4 years. In adults, median age at celiac disease diagnosis differs between males (52 years) and females (44 years) , and there is a large gender discrepancy with a female-to-male prevalence ratio of approximately 5:1. This may be important given the association between celiac disease and osteoporosis. Environmental factors contribute to the occurrence of celiac disease, such as changes in the quality and quantity of ingested gluten, in the intestinal microbiome, or in the spectrum of intestinal infections. In addition, greater clinical and diagnostic awareness of the disease and the availability of affordable and highly sensitive serological tools are believed to attribute to the apparent rise in celiac disease prevalence .
Epidemiology of osteoporosis in celiac disease
Bone mineral density (BMD) alterations are reported in more than half (60%) of newly diagnosed adult celiac patients. Celiac disease–related osteoporosis was associated with male gender, with an age over 45 years, with underweight, and with more severe histopathological atrophy according to the Marsh-classification . Osteoporosis may even be the presenting symptom of unrecognized celiac disease. There is a lack of epidemiological data, associating BMD values in celiac disease patients with the occurrence or frequency of (fragility) fractures. BMD is not the only factor associated with fracture risk in celiac disease patients. Secondary hyperparathyroidism and osteomalacia from calcium and vitamin D malabsorption (and other nutritional deficiencies) have also been described to influence bone strength . Other factors that may contribute to fragility and fracture risk in celiac disease patients include zinc deficiency and low insulin-like growth factor (IGF)-1, low body mass index (BMI), malnutrition and hypogonadism, and bone-specific autoantibodies . In any case, an increased fracture risk in adult celiac disease patients has been observed at initial diagnosis, and, in addition, after long-term gluten-free diet .
Despite the strong association between low BMD and celiac disease, different opinions exist whether each patient with a newly diagnosed celiac disease should undergo a dual-energy X-ray absorptiometry (DXA) scan . Previously, DXA investigations were only advised for patients with celiac disease who were peri- or postmenopausal or males over 55 years, and those with overt malabsorption or a history of fragility fractures , since studies on BMD in celiac disease patients have led to equivocal results. Moreover, in several of these studies, patients who had already adopted a gluten-free diet for years were included. In addition, bone studies in celiac disease patients have commonly been designed to exclusively include females in the postmenopausal period, because of the well-known gender effect of osteoporosis in the general population. Altogether, it is therefore difficult to calculate the true prevalence of osteopenia, osteoporosis, and reduced bone health in (newly diagnosed) adult celiac disease patients. Recently, the American Gastroenterological Association advised to consider a DXA scan in all adults with newly diagnosed celiac disease 1 year after initiation of a gluten-free diet to establish bone health .
Currently, active case-finding (serologic testing) for celiac disease in patients with symptoms or conditions closely associated with celiac disease is the favored strategy to increase detection of celiac disease . The frequency of celiac disease is substantially increased in persons who have a first-degree family member affected with celiac disease, with reported prevalences of 5%–10% in both first- and second-degree relatives of affected individuals.
Patients with unexplained elevation of liver enzymes should also be assessed for celiac disease; normalization of elevated activity of serum transaminases is reported after initiation of a gluten-free diet in more than 95% of patients. Clearly, in unexplained osteopenia or osteoporosis celiac disease should be assessed as well .
In patients with features of autoimmune diseases in general, such as type 1 diabetes mellitus, thyroid disease, rheumatoid arthritis, psoriasis, and microscopic colitis, the prevalence of celiac disease is substantially increased as compared to the general population . In general, those so-called associated autoimmune diseases with chronic inflammation might be considered as additional risk factors for osteopenia.
It was with the advent of autoantibodies, first directed against reticulin, then endomysium (EMA), and finally TTG, that truly celiac-specific testing has been developed. The antitissue transglutaminase test is the most sensitive test for celiac disease, whereas IgA-EMA autoantibodies are the most specific test .
Endoscopic (macroscopic) findings are neither sensitive nor specific in celiac disease. Thus the mucosal appearance during endoscopic visualization does not preclude the necessity to perform serological testing and routine harvest of a duodenal biopsy specimen for histopathological diagnosis to make or reject the diagnosis of celiac disease. Multiple biopsies (preferably four or more) of duodenal mucosa should be taken if a diagnosis of celiac disease is being considered.
Celiac disease occurs almost exclusively in patients who express HLA-DQ2 or DQ8 molecules, thus seemingly a prerequisite for specific gluten presentation as an antigen to develop celiac disease . Most individuals with this HLA-signature, however, do not develop celiac disease.
The definitive diagnosis of celiac disease relies on a combination of clinical, serological, and histopathological findings, eventually corroborated by the genetic profile. The histological specimens should be classified according to the well-established criteria of Marsh, and modified by Rostami .
DXA at the femoral neck and lumbar spine is considered the gold standard to confirm the diagnosis of osteoporosis . In the 2019 European Society for study of Coeliac Disease (ESsCD) guidelines for follow-up in adult celiac patients, it has been advised to perform a DXA scan only in symptomatic adult celiac disease at diagnosis (ESsCD website and ).
Treatment of celiac disease
The mainstay of treatment of celiac disease is a gluten-free diet . Patients with celiac disease should be educated to avoid cereals and food products derived from wheat, barley, or rye and food made from gluten-contaminated cereals, during food processing, which are normally gluten free such as maize and oats. Food labeling is important, and recent regulation by food authorities in Western countries has improved identification of gluten content in food. There is evidence that compliance with a gluten-free diet is improved in those who are more knowledgeable about celiac disease and its diet.
The majority of patients report clinical improvement within weeks. However, mucosal recovery in adults may take years after initiation of a gluten-free diet. Most patients diagnosed above 50 years have a slow histological recovery, which might even take several years to fully recover, if at all. In a minority, partial intestinal healing can only be achieved. Adherence to a gluten-free diet usually leads to improvement in nutrient absorption. However, a gluten-free diet itself has limitations in nutrient value and vigilant dietary monitoring is necessary. Vitamin D absorption is decreased in intestinal villous atrophy, partly due to fat malabsorption. Further, elimination of milk products in celiac disease, especially when concomitant lactose intolerance exists, will induce calcium deficiency as well, as a diet with a low lactose content (lactose-free) is usually also low in calcium content. A reduced overall physical health, concurrent with a diminished nutritional status, may lead to reduced physical activity and decreased sun exposure. Vitamin D and calcium levels may normalize within 1–2 years of a strict gluten-free diet that, in some patients, can—partially—reverse bone loss . Nevertheless, calcium and vitamin D should be supplemented in celiac disease patients documented with low serum levels or with loss of bone mineral density, or those who cannot achieve adequate intake via diet .
When a gluten-free diet fails to improve symptoms, other contributing factors, such as lactose intolerance or lactase deficiency or microscopic colitis, must be ruled out. However, in most cases, contamination of allegedly gluten-free diet or plain nonadherence to such a diet is the more common culprit of persistence of symptomatology or positive serology or histological atrophy.
Well-known complications of celiac disease comprise nutritional deficiencies, including iron-deficiency anemia and many other vitamin and mineral deficiencies leading to failure to thrive and below average body length, and (premature) osteoporosis . Also, an increased risk for malignant lymphoma of the small bowel exists, particularly in those celiac disease patients who are nonadherent to the gluten-free diet .
Although celiac disease usually runs a benign course, a small minority (<0.5%) is refractory to a gluten-free diet, presenting with aberrant intraepithelial lymphocytes and persistence of villous atrophy. This entity is called refractory celiac disease type II, with 50% of these patients developing a lymphoma, that is, enteropathy-associated T-cell lymphoma, within 4–6 years after diagnosis with a poor prognosis . Severe malnutrition, nutritional deficiencies, and osteoporosis are a given standard in this subgroup .
Bone health and celiac disease
Due to the broad clinical presentation of celiac disease, and the lack of clinical vigilance, many patients are not diagnosed, or with a (patients’ or doctors’) delay that may extend for years. Meanwhile, villous atrophy causes dietary malabsorption and maldigestion, which results in deficiency of calcium, vitamin D, and other nutrients important for bone health . Subsequently, the level of parathyroid hormone is increased to counterbalance or correct hypocalcemia, which causes calcium release from the skeleton reservoir. Early identification may improve motivation to comply with gluten-free diet and allow adequate calcium and vitamin D supplementation to reduce risk of fracture later in life . Other possible mediators to affect bone health are concomitant hypogonadism and the hypersecretion of celiac disease–associated proinflammatory cytokines, which may interfere with bone formation . As a net result, celiac disease patients have an increased risk for osteopenia or osteoporosis. Low BMD is a common finding in young patients with celiac disease, yet to routinely assess BMD in young patients is not currently supported by (inter)national guidelines .
Treatment of decreased bone health/osteoporosis in celiac disease
The risk of osteoporosis and bone fracture is increased in adult celiac disease . This excess risk may be reduced with good adherence to a gluten-free diet with subsequent normalization of intestinal villous atrophy . In this study, it has been suggested that bone density is particularly increased during the first year of gluten-free diet adherence, especially in younger patients (<40 years). Unfortunately, diet alone, and adherence to a strict gluten-free diet are not the only mediators for osteoporosis and increased fracture risk. In contrast, similar risks for fractures before and after celiac diagnosis were reported in a population-based study .
Based on the current evidence, it is strongly advocated to assess serum calcium concentration, alkaline phosphatase activity, and vitamin 25-OH-D concentrations at diagnosis, and provide supplemental nutrients, as necessary. Calcium intake should be maintained at, or above, 1000 mg/day .
Since evidence is lacking, a practical approach should be applied to the majority of patients in daily practice. A baseline bone density measurement (DXA) is suggested in all celiac adults, 1 year after adequate diet therapy, and repeat measurements is suggested for those with normal baseline measurement after 5 years, and also in patients who have low bone density on index measurement following initiation of appropriate treatment (to assess therapy response). Individuals who have ongoing villous atrophy, or who show poor dietary adherence (ESsCD guideline 2019) should be measured more frequent, but strict recommendations are lacking. This strategy aims to avoid the late initiation of treatment and may therefore prevent fractures.
Loss of bone density in follow-up at a greater than expected rate should prompt measurement of vitamin D levels, dietary review of gluten-free diet adherence, consideration of repeat intestinal biopsy, and review of additional risk factors such as hypogonadism. A consultation with an endocrinologist or a rheumatologist should be considered in difficult cases.
All of the latter patients with high risk for fragility bone fractures should be given appropriate calcium and vitamin D supplementation. In the case of osteoporosis, intravenous bisphosphonate use is recommended . This recommendation is based on probable unreliable or poor absorption of oral bisphosphonates in celiac disease patients at diagnosis or in those with persisting villous abnormalities. During yearly follow-up, renal function, calcium, alkaline phosphatase, vitamin D, and parathyroid hormone should be monitored . There are case reports suggesting that bisphosphonates may aggravate expression of celiac disease, a yet unexplained finding . An approach in celiac disease patients with normalized histology might be to use a 24–36-month treatment course with oral risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation .
Inflammatory bowel diseases
Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disease principally localized in the intestines with an array of systemic manifestations, including impaired bone health, leading to an increased prevalence of osteopenia and osteoporosis, potentially at an early age . The incidence of IBD, and for Crohn’s disease more so than for ulcerative colitis, is rising worldwide, with a north-to-south gradient, and has been introduced in the non-Western world concurrent with industrialization, and the accompanying dietary habits . The etiology of decreased bone health in IBD patients is multifactorial and comprises both general and IBD-related factors, partially overlapping (see Table 43.1 ). Therapy for decreased bone health in IBD patients is as a rule aimed at bone-protecting measurements, diet and medication, as well as suppression of IBD-associated inflammation .
|Low intake of calcium, decreased vitamin D concentrations, low magnesium and potassium concentrations, chronic acidosis, low bone peak mass, low body mass index, decreased physical activity, (passive/active) smoking, excessive alcohol consumption, family history, and genetic background|
|IBD therapy||Corticosteroids (detrimental)|
|Anti-TNF therapy (beneficial)|
|IBD-specific factors||Sex hormone deficiency|
|Low body mass index/bone peak mass|
|Gastrointestinal damage||Intestinal insufficiency (short bowel syndrome)|
|Inflammatory processes underlying IBD||Cytokine and other immunological networks in disbalance|
IBD comprises a group of chronic, relapsing, disbalanced inflammatory diseases, principally localized in intestinal mucosa. IBD is subdivided in to two main phenotypes: Crohn’s disease and ulcerative colitis, and a nonclassified subtype, known as unclassified or indeterminate colitis . IBD is most commonly diagnosed in patients between 15 and 35 years of age and is characterized by periods of active (intestinal) inflammation and periods of remission, spontaneously, or drug-induced .
The etiology of IBD is partly characterized and usually depicted as a combination of four domains, all believed to contribute to the clinical picture: (1) proinflammatory (mucosal) immunological disbalance; (2) genetic predisposition, with over 200 involved genes; (3) microbiome and diet; and (4) environmental factors, including smoking .
Worldwide, the incidence of IBD is rising. It seems to display a north-to-south gradient. IBD appears to have been introduced to the non-Western world concurrent with industrialization, including the accompanying dietary habits . In The Netherlands, a typical Western country with a high incidence and prevalence of IBD, the annual incidence increased from 17.90 per 100,000 in 1991 to 40.36 per 100,000 in 2010 for IBD, from 5.84 per 100,000 to 17.49 per 100,000 for Crohn’s disease, and from 11.67 per 100,000 to 21.47 per 100,000 for ulcerative colitis . The onset typically occurs in the second and third decade of life. IBD is most commonly characterized by periods of active disease (relapse) and periods of remission (i.e., quiescent phase) . IBD diagnosed in children and in adulthood is associated with osteopenia, osteoporosis, and fracture risk in several studies, both in Western and in Asian countries .
Crohn’s disease is typically localized in the terminal ileum, in segmental parts of the colon, or in both of these sites. Symptomatology may widely vary, depending on the phenotypic characteristics, which are primarily luminal, stenotic, or penetrating, and on localization of inflammatory disease. Undulating abdominal pain, general malaise, tiredness, fever, and diarrhea are variably present. Nutritional deficiencies (and attenuated growth in childhood) are common.
Ulcerative colitis most commonly presents with bloody diarrhea and (fecal) urgency, crampy abdominal pains, and fever, all in varying intensity depending mainly on severity of disease.
The diagnosis of IBD depends on a combination of symptoms, and evidence of bowel inflammation assessed by laboratory examination, including C-reactive protein and fecal calprotectin, endoscopic examination for mucosal ulcerations, or other inflammatory changes, sometimes in combination with radiologic findings. Also, histopathological examination of intestinal biopsy specimens contributes to the diagnosis.
Treatment of inflammatory bowel disease (essentials)
Lacking curative therapy, medical treatment of IBD is primarily based on the concept that the (intestinal) inflammation must be dampened, temporized, or hindered, if not by drugs, then by surgical resection. All commonly used pharmaceutical compounds interfere with inflammatory cascades.
The main drug therapy classes for IBD comprise (1) mesalazines; (2) corticosteroids; (3) immunosuppressives; (4) cytokine therapy (biologicals), currently including TNF-alpha inhibitors (TNFi), the integrin inhibitors vedolizumab, and the IL-12/IL-23 blockers ustekinumab; and (5) small molecules, of which tofacitinib, a relative nonselective JAK–STAT (Janus Kinases–Signal Transducer and Activator of Transcription proteins) inhibitor, is the first that is registered, exclusively for ulcerative colitis treatment.
Treatment goal is a matter of debate and appears to shift from complaints-based outcomes to objective dampening of intestinal inflammation, usually assessed by endoscopic evaluation. Together with this shift in therapeutic aim, the sequence of use of the five therapy classes is changing from sequential use of mesalazines via steroids and immunosuppressives to biologicals or small molecules to early use of biologicals. Whether or not the earlier use of biological medications will change the course of IBD, it is assumed that this new strategy to maximally dampen inflammatory burden may have a bone-protective effect .
Extraintestinal manifestations occur frequently and form part of the clinical picture of IBD. The most commonly observed extraintestinal manifestations comprise arthralgia or arthritis (between 5% and 15%), cutaneous eruptions (between 3% and 10%), idiopathic inflammation of eye compartments (1%–5%), inflammation of bile ducts (primary sclerosing cholangitis in about 1%), and an increased odds ratio for thrombosis and cardiovascular disease. Another one of these extraintestinal manifestations is impaired bone health, characterized by osteopenia, or osteoporosis and increased risk for bone fractures.
Bone health and inflammatory bowel disease
Impaired bone health may result in an increased risk for (fragility) fractures, as can also be observed in IBD patients . Characteristically, these patients have had a severe course of IBD, with a history of several courses of corticosteroid therapies, while these patients are in a poor physical and nutritional state. This, however, is the end stage of a spectrum resulting from a long medical history with organ damage of several tracts, during which many factors have contributed to a poor bone health. These factors may be identified during the disease course and should ideally have been counteracted or treated .
Epidemiology of osteoporosis in inflammatory bowel disease
To indicate the burden of diminished skeletal health in IBD patients, a prevalence of osteopenia from 32% to 36%, and of osteoporosis from 7% to 15% have been reported . This induces an estimated elevated risk for fracture of 30%–40% in Crohn’s disease patients , and an elevated risk for osteoporosis in ulcerative colitis patients, particularly at initial diagnosis .
Diagnosis of diminished bone health in inflammatory bowel disease
The ideal moment to diagnose of screen for diminished bone health has not been identified. An increased risk for osteopenia and osteoporosis has been documented in IBD patients from childhood onward. As the prevalence is relatively low in young patients, general screening of IBD patients at diagnosis, after several years of IBD or at a specified age seems not efficient . If, however, general risk factors for osteoporosis are present, one has to measure bone density in a similar way as in non-IBD patients (see Table 43.1 ). In addition, several risk factors for osteoporosis of diminished bone health are more usual in IBD patients, of which chronic, ongoing active disease, chronic corticosteroid use, undernutrition, and smoking apparently contribute most to the risk (see Table 43.1 ). In these patients, prompt DXA measurements are warranted as treatment for osteopenia or osteoporosis is indicated to prevent fragility fractures .
Diagnosis of impaired bone health in IBD patients primarily depends on DXA measurements expressed in T-scores, sometimes Z-scores. Densitometry remains a biomarker for fracture risk, whether expressed as T- or as Z-score. Both may be used in IBD patients in order to assess an increased risk, although most studies on therapy still rely on T-scores . Z-scores compare with the general population, which seems to be more suitable for the relatively young IBD patients but T-scores are commonly used in the diagnosis of osteoporosis in general, since the definition of osteoporosis is based on a T-score less than −2.5, despite the fact that IBD patients are most often relatively young. Bone turnover markers in serum or urine are not commonly being used in clinical practice. Similarly, bone biopsy and quantitative histopathology or CT-scanning are unusual.
Lumbar and thoracic lumbar X-rays are needed to substantiate osteoporotic vertebral fractures. Abdominal CT or MRI scan, commonly used to assess IBD patients, may accidently reveal osteoporotic fractures as well.
Applying the FRAX tool to predict risk for bone fracture and, hence, necessity of treatment is of limited value in IBD patients . By using this tool the calculated, elevated risk for fragility is too low to identify patients who might need preventative bone-protecting therapy .
Pathophysiology of decreased bone health in inflammatory bowel disease
The etiology of bone loss in IBD is multifactorial (see Table 43.1 ). It includes variables primarily associated with skeletal health in general, such as potentially insufficient intake of calcium, vitamin D, magnesium and potassium, smoking, a low bone peak mass, a low BMI, and decreased physical activity. In addition, IBD-associated factors contribute, due to IBD therapy, with detrimental effects of corticosteroids, and beneficial effects of anti-TNF therapy, or due to disease-specific factors, such as sex hormone deficiency, or due to gastrointestinal damage as a result of the ongoing inflammation, which potentially leads to malabsorption and intestinal leakage, or, finally, due to the inflammatory processes underlying IBD. Lately, both gut-derived serotonin and dysbiosis of the intestinal microbiome have been suggested to be involved in decreased bone health of IBD patients as well . These etiopathogenic concepts need further scientific corroboration in experiments in humans.
Sufficient nutrient intake may be hampered in IBD patients. It may be due to loss of appetite, abdominal pain, or diseased intestinal mucosa, diminishing digestive capacity. Increased intestinal leakage contributes to nutritional deficiencies. However, there is no indication that the recommended daily intake for nutrients is increased in quiescent IBD. In addition, exposure to sunlight and physical activity are usually less than required, not only leading to low vitamin D concentrations but also to insufficient anabolic bone signals . In short bowel syndrome, chronic acidosis may occur, which also deteriorates bone health.
When the disease is expressed in childhood, all of the abovementioned factors may lead to growth retardation, delayed sexual development, and/or decreased peak bone mass with structural damage .
General factors, such as smoking, excessive alcohol intake, a family history of osteoporotic bone fractures, and a genetic background associated with more fragile bone, contribute to decreased bone health in IBD patients as well.
In IBD, deficiency of sex hormone (testosterone) is more frequently observed, whereas menarche and menopause can occur later or earlier, likely due to an inadequate nutritional status. Interestingly, a higher estrogen concentration is associated with occurrence and activity of IBD .
Inflammatory bowel disease therapy and its influence on bone health
Mesalazines are believed to inhibit peroxisome proliferator–activated receptors type gamma (PPAR-gamma) generation. Theoretically, this may influence bone metabolism, since PPAR-gamma is a regulator of osteoclast activity; however, there is no substantiating evidence currently.
The detrimental impact of corticosteroids on bone health is well documented, no matter what age group is analyzed . A substantial impact of corticosteroids on the relative risk of fragility fractures has been acknowledged, though there remains debate at what dose of prednisolone–equivalent and, at which duration of therapy these detrimental effects become clinically relevant. In addition, it is questionable whether these effects are reversible following cessation of corticosteroid therapy. In IBD patients, there is epidemiological evidence that the use of corticosteroids is associated with skeletal fractures, probably with a more extensive effect when higher cumulative doses were used . The detrimental effects of corticosteroids comprise stimulation of bone resorption, due to enhanced osteoclast differentiation and prolonged osteoclast survival. Moreover, corticosteroids reduce bone formation due to decreased osteoblast recruitment and activity, and apoptosis of osteoblasts and osteocytes. Avoiding repetitive, high dose (i.e., >7.5 mg daily), and prolonged use (i.e., >3 months) of corticosteroids has been strongly advocated to protect bone structure and strength .
Commonly used immunosuppressives are thiopurine derivatives (azathioprine, mercaptopurine) and methotrexate. The antiinflammatory mechanism of action of thiopurine derivatives is allegedly mediated via inhibition of the immune-checkpoint regulating Rac proteins , which is only distantly related in cellular inflammatory networks to the documented mediators of bone metabolism. Adequately dosed thiopurine derivatives are therefore not believed to change bone metabolism. Similarly, methotrexate, presumably having antiinflammatory effect via interference with the pyrimidine pathway, is not related with bone health. Low-dose (antiinflammatory) methotrexate use has however been associated with an increase of the risk for osteonecrosis when concomitantly used with bisphosphonates .
The mechanism by which TNFi affect bone metabolism is not clear, but the net balance between degradation and formation of bone seems to lead to improvement of BMD . Proinflammatory cytokines are counteracted by TNFi, with subsequent regulation of the RANK–RANKL–OPG axis . Despite improvement in BMD with TNFi, it is unknown whether fragility fractures, including vertebral fractures, are prevented or diminished .
Other inhibitory cytokine therapies, such as ustekinumab, an IL-12 and -23 inhibitor, are less well characterized. Although potentially influencing similar bone pathways as TNFi does, this is yet hardly studied.
Tofacitinib is a JAK–STAT inhibitor with documented effects in rheumatoid arthritis for over 10 years . As JAK–STAT is a common intracellular mediator of cytokines and other cell surface signaling molecules, it has also a role in bone metabolism, in particular, in osteoclasts. Up till now, no documentation of the effects of tofacitinib on bone metabolism is available, either in rheumatoid arthritis or IBD patients.
To better understand the potential effect of antiinflammatory drugs on the bone homeostasis, several aspects have to be taken into account, including effects on the RANKL, its decoy receptor OPG, and macrophage colony-stimulating factor-induced osteoclast formation and activity. MAPK (mitogen-activated protein kinases), AKT (antiapoptotic serine/threonine kinase), and the JAK–STAT–RANKL pathway are the intracellular mediators that induce gene transcription through various promotors, encompassing activator protein 1, nuclear factor of activated T cells, PPAR-gamma, and NF-kappaB. Both surface and intracellular osteoclastic mediators are influenced by inflammatory signaling, and therefore also by drugs that down-regulate inflammation, such as in IBD.
Osteoblast activity is also, in a complex way, regulated by intracellular routings via MAPK, SMADs, and the JAK–STAT pathway, which are activated by various mediators, including transforming growth factor (TGF)-beta, bone morphogenetic proteins, parathyroid hormone, fibroblast and insulin-like growth factor, and the Wnt signaling pathway. During inflammation the generation of systemically or locally produced proinflammatory cytokines, particularly TNF-alpha and IL-6, interacts with MAPK and JAK–STAT signaling, which results in inhibition of osteoblasts .
Although bone density improves with disease remission in patients with IBD , in IBD patients in long-term remission, decreased BMD values were shown by DXA measurements . Factors involved in bone loss in active disease induce apparently long-lasting effects on bone health of these patients.
Treatment modalities of decreased bone health/osteoporosis in inflammatory bowel disease
Calcium and vitamin D
All therapeutic strategies for treatment (and prevention) of osteopenia or osteoporosis include recommendations for calcium supplementation and optimization of vitamin D concentrations. In two studies, supplementation with calcium and vitamin D was examined in an adult and a pediatric IBD population . It was reported that bone density improved in adult corticosteroid-treated patients and children with IBD, but statistical significance was not met. Similarly, as in non-IBD or other corticosteroid-using populations, supplementation of calcium seems intelligent, but not a rock-solid proven necessity.
The daily recommended dose of calcium is 1–1.2 g (approximately equivalent to 4–5 dairy products), vitamin D may be dosed depending on skin type, age, season, and geography. Serum values above 50 nmol/L are recommended in adults, above 75 nmol/L in seniors and supplementation therapy may accordingly be adapted, in any adequately documented therapeutic scheme.
Regular (routinely at yearly basis) evaluation of serum calcium and vitamin D concentrations may be advocated, especially when IBD is not in full remission. When clinically indicated, urinary calcium concentrations and serum parathyroid hormone concentrations may be helpful to optimize calcium and vitamin supplementation.
Several bisphosphonates have been studied in treatment of osteopenic or osteoporotic IBD patients, including clodronate, etidronate, ibandronate, pamidronate, risedronate, and zoledronate . Studies were mainly conducted in cohorts of Crohn’s disease patients, less so in ulcerative colitis. Also, in children with IBD, zoledronate use has been examined . The bone-protecting therapy with bisphosphonates has been the subject of extensive metaanalyses, which corroborated the likelihood that treatment with bisphosphonates improves bone density in osteopenic or osteoporotic IBD patients . The selected randomized controlled trials, including a therapeutic arm with bisphosphonate use, were employed in these thorough statistical analyses. Patient characteristics differed relevantly between the various studies with regard to age, IBD treatments, and more, the definition of low bone density varied also from osteopenia to osteoporosis. Although bisphosphonates increase bone density in IBD patients, clear-cut evidence that its use reduces the incidence of bone fractures is lacking. In another metaanalysis, comprising more or less the same studies, it was concluded that bone mineral density increased at the lumbar spine and total hip, but not at the femoral neck in bisphosphonate-using IBD patients . This underlines the open question whether hip or other fragility bone fractures will be prevented in the long run, a question that cannot be answered by currently available data. Indications that bisphosphonate use may reduce vertebral fractures in IBD patients however are present . Adverse events of bisphosphonate seem to occur infrequently and course of IBD is likely to be unchanged .
Moreover, the question addressing what patients have to be treated at what moment remains unanswered. Up till now, no evidence is available associating the use of bisphosphonates with an increased risk for exacerbations of IBD .
In general, it has been advocated that long-term use of corticosteroid above 7.5 daily prednisolone–equivalent necessitates bisphosphonate therapy in all IBD patients. Short-term courses with corticosteroids (a usual induction scheme with corticosteroids takes 2–3 months) may be concomitantly treated with bisphosphonates, as well as calcium and vitamin D supplementation, although this concept is still challenged. In the case of concurrent risk factors for osteoporosis in a given patient, there is a strong argument for bisphosphonate prescription in all IBD patients with osteopenia. Osteoporosis remains an indication for all patients, including those with IBD. Whether specific oral or subcutaneous or intravenous compounds may be preferred, depends on subtle differences, such as bioavailability of oral drugs, in particular, when small bowel disease is present, potential gastrointestinal damage with some bisphosphonate components, and ease of administration (favoring intravenous bisphosphonates such as zoledonate). Finally, optimal timing and duration of treatment with bisphosphonates has not been delineated. Concurrent bisphosphonate use with long-term corticosteroid treatment is generally accepted, whereas concomitantly with a short-term corticosteroid course is less clear-cut. Osteopenia in itself is generally not a rationale for bisphosphonate therapy, unless in patients at high risk for other reasons and/or those with severe IBD. Strict inflammation-targeted treatment of IBD may improve bone density by its own . When osteopenia is found in young IBD patients, it is not yet associated with a higher risk for fragility bone fractures. In time, however, bone density will decrease both due to ageing and ongoing disease activity. Preventative therapy may be considered, yet trial-based or epidemiological evidence is still lacking. Finally, IBD patients with established osteoporosis deserve bisphosphonate (or other) therapy, together with appropriate nutritional supplements and advice regarding physical exercise to improve bone strength and reduced risk for unintended falling.
Once initiated, duration of bisphosphonate therapy has never been studied in a cohort of IBD patients. It seems reasonable to follow a similar approach as done with primary osteoporosis, to evaluate therapy after 3–5 years and to consider discontinuation of therapy in those who appear to be at low risk for future fracture.
Treatment of osteoporosis with sodium-fluoride has been proposed in the past, but the bone is poorly mineralized, and osteomalacia and secondary hyperparathyroidism frequently occur. Sodium-fluoride treatment is not associated with a decreased risk for bone fracture . Hence, as such, it is not indicated for osteoporotic IBD patients, although an increase in bone density following its use has been reported in several studies and in metaanalysis .
Parathyroid hormone has anabolic effects on bone metabolism. It has been prescribed for corticosteroid-associated bone loss with beneficial effects on bone density . No studies in IBD patients have been performed.
Denosumab, a RANKL inhibitor, may be used in osteoporosis . Its effects may in a way be compared with the use of TNFi. When denosumab is prescribed, concomitant treatment with calcium and vitamin D is advised . Glucocorticoids increase the expression of RANKL . Denosumab may therefore be a sensible drug to treat corticosteroid-associated bone loss.
In IBD patients, this compound has not been examined. RANKL inhibition by denosumab might affect NF-kappaB function, a mediator of chronic intestinal inflammation, such as in IBD patients. Interestingly, the use of denosumab seems neither related to a higher risk for inflammatory activity (relapse of IBD) nor for an increased risk for infectious diseases . In rheumatoid arthritis patients, denosumab has been compared with risedronate to treat corticosteroid-induced bone loss . Effects of denosumab were similar or better when measured as increase in bone density. Adverse events with regard to infections were equally distributed. Others report similar findings on the effects of denosumab in corticosteroid-induced bone loss . Combination of denosumab with anti-TNF inhibitors, which are commonly used in IBD patients, revealed no increase in adverse events or decrease in effectiveness of denosumab . This calls for study in IBD patients with corticosteroid-associated bone loss, in particular, in short-term courses with prednisone.
Because denosumab discontinuation is associated with a rebound increase in remodeling and bone loss, with increased risk of multiple vertebral fractures, it is less appropriate for the younger IBD population .
Hormone replacement therapy has been abandoned for the treatment of IBD-related osteoporosis.
Calcitonin influences function of osteoclasts and has been used in patients with corticosteroid-induced bone loss, however, not in IBD patients. Initially, it has been applied to prevent osteoporosis but as of 2013, it is primarily indicated for Paget’s disease and not longer for osteoporosis.
Probiotics, in order to create an allegedly bone-supporting intestinal microbiome, is a theoretical, but unproven, treatment. Experimentally, a key bacteria of dysbiosis of the intestinal microbiome of IBD patients ( Fusobacterium nucleatum ), but not changes in the IBD-associated microbiome, has been associated with decreased bone health, yet an enigmatic finding .
General remarks on treatment of osteoporosis in inflammatory bowel disease patients
Prevention of osteoporosis and subsequent (or alleged) fragility bone fractures by supplements and treatment of decreased bone density is only partly documented by randomized, controlled trials. Timing of treatment is therefore rather difficult unless clear-cut osteoporosis is observed. The latter is primarily treated by adequate intake of calcium and vitamin D (supplementation) and bisphosphonates. In the case of individual high risks for osteoporosis or fragility bone fractures or when a disadvantageous IBD disease course is present, characterized by a high and longstanding inflammatory burden (disease activity) or long-term use of corticosteroids, initial treatment with a bisphosphonate is documented and reasonable in IBD patients in general.