Diabetes mellitus and osteoporosis are each one of the important diseases of the endocrine metabolic system. The pathogenesis of each is also very complex, and the situation becomes even more complicated when diabetes and osteoporosis coexist in one individual. This article provides a brief review of the association between diabetes mellitus and osteoporosis.
I. Changes in the prevalence of fragility fractures and bone mineral density in diabetic patients
The increased risk of fracture in patients with diabetes is indisputable. 48% – 72% of patients with type 1 diabetes have a high prevalence of bone loss and osteoporosis. In patients with type 2 diabetes, the risk of fracture is 47% to 62% higher in those with poor glycemic control than in non-diabetic patients and those with good glycemic control. The risk of femoral neck and spinal fracture was 2.1 and 3.1 times higher, respectively, than in the normal population.
A large meta-analysis showed that the risk of hip fracture was significantly higher in both type 1 and type 2 diabetics than in the normal population. Thus, the prevalence of osteoporosis and the risk of osteoporotic fracture were significantly increased in the entire population of diabetic patients compared to the general population.
However, the picture becomes more complex when the prevalence of osteoporosis in the diabetic population is examined from the perspective of bone mineral density. About 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 density, which is associated with an absolute deficiency of insulin and decreased bone matrix synthesis in type 1 diabetes.
However, alterations in bone mineral density in type 2 diabetic patients are still controversial. Numerous studies have found that the increased risk of fracture in type 2 diabetic patients is sometimes not accompanied by a decrease in BMD, and some data even suggest that their BMD levels are higher than those of normal control subjects. This is mainly related to the decreased bone mass in type 2 diabetes, which is affected by more complex factors than type 1 diabetes, such as body mass index (BMI), insulin resistance, protein glycation, increased risk of falling to, and the use of some oral hypoglycemic drugs.
Further studies found that although BMD was significantly higher in type 2 diabetic patients than in controls, this increase was mainly concentrated in trabecular bone sites, with no bone free changes in the cortex. Therefore, some experts believe that dual-energy x-ray absorptiometry (DXA) has difficulty capturing subtle changes in bone structure and bone mass in type 2 diabetic patients, resulting in an increased risk of fracture independent of BMD in type 2 diabetic patients that cannot be evaluated and monitored by DXA means.
Another study found that increased trabecular bone density content of the distal tibia and radius in diabetic patients was accompanied by increased porosity of the radial bone cortex, suggesting impaired bone cortical quality in type 2 diabetic patients and thus an impact on diabetic fracture risk.
II. Bone transition status in diabetic patients
Bone turnover status is an important component of the pathogenesis of osteoporosis. The classification of osteoporosis according to the rate of bone conversion is divided into three types: high conversion, normal conversion and low conversion. For example, postmenopausal osteoporosis, hyperparathyroidism and glucocorticoid-induced osteoporosis all belong to the high conversion type of osteoporosis.
The medical definition of bone turnover refers to the bone metabolic activity of osteoblast bone formation and osteoclast bone resorption, during which various biomarkers of bone turnover are secreted, such as osteocalcin, bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPC), and type 1 procollagen amino-terminal peptide (PINP), which are indicators of bone formation, and type I collagen N-terminal peptide (NTX), type 1 collagen C terminal peptide (CTX) are indicators of bone resorption, and the change of bone turnover indicators is faster than the change of bone density, which can reflect the status of bone metabolism more rapidly and sensitively;
Bone resorption indexes decline rapidly in 2-4 weeks after treatment with anti-bone resorption drugs such as alendronate, and reach a plateau in 3-6 months, while bone resorption indexes change slightly later than bone resorption indexes, reaching a plateau only in about 6-12 months. What about bone conversion in diabetic patients?
Studies have shown a nearly 4-fold decrease in osteocalcin levels in type 1 diabetic patients, and a negative correlation with HhA1c. Bone fragility is more pronounced in type 1 diabetic patients with poor glycemic control than in those with ideal 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 patients. 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 diabetes-induced osteoporosis
The prohibition of diabetes mellitus-induced osteoporosis is complex and not yet fully understood. In addition to gender, age, weight, race, nutritional status, etc., it is also related to bone metabolism regulation factors and bone mineral metabolism, and diabetes can affect bone metabolism through a variety of mechanisms. The following factors are currently thought to contribute to the development of osteoporosis in individuals with diabetes.
1, the effect of high glucose on osteoblasts: It was found that high glucose concentration (12 mmol/L or even 24 mmol/L) can alter the biomineralization process of osteoblasts and enhance mineralization, increase RANKL, bone salivary protein and transcription receptor Runx2 mRNA expression, and decrease OPG mRNA expression, thus reducing 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 has a series of effects on osteoblasts, which ultimately leads to a decrease in serum osteocalcin levels, a key factor in bone mineralization.
Recent studies have found that osteocalcin is an HbA1c-independent factor and is closely associated with increased glucose metabolism disorders. The lower levels of osteocalcin in diabetic patients may reflect a decrease in osteoblast activity. The effect of different concentrations of glucose levels on osteoblasts varies. Progressively increasing glucose concentrations showed a promotive and then inhibitory effect on 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. Basic studies suggest 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.
2. Effect of hyperglycemia on osteoblasts: Osteoblasts are differentiated from hematopoietic stem cells through RAhKL, OPG, etc. by osteoblast regulation. Glucose as their original energy source can stimulate osteoclasts. It was found that a glucose concentration of 7-25 mmol/L can maintain the maximum bone resorption activity. Thus, the bone resorption effect of osteoclasts is glucose concentration-dependent, and rapid bone loss exists in the presence of hyperglycemia.
The effect of insulin-like growth factor 1 (IGF-I) on bone metabolism: IGF-I can promote cell mitosis, stimulate DNA synthesis when acting on osteogenic cells, promote osteoblast differentiation and enhance their activity, while regulating bone resorption and inhibiting collagen degradation, and is an important growth factor secreted by skeletal cells. the proliferative effect of IGF-I stimulating osteoblast-like cells is now recognized. 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 osteogenic effects through insulin receptors on the surface of bone cells, and can promote the synthesis of bone collagen. The 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.
Type 1 diabetes affects collagen synthesis by osteoblasts due to absolute insulin deficiency, which can accelerate collagen tissue metabolism and thus enhance bone resorption by osteoclasts, while insulin deficiency inhibits osteocalcin synthesis by osteoblasts, thus making bone resorption greater than bone formation and eventually leading to the formation of osteoporosis. Therefore, insulin therapy is not only beneficial to the prevention and treatment of chronic complications of diabetes, but also has positive significance in the prevention of osteoporosis. If osteoporosis is considered a chronic complication of diabetes, the status of insulin cannot be ignored.
5. The effect of advanced glycosylation end products (AGEs) on bone: high sugar leads 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 causes apoptosis of mesenchymal stem cells, preventing their differentiation into adipose tissue, cartilage and bone, causing a significant reduction in osteogenesis. The modification of bone proteins by glycation in diabetic patients affects two processes of bone reconstruction, namely bone resorption by osteoclasts and bone formation by osteoblasts.
In addition, 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 the osteoclast and osteoblast nuclear factor pathways, alter the physiological function of bone collagen, promote the maturation of osteoclast precursors, stimulate osteoclast aggregation and inhibit their apoptosis, increase osteoclast activity, accelerating bone resorption, which in turn leads to disruption of the bone reconstruction process and plays an important role in the development of osteoporosis.
6, the impact of diabetic complications on the skeleton: the majority of diabetic patients in long-term sugar control is not ideal in the case of diabetic vascular complications, there is also a negative impact on bone metabolism. Diabetic nephropathy secondary to hyperparathyroidism can lead to increased bone calcium mobilization and increased bone loss. When combined with peripheral vasculopathy, the microcirculation is impaired, capillary permeability increases, and the surrounding basement membrane thickens, thus affecting bone reconstruction; it also affects the vascular distribution of bone resulting in inadequate blood supply to bone tissue and causing abnormal bone metabolism.
After diabetic cerebral infarction, the muscle strength of the affected limb decreases and the balance ability decreases, leading to an increased risk of falling, and diabetic retinopathy also leads to an increased risk of falling, which is an important reason for the increase of diabetic fractures.
Fourth, the effect of glucose-lowering drugs on osteoporosis
The ADOPT study found that thiazolidinediones (TZDs) can cause increased bone loss and fracture risk in diabetic patients, especially in diabetic women. Clinical data showed that in older postmenopausal women, patients taking TZDs lost 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. TZDs were found to promote the development of osteoclastogenesis and also induce differentiation of mesenchymal stem cells to adipocytes by inhibiting their differentiation to osteoblasts, which ultimately leads to osteoporosis.
Sulfonylureas, the most widely used drugs in the country, 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 the phosphodiesterase catalyst by increasing cAMP, competitively inhibiting enzyme activity and increasing calcium salt loss. Recent domestic studies have found that sulfonylurea Lou drugs reduce MC3T3 E1 cell survival and increase autophagy and apoptosis marker protein expression, suggesting that medium and high concentrations of sulfonylureas can induce autophagy and apoptosis in osteoblasts and reduce osteoblast differentiation function.
V. Treatment and prevention
First of all, good glycemic control should be achieved and maintained, and the value and status of insulin therapy should be emphasized. Oral hypoglycemic drugs, such as TZDs and sulfonylureas, should be used carefully for diabetic patients with osteoporosis risk factors to reduce or delay the occurrence of diabetic complications. Diabetic patients with uncomplicated osteoporosis should pay attention to calcium and vitamin D supplementation while treating diabetes to prevent the development of osteoporosis.