Zhang Dandan1, 2, Wang Meng1, Zhao Chengjun3, Li Ruosong3, Yao Ying1, 4*(1.Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; 2. The Second Affiliated Hospital of Zhengzhou University Department of Medicine, Zhengzhou 450014, China; 3. Wuhan Huaying Kangze Collagen Medical Engineering and Application Research Institute, Wuhan 430056, China; 4. Department of Clinical Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China)
Abstract: Objective To investigate the clinical efficacy and possible mechanism of type II collagen in the treatment of glucocorticoid-induced osteoporosis. Methods From October 2015 to June 2016, 30 patients with glucocorticoid-induced osteoporosis were enrolled in the Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. They were randomly divided into experimental group and In the control group, 15 cases each. The control group was treated with calcium carbonate and calcitriol, and the experimental group was treated with type II collagen on the basis of the control group. The bone mineral density and bone turnover markers such as serum osteocalcin were observed before and after treatment in the two groups. Results After 4 months of treatment, the bone mineral density of lumbar vertebrae and femoral neck increased in both groups, and the increase in the experimental group was more significant. The difference between the two groups was significant (P<0.05). Compared with the control group, serum osteocalcin levels were significantly increased in the experimental group (P<0.05). There were no significant differences between the two groups before and after treatment with serum calcium, serum phosphorus and serum alkaline phosphatase (P>0.05). Conclusion Type II collagen can increase serum osteocalcin level and increase bone density. Combined with calcium carbonate and calcitriol, it can effectively treat glucocorticoid-induced osteoporosis with good safety.
Key words: glucocorticoid; osteoporosis; type II collagen; osteocalcin; bone density
CLC number: R681 Document code: A Article ID: 1008-1070(2018)09-0989-04
Doi:10.3969/j.issn.1008-1070.2018.09.011
Clinical exploration of collagen Ⅱ combination of calcium carbonate and ossification alcohol on treatment of
glucocorticoid-induced osteoporosis
ZHANG Dan-dan1, 2, WANG Meng1, ZHAO Cheng-jun3, LI Ruo-song3, YAO Ying1, 4* (1. Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology,Hubei Wuhan 430030, China; 2. Intensive Care Unit, Second Hospital Affiliated to Zhengzhou University, Henan Zhengzhou 450014, China; 3. Wuhan Huaying Kangze Collagen Medical Engineering and Application Research Institute, Hubei Wuhan 430030, China; 4. Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Hubei Wuhan 430030, China)
*Corresponding author, Email: yaoyingkk@126.com
Abstract: Objective To investigate the clinical effect of Collagen II on treatment of glucocorticoid-induced osteoporosis. Method From October 2015 to June 2016, 30 patients of Glucocorticoid-Induced Osteoporosis were divided into the observation group and the control group randomly, 15 cases each. Patients of the control group taken calcium carbonate and calcitriol, while patients of the observation group taken Collagen Ⅱ, calcitriol and calcium carbonate. The changes of bone mineral density and bone turnover markers such as serum osteocalcin were recorded before and after treatment, then to compare the indicators of two groups. Result After 4 month’s treatment,the bone mineral density of lumbar vertebrae and femoral neck in the observation group increased significantly (P＜0.05), and the serum osteocalcin level increased significantly as well(P＜0.05). There were no statistical differences in serum calcium, phosphorus and Alkaline phosphatase between the observation and the control group before and after therapy(P＞0.05). Conclusion Collagen Ⅱ is an effective drug on treatment of glucocorticoid-induced osteoporosis by increasing of serum osteocalcin and bone mineral density with less adverse effect, and worthwhile for spreading in clinical practice.
Keywords: Glucocorticoid; Osteoporosis; Collagen II; Osteocalcin; Bone mineral density
Glucocorticoid (GC) is a steroidal compound synthesized and secreted by the bundle of the adrenal cortex.
[1], due to its strong anti-inflammatory and immunosuppressive effects, it is widely used in clinical work to treat nephrotic syndrome.
[2], bronchial asthma
[3] and rheumatoid arthritis, systemic lupus erythematosus, rheumatoid diseases such as various vasculitis
[4]. A retrospective study showed that for 365 patients with rheumatic diseases
With a continuous follow-up of 10 years [mean follow-up (14.2 ± 4.0) years], more than 80% of patients took glucocorticoids for an average of 8 years [5].
In 2004, Kanis et al [6] estimated that approximately 3% of patients over the age of 50 used glucocorticoids, a proportion that rose to 5.2% in people over 80 years of age. Glucocorticoid is a double-edged sword with good pharmacological effects, but it also produces many adverse reactions. Osteoporosis is one of the most common and serious adverse reactions. Glucocorticoid induced osteoporosis (GIOP) is the most common drug-induced bone disease, and it ranks first in secondary osteoporosis [7]. Its main feature is low bone mass, Bone microstructural damage, prone to brittle fracture [8]. Oral glucocorticoids can cause a decrease in bone mineral density (BMD) for more than 3 months. The bone loss in the first year can reach 12%, and then the rate of bone loss is slightly slow, about 2% to 3% per year. 9]. Most patients with kidney disease need long-term treatment with glucocorticoids, and follow the principle of initial dose reduction and reduction. Therefore, the cumulative dose of hormones is large and the maintenance time is long, which increases the incidence of osteoporosis and fracture risk. The quality of life of the patient. At present, the prevention and treatment of GIOP is mainly from the perspective of supplementing bone minerals, and routinely supplementing calcium and vitamin D [10]. Recent studies have found that osteoporosis in patients with reduced bone collagen content [11], accompanied by significant reduction in bone biomechanical properties [12, 13]. Collagen is the main component of bone organic matter and plays an important role in maintaining bone microstructure, providing a framework for mineral mineralization [14]. Therefore, supplementation of collagen is beneficial to the deposition of calcium salts, promote bone mineralization, and improve osteoporosis. This article explores the clinical efficacy and possible mechanism of type II collagen in the treatment of GIOP.
1 data and methods
1.1 Clinical data
The subjects were selected from October 2015 to June 2016 at the Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The condition was relatively stable. 30 patients who needed long-term glucocorticoid therapy were included in the study. Primary kidneys were included. There were 23 cases of disease and 7 cases of lupus nephritis. Thirty subjects were divided into experimental group and control group by dynamic randomization method, 15 cases in each group. There were no significant differences in baseline data between gender, age, and time of taking hormones (P > 0.05), which were comparable. This study was reviewed by the hospital ethics committee. See Table 1 for details.
1.1.2 Inclusion criteria 1 long-term use of glucocorticoid therapy, time ≥ 3 months, prednisone dose ≥ 7.5mg / d; 2 in line with WHO diagnostic criteria for osteoporosis, T value ≤ -2.5SD; 3 women of childbearing age The urine pregnancy test was negative and agreed to take effective birth control measures during the study period; 4 informed consent, voluntary participation in the study, and signed informed consent in accordance with the regulations.
1.1.3 Exclusion criteria 1 Pregnancy or lactation and menopausal and perimenopausal women; 2 combined with other systemic diseases affecting bone metabolism: primary hyperparathyroidism, Cushing's syndrome, type 1 diabetes, etc.;
3 combined with skeletal system diseases; 4 have gastrointestinal system disease or history of gastrectomy; 5 with kidney stones, idiopathic hypercalcemia, high urinary calcium;
6 other diseases that affect alkaline phosphatase, such as hepatobiliary diseases;
7 serious serious primary diseases such as heart, lung, brain and mental illness.
1.2 Treatment method The control group was given calcium carbonate (specification: 600mg/tablet, national medicine standard H10950029, Wyeth Pharmaceutical Co., Ltd.),
600mg/time, 1 time/day; calcitriol (specification: 0.25mg/granule, national medicine standard J20150011, Shanghai Roche Pharmaceutical Co., Ltd.),
0.25mg / time, 1 time / day. Experimental group: On the basis of the control group, oral type II collagen (complex collagen, specification: 1.0g/tablet, Guoshijianzi G20070258, Wuhan Hege Biotechnology Co., Ltd.), 3 minutes before the three meals Piece / time, 3 times / day. Continuous treatment for 4 months.
1.3 Observation indicators Regular observation of changes in symptoms and signs related to osteoporosis in the subjects, and recording the levels of serum osteocalcin, serum alkaline phosphatase, serum calcium, blood phosphorus and other bone turnover markers before and after treatment.
Lumbar vertebrae before and after treatment with a dual-energy X-ray absorptiometry
(L2-4) and femoral neck were measured for bone mineral density and the changes in bone density were recorded.
1.4 Statistical analysis Statistical analysis was performed using SPSS 18.0 software. The count data were analyzed by χ2 test. The measurement data were expressed as mean ± standard deviation (x ± s). The comparison within the group was based on the non-parametric test of the relevant samples. The comparison between groups was performed by two independent samples (Mann-
Whitney test). P < 0.05 was considered significant.
2 results
2.1 Comparison of bone turnover markers between the two groups before and after treatment Compared with before treatment, serum osteocalcin levels in the experimental group increased significantly after treatment, and there was no significant change in the control group. The difference between the two groups was significant.
(P < 0.05); there were no significant differences in serum phosphorus, serum calcium, serum alkaline phosphatase levels between the two groups before and after treatment (P > 0.05, Table 2).
2.2 Comparison of bone mineral density before and after treatment in both groups After treatment, the bone mineral density of lumbar vertebrae (L2-4) and femoral neck increased in both groups, and the experimental group was significantly higher than the control group, the difference was significant (P < 0.05). , table 3).
2.3 Comparison of Adverse Drug Reactions in Two Groups According to the national routine test standards and operating procedures, subjects were tested for blood routine, urine routine, electrocardiogram, liver and kidney function, electrolyte and fecal occult blood before and after treatment. During the treatment period, no significant adverse reactions occurred in the experimental group and the control group.
discuss
In addition to kidney disease, glucocorticoids are also commonly used in respiratory diseases, rheumatic diseases and organ transplants. Long-term use of glucocorticoids can lead to loss of bone mass and increase the risk of fragility fractures [15]. Studies have shown that continuous treatment with prednisone at 10 mg / d exceeds
90 days can increase the risk of hip fracture by 7 times and the risk of vertebral fracture by 17 times [16]. The GIOP mechanism is very complicated. On the one hand, glucocorticoids inhibit the synthesis of the hormone 1,25-(OH)2-D3, which promotes intestinal calcium absorption, by inhibiting 1-hydroxylase, thereby reducing the absorption of calcium in the gastrointestinal tract and increasing renal excretion [17] , 18]. Glucocorticoid inhibits the osteogenic activity factor core binding factor 1 (core binding)
Factor1, Cbf1), insulin-like growth factors-1 (IGF-1) [19], bone morphogenetic protein-2 (BMP-2), enhanced into Reactive oxygen species (ROS) and peroxisome proliferator-activated receptor gamma (PPAR2) reduce bone formation [20, 21], regulate OPG The /RANKL/RANK pathway promotes bone resorption, causing the dynamic balance of bone formation and absorption in normal bone tissue to be broken [22, 23]. IGF-1 not only stimulates the differentiation of bone marrow mesenchymal cells into osteoblasts, but also regulates collagen gene expression and promotes collagen synthesis [24, 25].
Inhibition of IGF-1 activity leads to a decrease in collagen synthesis. Zhang Jianfeng et al [26] resection of bilateral ovaries in rats to establish a model of osteoporosis
At 12 weeks, the collagen content of ovariectomized rats decreased significantly and was positively correlated with the decrease of bone biomechanical strength. Human bone consists of 2/3 of bone minerals and 1/3 of bone matrix, of which collagen accounts for approximately 80% to 90% of bone matrix components [27], maintaining bone structural integrity, bone biomechanical properties and completion. Bone mineralization is extremely important. Therefore, supplementation of collagen is very important for the prevention and treatment of glucocorticoid osteoporosis.
Type II collagen contains hyaluronic acid, chondroitin sulfate, keratan sulfate, glucosamine, 4 kinds of negatively charged mucopolysaccharides and 19 kinds of amino acids. The content of proline and hydroxyproline is significantly higher than other collagen. The results of this study showed that the experimental group treated with calcium carbonate, calcitriol and type II collagen in the treatment of GIOP, the bone density of the lumbar spine and femur neck was significantly improved, which was superior to the control group. Therefore, patients with osteoporosis have an important role in collagen supplementation. The possible mechanism is that hydroxyproline in bone helps transport calcium ions in plasma to bone cells [28], and its content directly reflects bone metabolism. Studies have confirmed a significant reduction in hydroxyproline content in the bones of patients with osteoporosis. The content of hydroxyproline in type II collagen is significantly higher than that of other collagens, which is more conducive to promoting the absorption and utilization of calcium ions in plasma by bone cells. The complex mucopolysaccharide has negative electron characteristics and has large cations such as calcium and phosphorus. The affinity can further promote the deposition of minerals in the bones; while the collagen fibers are interwoven into a net, which provides a framework for mineral deposition such as calcium and phosphorus, repairs tissues and promotes bone formation. Therefore, the addition of collagen on the basis of calcium supplementation is more conducive to the prevention and treatment of osteoporosis. In addition, studies have confirmed that collagen hydrolysates can stimulate the increase and differentiation of osteoblasts [29], reduce osteoclast activity, reduce bone resorption [30], thereby adjusting bone composition and bone mineral distribution, effectively maintaining bone density, and expanding The area of the cortical bone increases the firmness of the bone. In this study, the serum osteocalcin level was significantly increased in the experimental group. Osteocalcin was secreted by osteoblasts, and its level directly reflected the activity of osteoblasts. It was a special marker of osteoblast function and bone mineralization. Collagen is good for bone formation. In this study, there was no significant difference in the changes of alkaline phosphatase levels between the two groups before and after treatment. It may be due to the fact that serum alkaline phosphatase is the sum of various isoenzymes and is susceptible to extra-osseous factors. Due to low sex.
In short, the combination of calcium and vitamin D combined with type II collagen treatment of GIOP can improve serum osteocalcin levels, increase bone density, clinical effect is more significant, and type II collagen belongs to the essential nutrients of the human body, without any Adverse reactions will not cause adverse reactions with other drugs (including antihypertensive drugs, hypoglycemic agents, gout drugs, etc.) and have good safety. It provides a new way to prevent and treat GIOP, but its exact role and mechanism still need further the study.
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(Received date: 2018-06-21; Revised date: 2018-08-03)
(Editor: Quiet)
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