Histomorphometric Analysis Reveals Reduced Bone Mass and Bone Formation in Patients With Quiescent Crohn's Disease

doi:10.1053/j.gastro.2010.09.007

Gastroenterology

Volume 140, Issue 1, January 2011, Pages 116-123

https://doi.org/10.1053/j.gastro.2010.09.007 Get rights and content

Background & Aims

Crohn's disease (CD) is associated with an increased prevalence of osteoporosis, but the pathogenesis of this bone loss is only partly understood. We assessed bone structure and remodeling at the tissue level in patients with quiescent CD. We also investigated the roles of osteocyte density and apoptosis in CD-associated bone loss.

Methods

The study included 23 patients with quiescent CD; this was a subgroup of patients from a large randomized, double-blind, placebo-controlled, multicenter trial. We obtained transiliac bone biopsy samples and performed histomorphometric analysis. Results were compared with data from age- and sex-matched healthy individuals (controls).

Results

Trabecular bone volume was decreased among patients with CD compared with controls (18.90% vs 25.49%; P < .001). The low bone volume was characterized by decreased trabecular thickness (120.61 vs 151.42 μm; P < .01). Bone formation and resorption were reduced, as indicated by a decreased mineral apposition rate (0.671 vs 0.746 μm/day; P < .01) and a low osteoclast number and surface area compared with controls and published values, respectively. In trabecular bone of patients with CD, osteocyte density and apoptosis were normal. The percentage of empty lacunae among patients was higher than that of published values in controls.

Conclusions

In adult patients with quiescent CD, bone histomorphometric analysis revealed a reduction in bone mass that was characterized by trabecular thinning. The CD-associated bone loss was caused by reduced bone formation, possibly as a consequence of decreased osteocyte viability in the patients' past.

Section snippets

Patients

Twenty-three patients with quiescent CD participated in this study. These patients were a subgroup included in a large randomized, double-blind, placebo-controlled, multicenter trial on the effect of risedronate in patients with quiescent CD who had osteopenia (N = 131, Crohn and Bone Study). The current study describes data obtained from patients at baseline. Patients were diagnosed with CD using clinical, endoscopic, histologic, and radiologic criteria according to Lennard-Jones.¹⁹ Patients

Patient Characteristics

Patient characteristics are listed in Table 1. Because several parameters showed relatively high variation in the total population, data are presented for men and women separately. The quiescent state of disease in our CD population was ascertained by a mean CDAI of 93.8 ± 71.7 and a mean C-reactive protein level of 7.3 ± 8.4 mg/L. Disease activity was similar in men and women with CD. Disease duration tended to be longer in male patients with CD (P = .067). Levels of biochemical parameters

Discussion

In this study, bone structure and remodeling in transiliac bone biopsy specimens from patients with quiescent CD were investigated. In short, our results indicate that trabecular bone volume was lower in patients with CD than in healthy age- and sex-matched controls. The reduction of bone mass was more pronounced in men than in women and was characterized by a reduction in trabecular thickness as well as trabecular number. Besides structural differences, we observed a change in bone remodeling

Acknowledgments

The authors thank Prof Dr Juliet Compston and Linda Skingle for supplying the control material and data.

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Inflammatory bowel disease (IBD) is characterized by severe gastrointestinal inflammation, but many patients experience extra-intestinal disease. Bone loss is one common extra-intestinal manifestation of IBD that occurs through dysregulated interactions between osteoclasts and osteoblasts. Systemic inflammation has been postulated to contribute to bone loss, but the specific pathologic mechanisms have not yet been fully elucidated. We hypothesized that intestinal inflammation leads to bone loss through increased abundance and altered function of osteoclast progenitors.
We used chemical, T cell driven, and infectious models of intestinal inflammation to determine the impact of intestinal inflammation on bone volume, the skeletal cytokine environment, and the cellular changes to pre-osteoclast populations within bone marrow. Additionally, we evaluated the potential for monoclonal antibody treatment against an inflammation-induced osteoclast co-receptor, myeloid DNAX activation protein 12-associating lectin-1 (MDL-1) to reduce bone loss during colitis.
We observed significant bone loss across all models of intestinal inflammation. Bone loss was associated with an increase in pro-osteoclastogenic cytokines within the bone and an expansion of a specific Cd11b^-/loLy6C^hi osteoclast precursor (OCP) population. Intestinal inflammation led to altered OCP expression of surface receptors involved in osteoclast differentiation and function, including the pro-osteoclastogenic co-receptor MDL-1. OCPs isolated from mice with intestinal inflammation demonstrated enhanced osteoclast differentiation ex vivo compared to controls, which was abrogated by anti-MDL-1 antibody treatment. Importantly, in vivo anti-MDL-1 antibody treatment ameliorated bone loss during intestinal inflammation.
Collectively, these data implicate the pathologic expansion and altered function of OCPs expressing MDL-1 in bone loss during IBD.
Effect of mineral status and glucocorticoid use on bone mineral density in patients with Crohn's disease
2018, Nutrition
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In this regard, studies indicate the importance of interventions with micronutrients such as calcium and magnesium for the purpose of bone loss control in these patients [6,7]. Bone loss pathogenesis in patients with CD is complex and multifactorial and remains fully elucidated [8,9]. Patients with CD have a higher prevalence of bone mineral density (BMD) reduction than healthy individuals and those with other types of inflammatory bowel diseases.
Crohn's disease (CD) is a condition that is characterized by chronic inflammation. The presence of multifactorial pathogenesis that results from inflammation is associated with low micronutrient consumption and glucocorticoid use, which may be related to bone health. This study aimed to evaluate the relationship between dietary mineral intake and glucocorticoid use in bone mineral density (BMD) in patients with CD.
A cross-sectional study of 62 patients with CD ages 20 y to 40 y measured their macro- and micronutrient intake with a 3-d food record. The lumbar spine and femoral neck BMDs were determined using a bone densitometry technique. The C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) values were also noted.
Dietary intake of calcium, zinc, and magnesium was below the reference values but the phosphorus intake level was within the normal value range. Patients with osteopenia and osteoporosis accounted for 17.7% and 14.5%, respectively, of the total number of participants. Significant bone loss was found in 22.6% of patients taking glucocorticoid medications. BMD was significantly reduced and also observed in patients in the active phase of their disease. Zinc and calcium intakes were found to be correlated with reduced femoral neck BMD. The mean CRP and ESR values were above the normal ranges. Significant differences in age and ESR were observed between patients with normal and reduced BMD (P <0.05).
Low calcium and zinc intake, glucocorticoid use, and active disease phase are favorable conditions for bone loss in patients with Crohn's disease.
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One of the patients in whom implants failed suffered from Crohn's disease and was treated with immunomodulator drugs. Bone metabolism is altered in inflammatory bowel diseases, leading to bone demineralisation (Oostlander et al., 2011) (van Hogezand and Hamdy, 2006) (Ghishan and Kiela, 2011) (Wu et al., 2012). Immunomodulating drugs used in the Crohn's disease treatment also influence bone metabolism with a positive bone turnover although long terms effect and the incidence on fracture risk is yet unknown (Ryan et al., 2004; Veerappan et al., 2011).
Long standing maxillary edentulism leads to alveolar ridge resorption which prevent implant placement and causes prosthetic malocclusion. The aim of the study was to assess vertical and transversal bone increase following Le Fort 1 osteotomy associated with calvarial bone grafting.
66 patients who presented severely atrophic maxillae were treated with Le Fort 1 osteotomy with bone grafting from 2003 to 2014. Vertical and transversal bone level was measured preoperatively and 6 months post-operatively to calculate the alveolar ridge augmentation. Follow up ranged from 10 months to 11 years.
The mean increase of bone height was 9.3 mm and the mean increase of bone width was 6 mm 417 endosseous implants were placed in the grafted maxilla. Mean endosseous implant length was of 10.7 mm at the first molar site (range: 8–16 mm). A total of 25 implants failed, the overall implant survival rate is of 94%. The definitive prosthetis was fixed in 65% of the patients and removable in 35% of the patients.
Le Fort 1 osteotomy associated with calvarial bone grafting is the main treatment option able to offer fixed bridge and perfect class 1 occlusion in cases of severe maxillary atrophy.
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Nevertheless, these patients, who tend to have a longer disease duration, had more severe metabolic bone disease than females [33]. Serum concentrations of alkaline phosphatase were higher in males than in females with CD, which may be due at least partly to increased bone turnover in males [33]. However, healthy men and women had similar bone structure [34], and a study in England found that about 6% of males with CD had secondary hypogonadism, characterized by a low androgen index, normal gonadotropins and increased bone turnover [35].
Although inflammatory bowel disease (IBD) patients are at risk for metabolic bone disease, studies analyzing this correlation have identified various risk factors, including disease phenotype, age, sex and steroid therapy. Furthermore, few studies have assessed risk factors for bone loss in Japanese IBD patients. This study analyzed risk factors for metabolic bone disease in Japanese IBD patients.
This cross-sectional study assessed 388 patients with IBD aged 20–50 years, including 232 with ulcerative colitis (UC) and 156 with Crohn's disease (CD). Bone mineral density of the femoral neck, total femur and lumbar spine was quantified by dual-energy X-ray absorptiometry. The blood concentrations of bone metabolism markers were measured. History of smoking and bone fracture, and nutritional intake were assessed using questionnaires.
Of the 388 patients with IBD, 78 (20.1%; UC, 17.2%; CD, 24.4%) had osteopenia and 17 (4.4%; UC, 3.4%; CD, 5.8%) had osteoporosis, as assessed by T-score. Bone mineral density of the lumbar vertebrae was lower in males than in females. Multivariate regression analysis showed that risk factors for bone loss in UC patients were male sex, low body mass index (BMI), high steroid dose and disease location. Risk factors for bone loss in CD patients were male sex and low BMI.
Among Japanese patients with IBD, male sex and low BMI were associated with increased risk for metabolic bone disease. In addition, Steroid therapy shouldn't be indiscriminate in UC patients. These findings may help identify patients at particularly high risk of metabolic bone disease and may help implement appropriate therapies in a timely manner and improve long-term quality of life.
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Osteoporosis and osteopenia are frequently observed in patients with inflammatory bowel disease (IBD), especially in Crohn's disease (CD), with a prevalence that varies between 3–6% and 22–55%, respectively.2 The pathogenesis of bone loss in CD is yet elusive but multiple factors contribute to its prevalence.3 Pathogenic factors for decreased bone mass appear to be a mixture of malnutrition and malabsorption, a decrease of physical activity, and IBD-associated inflammation affecting the RANKL/OPG system, next to drug use such as glucocorticosteroid treatment.2,4–6
Decreased bone mineral density (BMD) is common in Crohn's disease (CD) patients. This paper reports on the prevalence of decreased BMD in a referral cohort study of CD-patients next to the change of BMD over time in relation with CD-associated clinical characteristics.
205 CD patients of a referral hospital were enrolled between januari 1998-January 2010 when measurement of BMD by dual X-ray absorptiometry (DXA) was available. Follow-up DXA scan was performed in subjects with known risk factors besides Crohn indicative for low BMD. Treatment of CD patients was according to a protocol which is comparable to the current (inter)national guidelines. In osteopenic patients, supplemental vitamin D (800 IU) and Calcium (500–1000 mg) were prescribed.
Mean BMD at baseline was 0.97 ± 0.16 gram/cm² in lumbar spine and 0.87 ± 0.12 gram/cm² in the total hip. At baseline, higher age and low Body Mass Index (BMI), were negatively correlated with BMD. Eighty-four patients underwent a second BMD assessment with a median interval period of 4 years (IQR 3–6). A mean annual increase of + 0.76% (95%CI: − 2.63%; + 3.87%) in lumbar spine and + 0.43% (95%CI: − 2.65% ; + 1.11%) in total hip was observed.
Higher age, male sex, low BMI, and a higher age at diagnosis of CD were associated with low BMD. Follow-up of BMD in CD patients showed a contraintuitive small increase of BMD at lumbar spine and total hip in CD patients only using supplemental vitamin D and calcium next to strict treatment of CD.
Osteocyte Biology
2013, Osteoporosis: Fourth Edition
Osteocytes are defined as cells embedded in the mineralized bone matrix and compose over 90% to 95% of all bone cells. They are regularly dispersed throughout the mineralized matrix, connected to each other and cells on the bone surface through slender, cytoplasmic processes radiating in all directions but generally perpendicular to the bone surface. The cell processes or dendrites pass through the bone in thin canals, called canaliculi, which connect osteocytes with cells on the bone surface. These cells are defined by their location, not by their function as is the case for osteoblasts and osteoclasts. This lack of a functional definition implies a lack of knowledge of function. Since this chapter was first written in 2005, a virtual explosion of data regarding osteocyte function has occurred within the last 6 years. Previously the major function of osteocytes was thought to be to translate mechanical strain into biochemical signals between osteocytes and cells on the bone surface to affect (re)modeling. Osteocytes are thought to respond to mechanical strain to send signals of resorption or formation. Not only do these cells communicate with each other and with cells on the bone surface but their dendritic processes are in contact with the bone marrow. Multiple connections through the tips of their dendritic processes imply that osteocytes function as “communicators”. Not only do these cells function as mechanosensors, communicators, and orchestrators of bone modeling and remodeling, but also as regulators of calcium and phosphate homeostasis and function as endocrine cells sending signals to distant tissues. These cells have proven to be multifunctional as outlined in this chapter.

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: Conflicts of interest The authors disclose no conflicts.

: Funding The Initiative on Crohn and Colitis (ICC) Foundation received a research grant from Sanofi-Aventis.

View full text

Clinical—Alimentary TractHistomorphometric Analysis Reveals Reduced Bone Mass and Bone Formation in Patients With Quiescent Crohn's Disease

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients

Patient Characteristics

Discussion

Acknowledgments

Am J Gastroenterol

Gastroenterology

Bone

Metab Bone Dis Relat Res

Bone Miner

Review article: osteoporosis and inflammatory bowel disease

Aliment Pharmacol Ther

Bone loss associated with gastrointestinal disease: prevalence and pathogenesis

Eur J Gastroenterol Hepatol

The pathophysiology of bone disease in gastrointestinal disease

Eur J Gastroenterol Hepatol

The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss

Gut

Increased bone resorption in patients with Crohn's disease

Aliment Pharmacol Ther

Altered levels of biochemical indices of bone turnover and bone-related vitamins in patients with Crohn's disease and ulcerative colitis

Aliment Pharmacol Ther

Altered bone metabolism in inflammatory bowel disease

Am J Gastroenterol

Clinical—Alimentary Tract
Histomorphometric Analysis Reveals Reduced Bone Mass and Bone Formation in Patients With Quiescent Crohn's Disease