Osteoporosis (osteoporosis) is a metabolic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, resulting in decreased bone strength, increased fragility and susceptibility to fracture. With the aging of the world population, osteoporosis has become a global health problem. The 2013 Blue Book on Osteoporotic Fracture Prevention and Treatment in China states that the prevalence of vertebral fractures in Chinese women over the age of 50 is 15%, and the prevalence of osteoporosis in people over the age of 60 is also significantly higher, especially in women.
This not only affects the physiological and psychological health of patients, greatly reduces the quality of life, but also brings a serious economic burden to society. Since the onset of osteoporosis is insidious and is often diagnosed only after fracture injury occurs, tertiary prevention is particularly important. The identification of the pathogenesis of osteoporosis and the factors affecting bone metabolism is essential for the prevention of osteoporosis.
I. Current status of osteoporosis in China and reference standards
Bone mineral density (BMD) is currently the best quantitative index for diagnosing osteoporosis, predicting the risk of osteoporotic fracture, monitoring the natural course of the disease, and evaluating the efficacy of drugs, but this index varies by gender, age, genetic background, nutritional status, physical activity, and environment.
According to the World Health Organization (WHO) diagnostic criteria, the diagnosis is established if the BMD is lower than 2 standard deviations from the peak BMD. Therefore, the establishment of corresponding BMD reference standards for different populations is of clinical guidance for the prevention, early diagnosis and treatment strategies of osteoporosis.
The results of a BMD test in 16019 adult Han Chinese population in Changchun city suggested that the peak BMD of adult distal radius and non-dominant forearm ulna occurred at the age of 30-34 years, with an average of (0.625±0.109) g/cm2 for men and (0.506±0.058) g/cm for women. In the age group of 50-59 years, the prevalence of osteoporosis was 7.70% in men and 6.97% in women; however, by the age of 60-69 years, the prevalence was 18.13% in men, while it increased significantly to 35.95% in women;
With increasing age, the prevalence reached 59.55% in women and 36.41% in men at the age of 70-79 years. In addition, there were significant differences in BMD levels between different ethnic groups in the country. Therefore, this study provides reference data for peak BMD and diagnostic criteria for the local population.
In another study, domestic scholars established a set of assessment and reference database of osteoporosis prevalence suitable for the Chinese adult population, covering a total of 51,906 women and 88,006 men from 38 cities in the literature published before 2013. The resultant data suggested that the peak lumbar spine BMD in women appeared at the age of 30-39 years at 1.088 g/CII12; while men reached the peak at the age of 20-29 years at 1.066 g/cm2 relatively earlier.
According to the diagnosis of osteoporosis with less than 2.5 standard deviations from T value, the recommended cut point in women is 0.746 g/cm2 and in men 0.680 g/cm2. Therefore, establishing the reference range of peak BMD in different populations is of great clinical significance for early diagnosis and assessment of osteoporosis.
II. Fracture assessment and risk prediction
The results of a study on the assessment of systemic vertebral fractures were presented at the ASBMR annual meeting held in 2013. The study compared the incidence of vertebral fractures predicted by new non-vertebral fractures before and after the use of the Systematic Vertebral Fracture Assessment Tool in a population of 1370 people over the age of 50.
The results showed that the rate of vertebral imaging increased from 16.5% to 95.4% in accordance with the assessment tool, and that 26.3% of patients with new nonvertebral fractures had one or more newly diagnosed vertebral fractures after adequate assessment, including 44.6% of patients with hip fractures, 33% of patients with osteoporosis, and 21.4% of patients with normal bone density levels.
According to the Genant semi-quantitative grading scale for vertebral fractures, the percentage of vertebral fractures with Genant grade 1 (20%-25% vertebral compression), grade 2 (25%-40% vertebral compression) and grade 3 (>40% vertebral compression) was 1.4%, 0.5% and 0.1%, respectively, before the evaluation, which increased significantly to 11.2%, 12.3% and 2.8%, respectively.
This shows that with a comprehensive systematic vertebral fracture assessment, the rate of spinal imaging can be increased by 20-fold and the diagnosis of vertebral fractures by 10-fold. Therefore, the use of vertebral fracture assessment tools in post-fracture patients may help to accurately define the population at high risk for vertebral fracture that requires treatment.
In addition, at the congress, the OLEFY study of people at high risk of fracture gave a report on the assessment of fracture risk in women over 40 years of age at 10 and 20 years later. The study included 868 women with a mean age of (59 ± 10) years at baseline, 78% of whom were menopausal, and assessed bone mineral density by DXA testing, as well as radiography of the extremities and spine to clarify the occurrence of fragility fractures.
During a mean follow-up of 19.7 years, a total of 245 women developed fragility fractures. BMD levels at baseline at different testing sites were significantly associated with fracture risk: for each standard deviation decrease in BMD levels at the femoral neck, hip, spine, and radial end of the forearm during the first 10 years of follow-up, the corresponding fracture risk increased by 61%, 69%, 67%, and 79%, respectively;
For each standard deviation decrease in BMD levels at the femoral neck, hip, spine, and forearm radius over the entire 20-year follow-up period, the corresponding fracture risk increased by 49%, 54%, 47%, and 72%, respectively. This shows that the predictive power of BMD levels at baseline for fracture risk does not decrease over time, and therefore BMD is a reliable predictor of long-term fracture risk in women.
III. Bone and cardiovascular system
Cardiovascular disease and osteoporosis are common and prevalent diseases in the elderly, and the finding that both vascular calcification and osteoporosis are present in patients suggests that there may be common ground in the pathogenesis of both. Bone and vascular tissues share the same characteristics at the molecular cellular level: the bone marrow contains endothelial cells, precursor osteoblasts, and osteoclasts of monocyte origin, while similar cells are also present in the arterial wall.
In addition, both bone and calcified arteries contain bone bridging proteins, bone morphogenetic proteins, matrix Cla proteins, type I collagen, osteonectin, osteocalcin, and matrix vesicles. There is evidence of a correlation between osteoporosis, cardiovascular disease and mortality. Bone loss has even been shown to be significantly associated with cardiovascular mortality.
Even in people without cardiovascular disease, low levels of BMD were found to be a major factor in the development of cardiovascular disease after 5 years of follow-up, showing that the risk of cardiovascular disease increased 3.5-fold in the lowest quartile of BMD compared to the highest quartile, and that severe bone loss also increased the risk of cardiovascular disease by up to 2.9-fold.
The LURIC study showed a U-shaped association between type I collagen carboxy-terminal peptide β special sequence (β-CTX) and mortality in men at high cardiovascular risk, while in women, high levels of 3-CTX were independently associated with all-cause and cardiovascular mortality in women at high cardiovascular risk, and osteocalcin concentrations were independently associated with non-cardiac mortality. J-shaped negative association with non-cardiac mortality.
The mechanisms of reduced BMD and cardiovascular disease pathogenesis are not yet fully elucidated, but may be related to the following two points: (1) atheromatous calcified plaques and calcified injury areas contain a variety of bone matrix proteins and osteoblast markers, and the mineral hydroxyl phospholime in calcified atherosclerotic plaques is also present in bone, and the matrix vesicles, the site of initiation of mineral hydroxyl phospholime aggregation in bone, can also be found in atheromatous This has led to the hypothesis that there is an intrinsic link between vascular calcification and atherosclerosis.
(2) Certain specific protein (such as osteoprotegerin and matrix gla protein) gene deletion can increase the risk of coronary calcification and osteoporosis.
Fourth, the bone and obesity
In recent years, people are gradually concerned about the brown fat has a certain impact on bone metabolism. Healthy women can activate more brown fat than men after cold stimulation, and its content is significantly correlated with total bone density and lumbar spine bone density, and as an independent predictor of total bone density and spine bone density, suggesting that brown adipose tissue may be related to the regulation of bone density.
Because of the unique microenvironment of bone marrow, where fat coexists with the cells and mesenchymal vessels of bone, the process of brown adipose tissue formation generates a hypoxic gradient, which creates conditions for chondrocytosis and bone formation.
Thus for individuals with higher active brown adipose, there is perhaps a bone marrow microenvironment with a greater capacity for osteocytosis, leading to a higher bone mineral density content. The above findings were not observed in men, so whether brown fat has an actual positive effect on bone metabolism needs to be confirmed in further studies with larger samples.
V. Effect of body weight on bone
Previous epidemiological studies have shown that elevated body weight is associated with increased bone mass, and that weight loss can cause varying degrees of bone loss. Body weight is mainly composed of muscle content and adipose tissue, and the metabolic effects of the two differ greatly, so the effects on bone need to be analyzed according to the different components of body weight. Excessive adipose tissue is detrimental to the maintenance of bone density. Obesity is accompanied by a corresponding increase in bone marrow fat content, which increases bone fragility.
A recent Korean health and nutrition survey found that excess adipose tissue increased the risk of osteoporosis by 3.69 times, and even up to 5.64 times in people with a body mass index >25 kg/m2, while lean body mass showed a protective effect on bone health.
Although obesity increases the risk of osteoporosis, sustained weight loss also carries the risk of skeletal deformities, especially bone loss in weight-bearing areas. With the increasing availability of bariatric surgery, its benefits for obesity complications are becoming more recognized, but surgical patients face the possibility of osteoporosis risk at weight-bearing sites.
Recent studies have found that an average weight loss of 28 kg via Roux-en-Y bypass results in a 23% decrease in parathyroid hormone (PTH) levels, a 144% increase in type I collagen C-terminal peptide levels, and a 5.2% and 4.5% decrease in area bone mineral density in the hip and femoral neck, respectively. By high-resolution peripheral quantitative computed tomography (HR-pQCT), cortical bone, especially in the tibia, showed significant changes, with varying degrees of reduction in cortical area (-2.7%), thickness (-2.1%), and density (-1.7%).
Multiple regression analysis showed that weight loss was a predictor of bone loss at the hip and femoral neck. And only elevated PTH was able to predict bone cortical decay at the tibial site. Thus, bone loss at the hip after bariatric surgery reflects the release of skeletal weight-bearing, whereas bone loss in cortical bone reflects secondary hyperparathyroidism, which may be a new mechanism for bone loss after bariatric surgery.
VI. The relationship between inflammation and bone
Chronic inflammation has been found to have a detrimental effect on bone health in recent years. An increasing number of studies have found a correlation between C-reactive protein, one of the markers of systemic inflammation, and fragility fractures, but the findings of current reports on the correlation between C-reactive protein and BMD levels detected by DXA are inconsistent.
Data from the SWAN study, disclosed at the 2013 JBMR, showed that the composite index of bone strength related to the femoral neck was negatively correlated with C-reactive protein levels, implying that increased C-reactive protein levels can increase fracture risk, but are not correlated with BMD levels.
The data are from the SWAN study, a multicenter, multiethnic, prospective cohort study including 1872 community-based women of childbearing age and early menopause. Bone strength-related indices were calculated from femoral neck width, femoral neck shaft length, bone mineral density at the femoral neck, and body size obtained from DXA testing and analyzed for correlation with C-reactive protein levels.
This was calculated as follows: compressive strength = BMD × femoral neck width/body weight, flexural strength = BMD × femoral neck width2/(femoral neck shaft length × body weight), and impact strength = BMD × femoral neck width × femoral neck shaft length/(height × body weight).
During the 9-year follow-up period, a total of 194 women had fractures (10.4%), and C-reactive protein levels were found to be negatively correlated with bone strength coefficients but not with femoral neck or lumbar spine bone density levels after correcting for age, sex, ethnicity, diabetes mellitus, body mass index, history of smoking and alcohol, exercise, medications, and previous fracture history.
A linear increase in fracture risk with C-reactive protein level was found only at C-reactive protein ≥3 mg/L by COX risk proportional analysis, but no correlation with bone density level was suggested. This study confirms for the first time the presence of chronic inflammation in the presence of low bone strength and clarifies the magnitude of the weight of reduced bone strength and thus fracture occurrence due to inflammation in the overall inflammation-fracture relationship.
Moreover, the early menopausal women included in this study had not yet experienced a significant decrease in estrogen levels, thus better illustrating the importance of inflammation in the assessment of bone strength.
VII. Bone and insulin-like growth factor (IGF) and its binding globulin (IGFBP)
As one of the most abundant growth factors in osteoblasts, IGF-1 plays an important role in bone metabolism by regulating osteoblast function in the form of autocrine and paracrine secretion.
However, there is still controversy about the relationship between IGF-1 and bone turnover markers. One study found that ICF-I showed positive correlation with the bone formation markers type I procollagen amino-terminal peptide (PINP) and β-CTX in men younger than 55 years old and premenopausal women, but no association was found in the elderly population, suggesting that the effect of IGF-I on bone metabolism may be stronger in the young and middle-aged population than in the elderly population.
IGFBP-2 binds IGF-1 in the circulation, thereby inhibiting its physiological effects and reducing the occurrence of bone turnover. In normal women, IGFBP-2 levels were negatively correlated with brown fat content and hip BMD levels activated by cold stimulation, and was shown to be a negative regulator of brown fat and BMD, independent of ICF-1. Therefore, this may be an evidence for the involvement of IGFBP-2 in brown fat-mediated osteogenesis.
VIII. Bone physiological signaling pathways and gene loci
Notch is an evolutionarily well-conserved signaling pathway involved in the regulation of cell proliferation and differentiation, and plays an important role in bone formation and fracture prognosis. It functions through the hydrolysis of a secondary protein that releases the intracellular structural domain of Notch and transfers it to the nucleus, where it binds to recombinant signal binding protein (RBPjk) and Mastermind-like protein (MAML) in the kj region of immunoglobulin. Among them, MAML acts as a structural scaffold to recruit other co-activators to initiate transcription of Hes and Hey in the classical Notch target gene family.
A study conducted in a time-controlled induced transgenic mouse model (Mxl-Cre;dnMAMLf/-) found that inhibition of the Notch signaling pathway prolonged inflammatory factor expression in the bone scab as well as neutrophil inflammation, while reducing the proportion of cartilage components in the bone scab 10 d after fracture. Although it did not affect early bone formation 10 d after fracture, it significantly altered bone maturation and reconstruction 20 d later: bone volume fraction increased and bone trabeculae thickened but connection density decreased.
Inhibition of the Notch signaling pathway resulted in a decrease in overall osteoblasts, implying that more osteocytes than osteoblasts were present in new bone. The above results suggest that the effect of Notch signaling pathway on fracture prognosis is divided into direct effects on different cells and indirect effects triggered by temporary upstream signals during the fracture prognostic cascade response.
This study confirms that temporal cascade of Notch signaling is still required during fracture prognosis, and therefore the authors suggest that a blanket inhibition of this signaling pathway may not be an ideal therapeutic option to promote bone regeneration.
A genome-wide meta-analysis of a European population published in 2012 uncovered 56 bone density-associated loci. A subsequent genetic analysis in a southern Chinese population of 2670 cases successfully replicated 27 of these loci, suggesting the presence of the same osteoporosis susceptibility genes in both Chinese and European populations.
In addition, a significant interaction between MARK3 and plasma AIP levels was found, and the effect of MARK3rs11623869 locus on BMD would be more significant in the presence of high levels of plasma ALP, suggesting that plasma ALP levels could modify the effect of MARK3 on BMD.
IX. Anti-osteoporosis/fracture prevention therapy
Nakano et al. published a report on the efficacy of teriparatide injection (56.5 mgqw) treatment against osteoporosis. This randomized double-blind placebo-controlled study was conducted in 542 Japanese patients (65-95 years old) with osteoporosis. The results found a significantly lower incidence of vertebral fractures in the treatment group compared to the control group (2.7% vs. 13.2%, RRO.20).
In addition, the risk of re-fracture was also reduced to varying degrees in patients with one or more previous vertebral fractures (RRs of 0.08 and 0.29, respectively, p<0.01), and for vertebral fractures of grade 3 the RR was 0.26. reduce the risk of vertebral fracture in different populations and achieve fracture prevention.
Since lifetime teriparatide injections were previously found to cause a dose-dependent increase in the incidence of osteosarcoma in a rat toxicology study. However, in adult applications, the incidence of osteosarcoma was 2.7 cases per million person-1 per year-1, while 1,641 cases of osteosarcoma occurred from January 1, 2009 to December 2012 in 26,810 patients on the Third U.S. Oncology Registry for teriparatide use. Thus by evaluating the data from the previous 3 years, the drug is now shown to have no significant association with osteosarcoma.
Back in 2003 the New England Journal published 2 studies regarding the fact that the combination of antiresorptive drugs with PTH diminishes the positive effects of PTH on bone density and reconstructive markers mainly because the anabolic effects of PTH are largely based on remodeling rather than constructing. Therefore, inhibition of remodeling by bisphosphonates would diminish the efficacy of PTH. The investigators concluded that such a combination therapy might be ineffective or less effective than monotherapy in reducing fracture rates.
However, many subsequent studies did not observe similar results, so the idea has been challenged and questioned. One study compared cortical bone content and thickness after switching from raloxifene or adiponectin therapy for 12 months to teriparatide injection alone or teriparatide combined with raloxifene or adiponectin for 18 months, and found that the combination therapy resulted in a more significant improvement in cortical bone content than monotherapy, while there was no difference in cortical bone thickness. This suggests that the efficacy of combination therapy is not inferior to that of monotherapy, and further studies are needed.
It can be believed that the progress in the field of osteoporosis and diseases related to calcium and phosphorus metabolism has been extensive and intensive in the past year. This article focuses on new epidemiological data on osteoporosis in China, fracture assessment and risk prediction, bone and cardiovascular disease risk, the effects of obesity, weight and chronic inflammation on bone metabolism, bone and IGF and its binding globulin, the effects of Notch signaling pathway inhibition on osteoblasts, and anabolic therapy.