Osteoporosis is a worldwide health problem that is attracting increasing attention. Currently, about 200 million people worldwide suffer from osteoporosis, and its incidence has jumped to the seventh place of common diseases and multi-morbidity. Therefore, proper recognition and early prevention are particularly important. With a large population base in China and an aging society on the horizon, the dangers of osteoporosis are becoming more pronounced.
Researchers have found that patients with inflammatory bowel disease (IBD) have a significantly increased risk of fracture. Epidemiological studies have shown that people with IBD are more likely to develop osteoporosis compared to non-IBD populations. Osteoporosis and its serious consequence, fracture, are known as a silent epidemic in our country for constituting a serious public health problem.
I. Osteoporosis in IBD
Definition of Osteoporosis OP
Primary osteoporosis is a systemic bone disease characterized by reduced bone mass and degradation of bone tissue microstructure (thinning, fracture and reduction in the number of cancellous bone trabeculae; porous and thinning cortical bone), resulting in increased bone fragility and increased risk of fracture.
Prospective epidemiological studies have shown that bone mineral density (BMD) refers to the amount of bone mineral per unit of bone tissue, and BMD measurement is a reliable method for early diagnosis of osteoporosis and prediction of osteoporotic fractures, and the World Health Organization (WHO) diagnostic criteria for osteoporosis are also based on BMD measurement. Mata analysis of case-control studies of fractures published from 1990 to 1994 found that the risk of fracture increased nearly twofold for each standard deviation (SD) decrease in BMD. the incidence of osteoporotic fractures was significantly higher in IBD, and the risk of fracture increased by more than 40% compared to normal subjects.
Ardizzone et al. measured BMD, calcium-related hormones (parathyroid hormone, 25(OH)vitamin D3 , 1,25(OH)vitamin D3) and biochemical indicators of bone turnover (osteoclasts, total alkaline phosphatase, type I collagen carboxy-terminal peptide, ICTP) in 51 CD, 40 UC and 30 healthy individuals in the spine and femoral neck, and their study showed that CD and UC patients generally had reduced bone mass without differences in degree, bone turnover was significantly higher in UC, bone loss was associated with the duration of CD, and bone loss in UC was associated with men and corticosteroid treatment.
Lee et al. studied newly diagnosed Korean patients with IBD not treated with hormones (14 CD, 25 UC) and measured BMD of their lumbar spine and femoral neck by dual-energy X-ray absorptiometry, and measured their serum osteocalcin, parathyroid, VD, and urinary deoxypyridinoline, and confirmed that BMD of the lumbar spine was generally reduced in patients with CD and UC, similar to the West, and that the nutritional status and biochemical parameters of bone metabolism, the Differences in ethnicity were not important factors in bone loss.
Klaus et al. prospectively evaluated 293 CD patients from 1998-2001, 156 had osteoporosis and or bone loss, with a 22% incidence of vertebral fractures, and were younger than 30 years of age.
Lamb et al. found that BMD in patients with UC and CD was reduced at the time of initial diagnosis, earlier than hormone therapy, and their study suggests that the reduction in BMD was an increase in bone resorption rather than a decrease in bone formation.
II. Risk factors for osteoporosis due to IBD
The pathogenesis of reduced BMD in people with IBD is not fully understood. The application of hormone therapy, small bowel disorders, small bowel resection, persistent or extensive disease,, vitamin D deficiency, malabsorption, malnutrition, hypogonadism and systemic inflammation are high risk factors for bone loss, but many studies have found a high incidence of reduced BMD in patients newly diagnosed with IBD, and these results suggest the presence of other factors prior to the onset of IBD that contribute to low bone mass and increase bone loss.
1. Genetic factors Assessment of bone turnover markers suggests that the regulation of bone metabolism is influenced by genes and that genetic factors are important in the pathogenesis of osteoporosis. Genes affect peak bone mass and bone loss rate, but in many studies, various candidate genes are inconsistent, which may be due to polygenic regulation of BMD, and polygenic susceptibility is modified by environmental and lifestyle factors. the IL-1 family plays an important role in the regulation of bone formation. Allelic variants in the IL-1 receptor antagonist gene (IL1RN) have been found to be associated with vertebral bone loss in early menopause.
The production of IL-1β and IL-1ra proteins was associated with genetic polymorphisms in TaqI and AvaI and with polymorphisms in the variable number tandem repeat (VNTR) in the IL1RN gene.Allelic combinations of IL-1β gene polymorphisms were associated with the development of CD.A controlled study by Nemetz et al [9] found that the presence of the IL1β-511*2 allele in people with IBD was associated with bone osteoporosis and a high risk of bone loss was significantly associated. This allele is associated with increased IL-1β production by monocytes.
IL-1β increases bone resorption by increasing the number and activity of osteoclasts and has been found to reduce the synthesis of bone collagen and non-collagenous proteins, and IL-1ra, an antagonist of IL-1β, stimulates bone formation and reduces the number of osteoclasts. Animal studies also suggest that IL-1ra treatment reduces the number and activity of osteoclasts on the inner surface of the bone cortex. low bone mass in IBD can be partially explained by increased IL-1β levels and increased IL-1β/IL-1ra ratio, and the IL-1 gene determines bone mass.
In the study by Nemetz et al, the strongest correlation between the genotype of genetic polymorphisms and bone mass in IBD patients was in the femoral neck, which further confirms that the pathogenesis of bone loss in IBD is different from the hormone-induced bone loss mainly in vertebrae, suggesting that genetic variability may be the main determinant of bone loss in IBD, and that IBD carriers of the IL1β-511*2 allele are IL- 1β is a high secretion of IL-1β and there is a high risk of bone loss.
Glucocorticoids: Glucocorticoids have been widely used in clinical practice, and one of the main side effects of long-term high-dose glucocorticoid use is osteoporosis, the incidence of which ranks third after postmenopausal and senile osteoporosis. Studies have shown that oral corticosteroids are an important risk factor for increased fracture risk in patients with IBD. Glucocorticoids act directly on osteoblasts and osteoclasts and regulate local molecules of the bone microenvironment at the molecular level, resulting in bone resorption greater than bone formation and osteoporosis.
A controlled study by Jahnsen et al. showed that reduced BMD in CD patients was associated with glucocorticoid application, and Walsh et al. concluded that cumulative prednisone dose was strongly associated with the risk of fracture. Continuous uninterrupted application of steroids was associated with reduced BMD. Osteoporosis occurred in almost 50% of patients taking glucocorticosteroids for more than 6 months, while high doses of glucocorticosteroids (>10 mg/day prednisone) resulted in considerable bone loss in all patients. Glucocorticoid-induced bone loss is the result of a combination of systemic and direct effects on bone.
This loss appears to be most pronounced during the first 6-12 months of glucocorticoid therapy.
2, nutrition In IBD, the digestive tract is dysfunctional, the intake of nutrients in food such as protein, vitamin D, calcium, phosphorus, magnesium and many trace elements related to bone metabolism such as zinc, copper, fluorine, manganese, strontium, silicon, etc. is reduced, and digestion and absorption are impaired, because of its long-term cycle of recurrent morbidity, it is very easy to cause nutritional imbalance, protein intake is less, affecting the synthesis of bone matrix, calcium, phosphorus and other elements intake is reduced When the bone mineralization is impaired, the end result leads to the occurrence of osteoporosis OP with reduced bone mass.
On the other hand, due to the lack of calcium and phosphorus in the body, the body can maintain normal blood calcium through the adjustment of calcium-regulating hormones, but at the cost of secondary hyperparathyroidism, which results in increased bone conversion and bone resorption and bone loss, leading to OP. some studies have found that patients with CD are generally low in vitamin D and are at risk of low BMD.
Boot et al. observed 55 children with IBD, 22 with CD and 33 with UC, with reduced lumbar BMD and significantly lower CD than UC, and concluded that hormone therapy and nutritional status were important determinants of reduced BMD. Jong et al. studied 91 individuals with CD and found that body mass index (BMI) and history of bowel resection were important predictor variables of BMD.
3. Other relevant factors: There are other causative factors for osteoporosis in patients with IBD.
A cross-sectional study by Schulte et al. included 149 patients with IBD, and compared to normal subjects, bone resorption Significantly higher bone resorption was accompanied by reduced bone formation, suggesting that an imbalance in bone metabolism is responsible for the increased bone loss in IBD.
Schoon et al. investigated a group (32) of patients with inactive chronic CD, all with small bowel involvement, with no or only very low doses of steroids (<5 mg prednisone daily) in order to exclude the influence of hormones and disease activity on osteoporosis, and found that these patients had low serum and bone vitamin K status, and vitamin K deficiency was associated with low BMD in the lumbar spine, and multiple linear regression analysis showed that free osteocalcin was an independent risk factor for low BMD in the lumbar spine.
III. Prevention and treatment of osteoporosis
Prevention and treatment of osteoporosis include lifestyle interventions, regular weight training, reducing alcohol intake, quitting smoking, maintaining adequate dietary calcium intake, having enough calories to achieve ideal body weight, vitamin D supplementation, and limiting sodium intake (2 to 3 g/d). It is also important to control disease progression: reduce systemic inflammation and alleviate cachexia.
Hormone replacement therapy in postmenopausal women with IBD may reduce bone loss. Patients requiring long-term glucocorticoid therapy should be properly evaluated and proactive measures should be taken to prevent and treat glucocorticoid-induced osteoporosis. Because the magnitude of bone loss is related to the dose of glucocorticoids, the lowest effective dose possible and the use of topical preparations should be used.
There are three classes of drugs used for the prevention and treatment of osteoporosis.
(1) Anti-bone resorption agents, such as estrogens, calcitonin, and diphosphonates. Diphosphonates are the first-line agents for the prevention of IBD-related osteoporotic fractures [25]. Studies with alendronate and risedronate have shown to reduce fracture risk by reducing bone turnover and increasing BMD [26,27,28].
(2) Drugs that promote bone formation, such as fluoride and anabolic-promoting steroids. Fluoride stimulates the replication, differentiation and function of osteoblasts in patients on glucocorticoids and restores the glucocorticoid-induced decrease in serum osteocalcin levels. This suggests that fluoride may increase bone formation.
(3) Drugs that promote mineralization, such as calcium preparations, vitamin D, etc. As an essential nutrient and hormone, vitamin D plays an important role in maintaining the balance of calcium and phosphorus metabolism in the body. Calcium preparations are one of the drugs with more certain efficacy and safety in the treatment of osteoporosis. Medication can reduce the pain of osteoporosis, increase bone mass, and prevent fractures. In a prospective double-blind randomized parallel controlled study of 94 patients with IBD, calcium and vitamin D supplementation for one year was shown to increase lumbar spine BMD.
In addition, parathyroid hormone (PTH) enhances osteoclast lysis of bone calcium and osteoclast resorption of bone matrix, while promoting osteoblast formation and mineralized bone. In this way, bone calcium is continuously released to maintain blood calcium levels and old bone is continuously replaced by new bone. For example, a recent study by Dempster et al [30] demonstrated that PTH increased the thickness of the human bone cortex and the density of junctions.Cosman et al [31] reported through a three-year study that PTH was resistant to vertebral fractures. It increases bone strength and reduces the risk of fracture.
Vitamin K acts mainly by increasing osteocalcin (BGP) synthesis several secretion as a bone formation promoter. Others, such as growth hormone, anabolic hormone, bioestrogens, and selective estrogen receptor modulators, some of which have not been widely used clinically and need to be further evaluated.
Risk assessment of patients with IBD includes: age, BMD, -continued hormone use, history of previous fragility fractures. Guidelines for the prevention and treatment of osteoporosis have yet to be established.