Bone Markers in Glucocorticoid-Induced Osteoporosis

Glucocorticoids (GCs) are commonly prescribed to reduce pain and the inflammatory component in inflammatory joints, bowel and chronic lung diseases, and autoimmune diseases. Chronic GC therapy involves, as a side effect, the occurrence of osteoporosis, a pathological condition defined as glucocorticoid-induced osteoporosis (GCIO). GCIO represents the primary cause of iatrogenic osteoporosis. Fractures, the most dreaded consequence of osteoporosis, may occur in 30–50% of patients on chronic GC therapy. The risk of experiencing fractures increases exponentially in the first 1–3 months after starting GC therapy. The bone loss rate depends on the dose of GC and the duration of therapy. However, some patients receiving low doses of GC lose more bone than those receiving higher doses, indicating a solid individual genetic component to the response, probably related to specific receptor polymorphism.

GCs in pharmacological doses interfere with bone cell metabolism responsible for remodeling the tissue. In GCIO, there is a decoupling of the two physiological processes of bone formation and resorption, with a consequent reduction in bone mass and deterioration of bone quality. It has been demonstrated that, during GC therapy, the bone formation phase is profoundly inhibited as the proliferation and differentiation of osteoblasts are reduced, and the phenomenon of cell apoptosis is increased. Furthermore, studies have shown a decreased production of collagen and osteocalcin.

Regarding the process of bone resorption, the data in the literature are less well known and sometimes discordant, probably due to the pathologies at which GC therapy is aimed, which may in themselves be the cause of increased resorption. In addition to the direct effect on bone tissue, GCs indirectly alter tissue metabolism through extra-skeletal effects. From a biochemical point of view, the marked decrease in serum osteocalcin is peculiar, accompanied or not by a decrease in other markers of osteoblastic activity such as bone alkaline phosphatase and PINP. Some studies have also shown increased resorption marker levels, such as urinary NTX. International guidelines on the treatment of osteoporosis recommend, especially if GC therapy is planned for more than 3 months and if the patient is at high risk of fracture, that antiresorptive therapy is instituted as soon as possible.

Bone Markers in Immobilization-Induced Osteoporosis

 Studies in volunteers after immobilization have indicated that markers of bone resorption such as urinary CTX and NTX increase significantly due to a rapid increase in osteo clast activity. In a study conducted for 16 weeks, in addition to an increase in resorption markers, a reduction in formation markers was also observed, confirming that the mechanism underlying rapid bone loss after immobilization lies in the activation of remodeling cells. In a study conducted on a population of paraplegic patients with spinal cord injury, the biochemical picture of bone remodeling varied over time. During the first year after injury, urinary excretion of DPD markedly increased, while alkaline phosphatase and osteocalcin were normal or slightly increased. A recent study con firms in male subjects the change in biochemical markers following an experiment of bed immobilization for 14 days but hypothesizes a diverse effect on the risk of bone loss according to the age of the subjects studied.

Bone Markers in Inflammatory Bowel Disease

Patients with inflammatory bowel disease, especially Crohn’s disease, have low bone mass and are at high risk of fractures due to several causes. Among these are steroid therapy, hypogonadism, vitamin D deficiency, low body weight, and high levels of circulating cytokines released by inflammatory bowel cells. In one study, high levels of NTX in urine correlated with bone mass loss at the lumbar vertebrae. High levels of inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and TNF were reported in the same study. However, despite IL-1 and TNF being recognized inhibitors of the bone formation process, the formation markers were in the normal range. Bisphosphonate therapy led to an increase in bone density concomitant with a decrease in markers of resorption and formation. Inflammatory bowel disease therapy with infliximab, an anti- TNF- α drug, induces an increase in formation markers and a slight effect on resorption markers independent of the clinical response to therapy.

Bone Markers in Rheumatoid Arthritis

Patients with rheumatoid arthritis show an increased incidence of osteoporosis and fractures. Also, in this disease, several factors contribute to the loss of bone mass, from steroid therapy to vitamin D deficiency, decreased mobilization, and increased levels of cytokines active on bone tissue. In patients with rheumatoid arthritis, an increase in resorption markers was demonstrated, while no variation was shown in patients with osteoarthritis compared to control subjects. Regarding the markers of formation, the data in the literature are discordant, reporting in some cases an increase, in others a reduction. A comprehensive review of the literature reviewed the data on cartilage and bone damage biomarkers. Numerous studies have shown that bisphosphonate therapy prevents bone loss in these patients exposed to high doses of glucocorticoids to control disease symptoms and causes a decrease in circulating levels of bone markers. Infliximab therapy reduced the level of resorption markers with no adverse effect on formation, evidenced by the lack of reduction in PINP. A multicenter study on the effects of tocilizumab, an IL-6 monoclonal anti-receptor antibody, combined with methotrexate demonstrated a systemic reduction in bone resorption and cartilage turnover by measuring bio chemical markers in patients diagnosed with moderate to severe rheumatoid arthritis.

Bone Markers in Primary Hyperparathyroidism

Excessive secretion of parathyroid hormone causes an increase in osteoclast activity and subsequent increase in osteoblast activity, which can lead to loss of bone mass and increased incidence of fractures, especially in women in the postmenopausal period. Patients with advanced hyperparathyroidism show high levels of markers of formation and resorption, which are not evident in mild cases. Increased bone remodeling returns to normal within 6 months to 1 year after parathyroidectomy. In patients on drug therapy with estrogen, raloxifene, and alendronate, levels of both bone formation and resorption markers were reduced.

Bone Markers in Cancer Pathologies

 Bone metastases are a common complication in cancer dis eases. These may be osteolytic, osteoadhesive, or mixed types. Biochemical markers of bone remodeling can be used in assessing the extent of metastases, response to therapy, and in some cases, in defining the prognosis in terms of survival. Osteolytic metastases are common in breast cancer, and their occurrence is associated with an increase in markers of bone formation, the level of which may decrease by about 70% after intravenous bisphosphonate treatment. Some authors showed that patients with the highest urinary NTX had the highest risk of skeletal complications and dis ease progression compared to patients with lower levels. Increased activity of serum alkaline phosphatase and other training markers was detected in prostate cancer patients who typically show osteoadhesive lesions. In a study con ducted on the effects of zolendronic acid in patients with metastases from prostate cancer refractory to hormonal treatment, there was an increase in urinary NTX, which decreased significantly after intravenous infusion of the antiresorptive drug. According to some studies, the levels of bone markers correlated with an unfavorable prognostic index. In particular, in patients with prostate cancer, increased levels of PINP, bone alkaline phosphatase, and CTX were associated with a poor prognosis; this finding was also confirmed by a serial sampling of markers in the monitoring of hormone treatment. In another study, in patients with prostate cancer, con ducting a multivariate analysis, only high levels of bone alkaline phosphatase maintained a significant association with shorter survival, while no significance was demonstrated for urinary NTX levels. In an animal model, in the presence of osteolytic and osteoadherent metastases, the correlation between tumor dissemination and biochemical markers of bone remodeling is represented by osteocalcin, PINP, CTX, and tartrate-resistant acid phosphatase isoenzyme 5b, was investigated. The best markers, in terms of diagnosis of osteoadhesive and osteolytic metastases, proved to be the bone formation markers PINP, especially osteocalcin. The results also demonstrated the usefulness of the markers in monitoring zolendronic acid therapy in both types of metastases.

Bone Markers in Paget’s Disease

Paget’s bone disease is a chronic skeletal pathology characterized by enlargement and deformation in one or more bone districts. In Paget’s osteopathy, the two bone cell lines, osteoclasts and osteoblasts, do not interact in a balanced way. The altered cycle of bone resorption and neoformation produces a fragile bone, resulting in arthrosis, fractures, bone pain, and deformity. In the initial phases of the disease, an osteolytic type of phenomenon prevails, while in the second phase, the osteoblastic type is prevalent. In patients with extensive polyostotic disease, the formation and resorption markers can be very high. The biochemical feature is represented by the significant increase in alkaline phosphatase activity, up to 10 times and even more than the upper reference limit. The trend of the other markers of bone remodeling reflects the underlying bone pathological process. PINP and alkaline phosphatase correlate with the formation process, while serum osteocalcin does not correlate with the formation rate. The increase in resorption markers reflects the osteoclastic nature of the pathology. In untreated Paget’s cases, αCTX, derived from newly formed bone, increased much more than βCTX (about 16-fold), a marker that, in contrast, reflects resorption of bone of normal composition. In one study, the response of biochemical markers to ibandronate therapy was investigated. Markers were measured on samples taken at baseline and after 6 months of therapy. Total alkaline phosphatase, bone phosphatase, and PINP were the most effective markers of formation in demonstrating the effect of bisphosphonate, while markers of resorption were less sensitive. The study concluded, however, that no marker could be shown to be superior to total alkaline phosphatase, which is already widely used in clinical practice.

Bone Markers in Multiple Myeloma

Skeletal involvement in multiple myeloma is characterized by extensive osteolytic lesions predominantly affecting the flat bones of the skull, vertebrae, pelvis, and long bones, including humerus and femur and is frequently associated with fractures and spinal cord compression. The development of lytic lesions is due in part to the interaction of myelomatous plasma cells with the bone matrix and, in particular, with stromal cells, which are stimulated to produce osteo clastogenic factors; in addition, myelomatous cells can directly activate osteoclasts, causing their differentiation through the release of various osteoclastogenic factors in the bone marrow environment. The progression of the osteolytic process is associated with an essential inhibition of the process of bone formation, a consequence of decoupling the two phases at the basis of remodeling. Biochemical markers of bone remodeling have been used to monitor, in these patients, the treatment with bisphosphonates, and it has been hypothesized that they can be used in the diagnosis of bone lesions earlier than conventional imaging or to identify that sub group of patients who do not respond to therapy and therefore at higher risk of skeletal disease progression and death. These patients, identified by trends in biochemical bone markers, could benefit from alternative treatments.

In addition to the pathologic conditions discussed in the preceding paragraphs, many clinical studies have shown that biochemical markers of bone formation and resorption help test the skeleton’s response to various endogenous or exogenous stimuli. Changes in bone metabolism may be induced by the administration of drugs such as warfarin, heparin, androgens, and growth hormone or resulting from chronic alcohol abuse.

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مواضيع ذات صلة

Biochemical Markers of Bone Remodeling in Postmenopausal Osteoporosis

Free Radicals & Antioxidant Nutrients

Vitamin B12 is Found only in Foods of Animal Origin

Vitamin B6 is important in Amino Acid & Glycogen Metabolism & in Steroid Hormone Action

Niacin is not Strictly A Vitamin

Bone Tissue Biochemistry

Vitamin K is required for synthesis of blood-clotting proteins

Vitamin E does not have a precisely defined metabolic function

Vitamin D is really a hormone

Two groups of compounds have vitamin A activity

Protein & Amino acid requirements

Energy balance: over & undernutrition