Ankylosing spondylitis (AS) is a chronic progressive inflammatory osteoarthropathy that affects the spine, sacroiliac joints, and hip joints, with early manifestations of synovitis and ligamentous attachments, followed by peri-vertebral soft tissue ossification and intervertebral bone bridges, leading to spinal ankylosis and late onset of stiff thoracolumbar kyphosis.
Osteoporosis (OP), a common complication of AS, can lead to complications such as spinal fracture, kyphosis and neurological impairment, which can seriously affect the quality of life of patients. osteoporosis (OP) can appear in the early stage of AS, and the occurrence of fracture is significantly higher than normal. osteoporosis in the late stage of the disease leads to kyphotic deformity due to OP, and the X-ray shows a reduction of vertebral trabeculae and vertebral body In the late stage of the disease, due to OP, the hunchback deformity is caused. Although osteoporosis may occur in many chronic inflammatory osteoarthropathies, AS has its own characteristics: extensive osteoporosis occurs along with peri-spinal soft tissue ossification and new bone production. Wang Genrong, Department of Rheumatology, Shaoxing Hospital of Traditional Chinese Medicine
1. The effect of AS on bone mineral density
1. 1 Early bone mineral density in AS patients
AS is a systemic disease characterized by chronic inflammation of the midshaft joints and is often associated with OP, in addition to calcification and bony ankylosis of the intervertebral disc annulus and adjacent ligaments. Vasdev et al. used dual-energy X-ray absorptiometry (DXA) to measure the BMD of the lumbar spine and femoral neck in 80 young male AS patients and found that the incidence of osteoporosis was significantly higher than that of the control group.
El Maghraoui et al. used quantitative computed tomography (QCT) to measure the BMD of the lumbar spine in 43 patients with early AS and showed that it was significantly lower than that of the normal control group.
The comparison of BMD in AS patients with different spinal functional status stages showed that the differences in BMD of lumbar spine, femoral neck, triangle, and trochanter in AS patients with normal spine function were statistically significant compared with healthy controls. This suggests that in the early stage of AS, patients do not yet have ligamentous ossification and spinal ankylosis, and the spine still has considerable mobility, but osteoporosis is already present, suggesting that AS combined with osteoporosis may be an aspect of the pathological changes of the disease and is not solely caused by post-spinal ankylosis braking.
1. 2 Late bone density in patients with AS
The ossification of the ligaments around the vertebral body and the formation of a shell of dense new bone in late AS raises the BMD values of the local mineralized soft tissues, resulting in normal or increased BMD of the lumbar spine, while the BMD of the femoral neck remains reduced, indicating that bone loss continues.
The differences between the BMD of lumbar spine in patients with advanced AS and healthy controls were not statistically significant, while the differences between the BMD of femoral neck, triangle and ramus and healthy controls were statistically significant, which may be related to the calcified dense new bone formation shell of spinal ligaments in patients with advanced AS, which increased the BMD values of locally mineralized soft tissues (e.g.: ligamentous tuberosity, vertebral body ligament ossification, small joint fusion, etc.) and affected the DEXA posterior lumbar spine Kaya et al. used DXA to measure the BMD of the lumbar spine and proximal femur in 25 patients with AS who were not treated with medication and followed up for 2 years, and the BMD of the lumbar spine increased by 3. 4%, whereas the BMD of the femoral neck and femur decreased by 0. 9% and 0. 25%, respectively.
In another study, BMD of the lumbar spine was evaluated by DXA and QCT in 15 patients with AS who were asymptomatic and not treated with medication, and was followed up for 10 years. This further confirms that osteoporosis persists in the lumbar spine in advanced AS and that DEXA measurements of lumbar spine BMD do not reflect bone loss in patients with advanced AS. The BMD measurements of the femoral neck, triangle, and trochanter are not affected by ligamentous calcification and bone redundancy, so the above three sites can better reflect the bone loss in patients with advanced AS.
1.3 Factors influencing BMD in AS patients
The cause of OP in AS was initially thought to be due to spinal ankylosis. Recently, it is mostly believed that in patients with early AS, the decrease in BMD is related to the persistent activity of the disease and is caused by the inflammation of the disease itself. In advanced AS, hormones play an important role in the pathogenesis of OP due to the long-term application of large amounts of hormones to control inflammation.
Although the clinical characteristics of HLA-B27 negative and positive AS patients were different, there was no difference in bone mineral density between them. In a study of the correlation between bone metabolic indexes and HLA-B27, it was found that CICP values were lower in HLA-B27-positive patients than in negative ones, while CTX values were higher in HLA-B27-positive than in negative ones, suggesting that HLA-B27 may inhibit the synthesis of bone collagen in AS patients through the CTX and CICP pathways and promote the formation of bone destruction.
2. Pathological mechanisms of AS osteoporosis
2.1 AS osteoporosis and inflammatory response.
2.1.1 AS disease activity and OP
Patients with AS have the following pathological changes:
( 1) systemic inflammation;
( 2) Bone destruction;
(The pathological changes of AS are inflammation of tendon and ligament bone attachment points with localized bone erosion, followed by new bone formation and non-specific endochondral ossification during inflammatory repair, leading to joint ankylosis. The inflammation may be one of the reasons for the imbalance of bone metabolism in patients. This is because the inflammatory response accelerates bone resorption, increases bone loss, and leads to a decrease in bone mineral density. Grazio et al. analyzed the BMD of the lumbar spine and hip in 80 patients with AS with respect to blood sedimentation, C-reactive protein level, and AS disease activity index (BASADI) and AS function index (BASFI), and found a correlation between the degree of disease activity and the decrease of BMD.
The correlation between the degree of disease activity and the reduction of BMD was found. One study found a significant reduction in BMD only in the active group, with a mean reduction of 5% in the lumbar BMD (0.2% in the inactive group) and 3% in the femoral neck BMD (0.6% in the inactive group). In another study, 54 patients with AS were followed up for 2 years and showed that the reduction in femoral neck BMD was significantly greater in patients with persistent inflammatory response than in other patients. All of these studies confirm that inflammatory response is an important cause of bone loss in AS patients.
The BMD of AS is characterized by ossification of OP and ligaments, and the study showed that the BMD of lumbar spine, femoral neck, triangle, and trochanter were significantly negatively correlated with sacroiliac joint phase grading, ESR, CRP, and the more significant the sacroiliac joint destruction, the more bone loss. The study of BGP (serum osteocalcin), Pyr (pyridinoline) and Dpyr (deoxypyridinoline) in 56 patients revealed that BGP levels were reduced and positively correlated with ESR and CRP, and there were significant differences in Pyr and DPy compared with the control group.
Therefore, it is thought that the inflammation may have suppressed osteoblast activity, resulting in a decrease in serum osteocalcin levels and slowed osteogenesis, while the suppression of BGP activity led to enhanced CTX and urinary Dpyr activity and promoted bone destruction, resulting in reduced bone mass. The study of the pathogenesis and evolution of the coexistence of osteoporosis OP and ossification of the ligamentous joint capsule is of great importance to deepen the understanding of the disease, as the close balance between osteogenesis and bone resorption is imbalanced, thus changing the rate of osteogenesis and bone resorption.
2.1.2 The role of OC in AS
Osteoclasts are specialized bone resorbing cells that play an important role in bone remodeling. They are derived from bone marrow mononuclear macrophages, peripheral blood mononuclear cells, alveolar macrophages and alveolar bone macrophages, and differentiate and mature under the action of osteogenic P stromal cells or OPG/RANKL/RANK, TNF-α, IL-1, M-CSF, VEGF and other pro-differentiation factors, and then play a bone destruction.
Sarikaya et al. suggested that osteoporosis in AS patients is limited rather than systemic and that increased bone resorption due to local inflammation plays an important role. First, the higher density of OC distribution in the subchondral bone marrow may be due to the important role of OBPSC in the bone marrow, which contributes to the differentiation and maturation of OC, which in turn plays a role in bone destruction, causing subchondral cystic changes and local osteoporosis on X-ray. In addition, it has been recently studied that AS patients with osteophytes are more prone to bone loss, and osteophytes are mainly formed by the bone matrix secreted by OB.
2.1. 3 OP and RANKL/RANK/OPG signaling pathway system in AS patients
The RANKL / RANK / OPG system is the main system that directly regulates the formation and function of osteoclasts.RANKL, RANK and OPG belong to the same tumor necrosis factor superfamily. Firstly, RANKL is expressed in osteoblast precursor cells, mesenchymal cells and activated T lymphocytes. RANKL exists in two forms: membrane-bound (mRANKL) and free (sRANKL). mRANKL is expressed on the cell membrane of osteoblast precursor cells and osteoblasts, sRANKL is mainly secreted by activated T cells, and RANK is expressed on the surface of osteoblast precursor cells. OPG is secreted by bone marrow stromal cells and osteoblasts. When RANKL binds to RANK it initiates a signal transduction waterfall.
OPG is a soluble closed receptor that binds to RANKL to neutralize its action, thereby blocking the RANKL-RANK-induced signal transduction mechanism and inhibiting osteoclast precursor cell differentiation, survival, fusion, and inducing apoptosis of mature osteoclasts. Inflammatory factors can stimulate osteoblasts and other cells to produce RANKL, which increases RANKL/OPG and promotes osteoclast maturation. The degree of osteosclerosis correlates with the level of OPG. OPG-deficient mice develop OP early in development, with decreased bone mechanical strength and bone density. Adult OPG-deficient mice exhibited severe vertebral compression fractures and fragmentation of the femoral marrow.
RANKL expression is stronger in the synovial tissue of AS patients, and Kim et al. showed that the RANKL/OPG ratio is higher in AS patients with combined osteoporosis, and the RANKL/OPG ratio is positively correlated with the degree of imaging damage, which can promote the differentiation and maturation of OC, while the increased OPG level may be a response of OB to enhanced bone resorption, and may also explain the formation and sclerosis of spinal bone redundancy in AS patients. It may also explain the formation and sclerosis of spinal bone fragments in AS patients, and may be one of the important reasons for the lesser degree of bone destruction in AS compared with rheumatoid arthritis.
2.1.4. Bone formation and Wnt signaling pathway in AS: Local bone formation in AS is generated by a series of cartilage activities. This pathway includes the bone morphogenetic protein (BMP) and Wnt signaling pathway. The expression of osteosclerotic proteins is impaired in AS patients, indicating altered bone 1. cell function. Osteosclerin inhibits BMP-mediated bone formation, which has similar properties to the Wnt signaling pathway antagonist DKK-1 (dickkopf-1). Animal experiments showed bone formation in DKKl inhibitor-treated mouse models, while controls were missing. In AS patients, serum DKKl levels are very low, supporting the theory that the Wnt signaling pathway is active in AS. The key to this is the reduced DKKl binding receptors in AS patients.
There is a relationship between bone formation and inflammatory response in AS: BMP can be induced by TNF or other pro-inflammatory cytokines, while DKK production is also promoted by TNF. the BMP and Wnt signaling pathways are active at different stages of bone formation in cartilage and therefore play different roles in bone flab formation. However, this does not explain the characteristics of all AS patients, as bone redundancy may occur at sites without an inflammatory response, and bone formation and bone resorption may be temporarily or locally separated. In clinical studies, TNF-α significantly improves symptoms and increases BMD, but there is no evidence of structural changes in AS.
2.1.5 AS inflammatory factors and OP
Inflammatory mediators have also been associated with the development of osteoporosis in patients with AS. These mediators mainly include IL-1, IL-2, IL-6, TNF-α, TGF-β, PG, etc. These cytokines can activate osteoclasts, increase bone resorption, and cause bone deposition to be affected. Among them, IL-6 and TNF-α are key members of cytokines and play an important regulatory role in bone metabolism.
TNF-a is a pro-inflammatory cytokine, mainly produced by activated monocytes-phagocytes, and is located at the apex of a network of interconnected pro-inflammatory cytokines that are central to many immune-mediated diseases. It is the most potent cytokine known to stimulate bone resorption, enhancing osteoclast formation by promoting the proliferation of progenitor osteoclasts, and activating mature osteoclasts to promote the secretion of PGE2 by osteoblasts, which stimulates osteoclasts. Together, they enhance osteoclast activity and promote bone resorption, and also enhance early osteoclast production, which significantly inhibits collagen synthesis and induces bone resorption, leading to osteoporosis.
TNF-α, which can promote OC differentiation and maturation alone or dependent on the RANKL/RANK system, plays a particularly important role in certain inflammatory joint lesions. TNF-α is mainly derived from activated T lymphocytes and macrophages in inflamed synovial tissues, and can stimulate osteoclast production directly or indirectly in vitro and in vivo, and can enhance OC function in addition to mediating inflammatory responses.
TNF-α transgenic mice crossed with RANK knockout mice showed joint inflammation but no destruction of periarticular bone and cartilage, so inflammation itself did not mediate joint destruction and bone loss, while the severity of joint destruction and bone loss depended on the number and function of osteoclasts. In addition, TNF-α can promote the differentiation and maturation of OC by upregulating the expression of c-fms and M-CSF, the upstream pathway of RANKL, and then exert the bone resorption effect of OC.
When patients were treated with TNF inhibitors, symptoms greatly improved, inflammatory activity decreased, BMD increased, and serum type I collagen C-terminal peptide (sCTX) decreased, i.e., inhibited osteoclastic effects.
IL-6 acts on the early osteoclast formation stage, stimulates early precursor division proliferation, also stimulates the transformation of multinucleated cells into osteoclast phenotypes, promotes the function of mature osteoclasts, activates osteoclasts, and also mediates the action of various hormones and local cytokines on osteoclasts. It has been shown that serum TNF-α and IL-6 levels were significantly higher in AS patients than in other non-inflammatory low back pain and healthy controls.
Santos et al. also found that serum IL-6 levels were increased in patients with AS and were associated with inflammatory activity and bone loss. This suggests that TNF-α and IL-6 can cause increased bone resorption and play an important role in the pathogenesis of osteoporosis. oPG can block the effects of cytokines, including interleukin-1 and tumor necrosis factor-α, and a large number of hormones on bone resorption.
Other cytokines that promote OC differentiation, such as M-CSF, IL-1 and VEGF, are also expressed in the local lesion sites of AS. These cytokines can act directly or indirectly on OC or OC precursors through different pathways to induce their differentiation and maturation, exerting bone resorption effects and causing bone destruction or osteoporosis in AS.
2.2 Effect of 1,25(OH)2D3
1,25(OH)2D3 has a bi-directional effect on bone mineral metabolism, which not only promotes the calcification of new bone, but also facilitates the freeing of calcium from bone, and keeps the bone salts updated to maintain the calcium balance in bone, but also has a regulatory immune function, and plays an important role in regulating the progression of inflammation and bone transformation in AS.
It has been shown that the reduced level of 1,25(OH)2D3 disrupts calcium homeostasis, acts as an endogenous immunomodulator, suppresses activated T cells, and promotes cell proliferation in AS, accelerating the progression of inflammation. The increased synthesis of 1,25(OH)2D3 was found to promote intestinal calcium resorption and bone formation, and to promote the secretion of calcitonin and inhibit the secretion of parathyroid hormone, thereby reducing bone resorption. )2D3 and parathyroid hormone levels were significantly lower in 70 patients with early ankylosing spondylitis.
2.3 Endocrine hormones associated with bone metabolism in AS
Franck et al. found a positive correlation between hip BMD values and serum free estradiol levels in female patients with AS, and a positive correlation between hip BMD values and serum free testosterone in male patients, and a negative correlation with parathyroid hormone in male patients. This may suggest gender differences in the pathogenesis of OP in patients with AS. serum testosterone levels were higher in patients with AS than in healthy men, however, in men with AS, serum testosterone was lower than in those without OP. el Maghraoui et al. observed that serum calcitonin levels were lower, luteinizing hormone levels were higher, and prolactin levels were higher in patients with AS compared to healthy controls. In conclusion, small changes in sex hormones, parathyroid hormone, pituitary hormone, and vitamin D are potential endocrine mechanisms in the pathogenesis of bone loss in AS patients.
2.4 Genetics and genes
Genetic factors also have an influence on osteoporosis in patients with AS. The results showed that:BMD of lumbar spine showed negative correlation with HLA-B27, indicating that HLA-B27 has some correlation with osteoporosis in AS patients.
2.5 Physical factors
Reduced or restricted exercise can lead to disuse osteoporosis. The reason is that exercise can act on bone from all sides, causing bone to produce corresponding force, and through the stimulation of bone and muscle pulling force, osteoblasts are active, which is conducive to bone formation. When the normal load on bone is reduced or lost, bone reconstruction corresponding to the external load occurs, causing bone atrophy and a decrease in mechanical strength, which eventually leads to osteoporosis.
Maghraoui suggests that pain at the attachment end, stiffness of the spine, and ossification of the ligaments may limit motion in patients with ankylosing spondylitis. Therefore, disuse is one of the causes of osteoporosis or bone loss in patients with ankylosing spondylitis.
2.6 Drug factors
Hormones cause osteoporosis because of abnormal bone metabolism. It has been reported that the hip is a sensitive site for late onset of OP, and in patients taking prednisone at high doses, there is osteoporosis in the middle and early stages.
NSAIDs can inhibit COX, block the conversion of arachidonic acid into PG, reduce the synthesis of PG, especially PGE2, and affect the bone metabolism in AS patients. In addition, NSAIDs have stimulating effects on the gastrointestinal tract, which can affect the appetite of AS patients and reduce the absorption of calcium, protein and vitamins. Another study showed that long-term use of anti-inflammatory pain reduced spinal bone mass and bone strength in rats. Some scholars believe that NSAIDs can affect the stability of bone mass in patients with ankylosing spondylitis because NSAIDs can interfere with the synthesis of PGE2, which can cause osteoporosis in AS.
3. Changes in bone metabolism in AS patients
Bone metabolism is a process consisting of the formation of new bone by osteoblasts and the resorption of old bone by osteoclasts, and the amount of bone mass depends on the interrelationship between bone formation and bone resorption in the same bone reconstruction unit. There is no consistent opinion on bone metabolism in AS patients. Initially, Szejnfeld et al. concluded, by performing bone tissue biopsies in 16 AS patients, that the decrease in bone mass in AS patients was mainly caused by a decrease in bone formation, independent of bone resorption, and that it was the decrease in bone formation rather than the increase in bone resorption that led to OP.
In contrast, more studies on bone conversion indexes in AS showed that OP was caused by increased bone resorption.Yilmaz et al. analyzed that there was no difference in the indexes of bone formation (osteocalcin, alkaline phosphatase) compared with the control group, and the indexes of bone resorption (Pyr, Dpyr) were significantly increased.The results of Acebes et al. showed that the indexes of bone formation (Ñ-type precollagen amino-terminal prepeptide, Ñ-type precollagen carboxy-terminal pre The results of Acebes et al. showed that there was no change in bone formation indexes (pro-collagen amino-terminal peptide and pro-collagen carboxy-terminal peptide) and an increase in bone resorption indexes (Pyr, Dpyr, bone sialic acid protein). Therefore, most scholars now believe that OP complicated by AS is mainly due to increased bone resorption.
4. Treatment strategy for AS osteoporosis
The key issue is to distinguish the time and space of the following three events: systemic inflammatory activity, bone resorption, and bone formation. Systemic osteoporosis is a complication of long-term inflammatory activity. Prevention of osteoporosis is likewise an enabling factor for the complete control of inflammation and is also the aim of treatment.
4.1. anti-TNF-α therapy Anti-TNF-α biologics all exert their biological effects by inhibiting the production and differentiation of OC precursors. baraliako et al. treated AS with infliximide and found that both improved disease activity, improved bone mineral density, and significantly delayed remission of structural damage in patients.
In a study using the RANKL/OPG signaling pathway as a therapeutic target, rhOPG-Fc, obtained by recombinant gene technology, was shown to have a strong inhibitory effect on osteoclasts and bone resorption in in vitro experiments, and a single dose of rhOPG-Fc could reduce OC production and prevent bone loss, and slow down OC bone resorption in postmenopausal patients with osteoporosis.
When Bolon et al. administered OPG to rats with adjuvant arthritis, they found that injection early in the disease inhibited joint damage and confirmed that OPG protected joint bone and cartilage in a time- and dose-dependent manner. However, in AS patients, the expression of OPG was not reduced, but increased compared to normal controls, ultimately due to the imbalance of RANKL/OPG, which resulted in a relative reduction of OPG. Therefore, it is particularly important to regulate the balance of RANKL/OPG to inhibit the differentiation and maturation of OC and thus bone resorption.
IL-1 receptor blocker is also one of the important inducers of OC differentiation, which initiates the intracellular signaling pathway system by binding to OC surface receptors to promote OC differentiation and maturation. The recombinant human IL-1 receptor blocker molecule anakinra has also been used clinically and may be useful in alleviating clinical symptoms and disease progression of inflammatory AS.
4.3 Bisphosphonates Bisphosphonates reduce the bone resorption capacity of OC by inhibiting OC production and promoting apoptosis. However, the main efficacy of simple anti-bone resorption therapy is to improve systemic bone loss, but not to prevent local bone loss, while AS is mainly local bone loss, this result suggests that local use of drugs in the joint may be more reasonable.
4.4 Teriparatide is a bone formation-promoting drug, which can be used for primary osteoporosis and fracture prevention, but no study has been seen concerning the effect of teriparatide in the treatment of osteoporosis in AS patients.
In summary, patients with AS may have increased bone breaking activity triggered by an inflammatory response that allows osteoporosis to develop early, in addition to factors such as reduced spinal mobility and degree of disease activity due to joint ankylosis. Bone destruction due to the inflammatory response is the main trigger of new bone formation, in which biomechanical factors play an important role, while the bone formation process, once initiated, is not significantly related to the inflammatory response and is independent of each other.
The pathogenesis of osteoporosis in AS patients has been identified at the cytological and molecular biology levels, and further studies to clarify its pathogenesis can help better assist in early clinical diagnosis and warning, and provide an important theoretical basis for guiding clinical prevention and therapeutic use.