Diabetes mellitus and osteoporosis are 2 common metabolic disorders, and the prevalence of both is increasing every year. The relationship between diabetes and osteoporosis is complex, and many studies have shown a correlation between type 2 diabetes and fractures. In type 2 diabetic patients towel, the risk of fracture is increased and many patients are not accompanied by a decrease in bone mineral density.
I. Fracture prevalence and altered bone mineral density in diabetic patients
The increased risk of fracture in diabetic patients has been confirmed in many beryllium studies. the prevalence of reduced bone mass and osteoporosis in type 1 diabetic patients is as high as 48% -72%. Premenopausal women with type 1 diabetes also had a significantly higher incidence of fracture compared to age-corrected controls (37% vs. 24%) and a significant decrease in heel and forearm BMD (49% vs. 31%, OR=3.0).
In type 2 diabetic patients, the risk of fracture was 47% to 62% higher in those with poor glycemic control compared with non-diabetic patients and those with good glycemic control. Their risk of femoral neck and spine fracture was 2.1-fold and 3.1-fold higher than that of the normal population, respectively. A meta-analysis suggested that the risk of hip fracture was significantly higher in patients with either type 1 or type 2 diabetes than in the normal population. Thus, the prevalence of osteoporosis and the risk of osteoporotic fracture were significantly increased in both type 1 and type 2 diabetic patients compared to the general population.
The risk of fracture increases with the decrease in bone mineral density. About 1/2 – 2/3 of diabetic patients have reduced bone mineral density, and nearly 1/3 of these patients can be diagnosed with osteoporosis. 2/3 of type 1 diabetic patients are in a state of bone conversion with a predominance of bone resorption, resulting in an imbalance between bone formation and bone resorption thus explaining the increased risk of fracture due to reduced bone mineral density.
However, there is still controversy regarding the alteration of bone density in type 2 diabetic patients. Mendez et al. found that obesity, which has a higher prevalence in diabetic patients, has a positive effect on BMD, but in other studies, the difference in hip BMD between type 2 diabetic and non-diabetic patients was also noted independent of body mass index factors.
The Global Longitudinal Study of Osteoporosis in Women (GLOW) in 2011 included obesity as a risk factor for fracture.
Although bone strength was higher in the diabetic group than in the control group, there was no difference in the strength loading ratio between the two due to increased body weight, so diabetic patients did not benefit more from the increased bone density. Therefore, the increased risk of fracture independent of BMD in some type 2 diabetic patients may be caused by some structural changes in the bone that cannot be captured by dual-energy x-ray absorptiometry (DXA).
One study found that the increased trabecular bone density content of the distal tibia and radius in diabetic patients was accompanied by increased radial cortical porosity, suggesting that impaired bone cortical quality ( conicalhonequality) in type 2 diabetic patients has an impact on the risk of diabetic fracture.
Bone turnover in diabetic patients
Osteoclasts secrete several biomarkers of bone turnover, including osteocalcin, bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPC), type 1 procollagen amino-terminal peptide (PINP), type I collagen N-terminal peptide (NTX), type T collagen C-terminal peptide (CTX), and NF-KB receptor activator ligand (RANKL), etc.
Osteocalcin levels decreased nearly fourfold in type 1 diabetic patients and were negatively correlated with HhA1c. Bone fragility was more pronounced in type 1 diabetic patients with poor glycemic control than in those with good glycemic control, suggesting an impairing effect of hyperglycemia on bone formation. A significant decrease in osteocalcin and sclerostin was also observed in type 2 diabetic scar. The abnormalities of these biomarkers suggest that both type 1 and type 2 diabetic patients are in a state of low bone turnover rate, which leads to bone mineral loss.
III. Possible mechanisms of diabetic osteoporosis
The occurrence of diabetic osteoporosis is caused by a combination of factors, in addition to gender, age, weight, race, nutritional status, etc., but also related to bone metabolism regulatory factors and bone mineral metabolism, diabetes can affect bone metabolism through a variety of mechanisms.
1.The effect of high glucose on osteoblasts
It was found that high concentration of glucose (12mmol/L or even 24mmol/L) can alter the biomineralization process of osteoblasts and enhance mineralization, increase the expression of RANKL, bone salivary protein and transcription receptor Runx2mRNA, and decrease the expression of OPGmRNA, thus reducing the mineral quality.
The high osmotic pressure environment caused by high glucose also resulted in overexpression of TLR-2, -3, -4 and -9 in osteoblasts, which affected osteoblast and osteoclast differentiation, maturation and their functional regulation. The high glucose environment described above has a series of effects on osteoblasts, which ultimately leads to a decrease in serum osteocalcin levels, which play a key role in bone mineralization.
A recent study found that serum osteocalcin levels were associated with the glucose metabolism status of type 2 diabetic patients. The study found that osteocalcin was an independent correlate of HbA1c and was closely associated with increased glucose metabolism disorders in 66 type 2 diabetic patients by analyzing serum osteocalcin, carboxyinsufficient osteocalcin and glucose metabolism indicators. This suggests that the lower levels of osteocalcin in type 2 diabetic patients may reflect a decrease in osteoblast activity.
The effects of different concentrations of glucose levels on osteoblasts differ. Gradually increasing glucose concentrations showed a promotion and then an inhibition of MG63 osteoblast proliferation. When the glucose concentration increased from 11.1 to 33.3 mmol/L, its effect of inducing apoptosis of MC3T3-E1 osteoblasts was more obvious, and the apoptosis of MC3T3-E1 osteoblasts also increased significantly with the extension of culture time, and high glucose concentration could induce osteoblast apoptosis in a concentration- and time-dependent manner, suggesting that the high glucose environment has a toxic effect on osteoblasts.
High glucose concentration not only enhanced osteoblast apoptosis, but also inhibited their differentiation and maturation. Li Yuming et al. found that the mRNA expression of osteoblast markers alkaline phosphatase, osteocalcin and osteoblast-specific transcription factor Runx2 decreased with increasing glucose concentration, and osteoblast differentiation was gradually reduced, suggesting that glucose dose-dependently This suggests that glucose dose-dependently inhibits the differentiation of BMSC into osteoblasts.
High glucose not only affects osteoblast apoptosis and differentiation directly, but also affects osteoblast activity indirectly by regulating the expression of PPARy, a member of the intranuclear receptor transcription factor superfamily and an important transcription factor for adipokines. Chronic long-term hyperglycemia increases the expression of PPAHy, which has an inhibitory effect on osteoblasts.
Foreign scholars found that PPARy transfection and activation of thiazolidinediones (TZDs) in primary osteoblasts carrying Osf2/Chfa1-a transcription factor could promote adipocyte fat accumulation and inhibit Osf2/Cbfal-a and αl(I) pre-collagen expression and osteocalcin synthesis, thus blocking their mineralization, suggesting that high concentrations of glucose could enhance the expression of PPARy by enhancing PPARy expression. Inhibition of Osf2/Chfal-a and osteogenic-like biosynthesis.
2. Effect of high glucose on osteoclasts
Osteoclasts are differentiated from hematopoietic stem cells via RAhKL, OPG, etc. via osteoblast regulation. Williams et al. found that the survival of osteoclasts depends on a glucose concentration of at least 100 umol/L, while bone resorption requires at least 0.5 mmol/L. Glucose concentrations of 7-25 mmol/L are able to maintain maximum bone resorption activity.
Thus, the bone resorption of osteoclasts is glucose concentration dependent. Since normal physiological blood glucose ranges from 3-8 mmol/L, glucose concentrations in this range have a direct effect on bone resorption in osteoclasts, and also indicate the presence of rapid bone loss under high blood glucose conditions.
3. The effect of insulin-like growth factor 1 (IGF-I) on bone metabolism
IGF-I can promote cell mitosis, stimulate DNA synthesis, promote osteoblast differentiation and enhance its activity, regulate bone resorption and inhibit collagen degradation, and is an important growth factor secreted by skeletal cells. the proliferative effect of IGF-I on osteoblast-like cells is now clear.
Fang et al. also found that calcium uptake in osteoblasts cultured with high glucose alone was significantly decreased, whereas in the IGF- I group, mineralization and proliferation were the same as in the normal glucose concentration group, and the overexpression of glucose transporter (CLUT)-1 caused by high glucose was reduced, which had a positive effect on osteoblast mineralization. Therefore, long-term hyperglycemia in diabetic patients can inhibit the synthesis and release of IGF-I, thus weakening the osteogenic effect of IGF-I.
4.The effect of insulin on bone metabolism
Insulin exerts its osteogenic subterfuge through insulin receptors on the surface of bone cells, and can promote the synthesis of bone collagen tissue. Insulin deficiency or insulin resistance caused by ursuria can lead to impaired osteoblast action and reduced bone matrix content, and affect the synthesis of osteocalcin.
Since insulin deficiency affects collagen synthesis by osteoblasts, it can accelerate collagen tissue metabolism, thus enhancing bone resorption by osteoclasts, while osteocalcin synthesis by osteoblasts is inhibited in insulin-sol deficiency, thus making bone resorption greater than bone formation and eventually leading to the formation of osteoporosis. It was found that the number of osteoblasts increased significantly after adding insulin intervention to the same concentration of glucose medium, suggesting that insulin promotes the differentiation of BMSC to osteoblasts and ameliorates the inhibitory effect of high sugar on the differentiation of BMSC to osteoblasts.
The mechanism by which insulin promotes the differentiation of bone marrow MSCs to osteoblasts may be through (1) activating the release of IGF-I and mitogen-activated protein kinase (MAPK), the former of which initiates the differentiation of undifferentiated interrogative stem cells to osteoblasts by upregulating the expression of Runx2 in MC3T3-EI cells through the MAPK pathway.
The p44/42, p38 and JNK pathways of MAPK signaling pathway are all involved in osteoblast differentiation, proliferation and bone metabolism signaling. p44/42MAPK phosphorylation increases with the increase of insulin concentration, suggesting that insulin regulates osteoblast growth through the receptor tyrosine protein kinase-mediated MAPK pathway; (2) insulin can increase glucose utilization and promote glucose metabolism through GLUT-4 increases glucose utilization and promotes glucose metabolism, thereby attenuating glucose-induced apoptosis and reversing the inhibitory effect of high glucose on osteoblast differentiation.
5. Effects of advanced glycosylation end products (AGEs) on bone
High glucose led to the generation of large amounts of AGEs in various organ tissues including bone matrix, and the accumulation of large amounts of ACEs in bone tissue caused apoptosis of mesenchymal stem cells and prevented their differentiation into adipose tissue, cartilage and bone, causing a significant decrease in osteogenesis.
Dong et al. successfully detected the accumulation of AGEs in bone specimens by autofluorescence intensity measurement, and also found that the density of resorption pores on the bone surface was significantly increased when the fluorescence intensity of AGEs exceeded 80 (young) or 125 (old), suggesting that the bone resorption activity of osteoclasts was affected by the concentration of ACEs.
In diabetic patients, osteoproteins are modified by glycation, which affects two processes of bone reconstruction, namely bone resorption by osteoclasts and bone formation by osteoblasts. In addition to this, AGEs interact with their receptors to increase the expression of various inflammatory factors including interleukin (IL)-1, IL-6, TNF, intercellular adhesion molecules and vascular cell adhesion molecule 1 through osteoclast and osteoblast nuclear factor pathways, alter the physiological function of bone collagen, promote osteoclast precursor maturation, stimulate osteoclast aggregation and inhibit their apoptosis, and increase osteoclast The increase in osteoclast cell viability. It accelerates bone resorption, which leads to disruption of bone reconstruction process. It plays an important role in the development of osteoporosis.
6, the impact of diabetes complications on the bone
The vast majority of diabetic patients will develop diabetic vascular complications in the case of long-term unsatisfactory sugar control, which also have a negative impact on bone metabolism. Diabetic nephropathy secondary to hyperparathyroidism can lead to increased bone calcium mobilization and increased bone loss.
Reduced l,25 hydroxyvitamin D3 synthesis due to reduced 1-alpha hydroxylase activity as a result of renal insufficiency further leads to impaired calcium absorption, which affects the bone mineralization process and causes osteoporosis. When combined with peripheral vascular lesions, due to microcirculatory disorders, capillary permeability increases and the surrounding basement membrane thickens, thus affecting bone reconstruction; at the same time, it affects the vascular distribution of bone causing insufficient blood supply to bone tissue and causing abnormal bone metabolism.
Studies have found that bone density in the lumbar spine and hip of diabetic patients decreases as the severity of lower limb vasculopathy increases. Diabetic neuropathy, on the other hand, aggravates bone loss by affecting the neurotrophy of local tissues, leading to the occurrence of seminuric osteoporosis.
Fourth, the effect of glucose-lowering drugs on osteoporosis
Hyperglycemia can indirectly affect the maturation and differentiation of osteoblasts through the regulation of PPARy expression. With the accumulation of clinical data, it is gradually found that TZDs can cause increased bone loss and fracture risk in diabetic patients, especially in diabetic female patients. Data show that in older postmenopausal women, patients taking TZDs lose bone mass at a rate of 0.61% per year compared to those not taking them, accompanied by a decrease in serum osteocalcin levels.
Mice treated with rosiglitazone showed a significant decrease in bone mineral density and bone mass as well as changes in skeletal microarchitecture at 8 weeks. These data suggest that TZDs drugs affect bone formation in patients with type 2 diabetes. The mechanism of the negative regulatory effect of TZDs on bone metabolism is not fully understood. It was found that TZDs inhibit anabolic signaling in bone by reducing Wnt, TGF-β/RMP and IGF-1 signaling pathway activity and induce RANKL production, which promotes osteoclast development.
It also induces differentiation to adipocytes by inhibiting the differentiation of interrogative stem cells to osteoblasts, which eventually leads to osteoporosis. Sulfonylureas, the most widely used drugs in China, also have an effect on bone mass in diabetic patients.
UK-DPRD data show an increased risk of fracture in patients taking sulfonylureas. These drugs may interfere with the degradation of phosphodiesterase catalysts by increasing cAMP, competitively inhibiting enzyme activity and increasing calcium salt loss. Recent domestic studies have found that sulfonylurea Lou drugs reduce MC3T3E1 cell survival and increase autophagy and apoptosis marker protein expression, suggesting that medium and high concentrations of sulfonylureas can induce leukophagy and apoptosis in osteoblasts and reduce osteoblast differentiation function.
V. Other factors
In diabetic patients, due to hyperosmolar diuresis, it can cause a large loss of calcium and phosphorus, and at the same time impede the reabsorption of calcium, phosphorus and magnesium by renal tubules, leading to a decrease in serum calcium and phosphorus concentration, promoting parathyroid hormone secretion and enhanced osteoclast activity, resulting in osteoporosis. In addition, the occurrence of diabetic osteoporosis is associated with genetic factors.
A data from the American Diabetes Heart Study found a negative correlation between six bone morphogenetic protein 7 single nucleotide polymorphisms and bone mineralization. It has also been found that the combination of parathyroid BSTBl locus and vitamin D receptor gene polymorphism further widens the difference in bone mineral density by genotype groups, and diabetic patients with 2 susceptibility genes at the same time have a significantly increased risk of concomitant bone loss or osteoporosis (OR=4.0, 95% CI1.86 ~6.15).
VI. Treatment and prevention
Diabetes should first be controlled by giving oral hypoglycemic agents or insulin to reduce or delay the occurrence of diabetic complications. Patients with diabetes mellitus not yet complicated by osteoporosis should pay attention to calcium and vitamin D supplementation while treating diabetes mellitus to prevent the development of osteoporosis.
The treatment drugs for diabetes combined with osteoporosis are similar to other kinds of osteoporosis, including drugs to promote bone mineralization: mainly adequate calcium and active vitamin D; drugs to inhibit bone resorption: estrogen, calcitonin, bisphosphonates, etc.; drugs to promote bone formation: such as fluoride, androgens, eptifibatide, teriparatide, etc., mainly to make the new bone tissue mineralized in time, reduce bone fragility, increase bone density and bone mass.
In conclusion, diabetic osteoporosis is the result of a combination of physiological, pathological, genetic, nutritional, environmental and other factors. The metabolic disorders caused by diabetes and the glycosylation end products play an important role in the development of diabetic osteoporosis. An in-depth study of diabetic osteoporosis will help to provide appropriate interventions as well as effective treatment in the course of diabetes treatment.