Pathomechanism of Glucocorticoid-induced Osteoporosis
The first reports about steroid effects on bone tissue come from 1932 and were described by Harvey Cushing. Glucocorticosteroids, when administered in greater doses than physiological concentrations, interact indirectly and directly with important groups of bone cells involved in the process of bone turnover (osteoclasts, osteoblasts and osteocytes) stimulating the process of bone resorption and inhibiting bone formation. The reduced osteoblast differentiation may be related to lower concentrations of BMP-2 and expression of core binding factor α1 (Cbfa1). It has been demonstrated that high concentrations of glucocorticoids delay maturation and formation of osteogenic cell colonies, inhibit the synthesis of alkaline phosphatase, collagen and osteocalcin, and interfere with bone matrix mineralization. In addition, they lead to apoptosis of osteoblasts through disruption of the cytoskeleton. Apoptosis may be a result of decreased expression of the Bcl-2 gene and overexpression of the Bax gene. Glucocorticoids stimulate the synthesis of collagenase III, which is an enzyme involved in bone matrix degradation. Steroid treatment inhibits the synthesis of IGF and the expression of the IGF-2 receptor. These immunosuppressive drugs also affect the synthesis of the majority of IGF binding proteins, which further modulates the activity of anabolic growth factors. As a result of these changes, in every bone remodeling cycle, approximately 30% less bone tissue is produced than in normal conditions.[6–8] It has been demonstrated that the inhibition of skeletal growth by glucocorticoids may be related to the Wnt signaling pathway modulation. The Wnt signaling pathway plays a role in gaining peak bone mass, and in differentiation and function of osteoblasts. Immunosuppressive doses of glucocorticoids act directly on osteoclasts and delay their recruitment and maturation. On the other hand, high concentrations of glucocorticoids also inhibit osteoblasts and the synthesis of osteoprotegerin, while the production of RANKL is stimulated, which, in turn, increases the activity, proliferation and maturation of osteoclasts. The acceleration of bone resorption in the course of steroid treatment can also result from developing secondary hyperparathyroidism and the reduced synthesis of estrogen, testosterone and adrenal androgens.[6,11,12] Glucocorticoids also directly stimulate the secretion of parathormone. The sensitivity of osteoblasts and renal tubular cells to parathyroid hormone is increased during steroid therapy. Initially, this can lead to improved calcium balance (increased formation of active vitamin D metabolites, more efficient absorption of calcium in the intestine and its reabsorption in the kidneys) but, as a result of prolonged exposure to high concentrations of parathyroid hormone in bone tissue, its resorption is increased. Serum levels of 25-hydroxyvitamin D3 and calcitriol are diminished; however, they can also be elevated if resistance to vitamin D occurs. The serum concentrations of vitamin D metabolites also depends on the degree of stimulation of parathyroid hormone production and calcium blood levels. In the first days of steroid therapy, levels of serum calcitonin are elevated, which inhibits the resorptive activity of osteoclasts but increases the negative calcium balance. However, prolonged steroid therapy inhibits the secretion of calcitonin by C thyroid cells.[13,14] Glucocorticoids in high doses interfere with active transmembrane calcium transport. They also inhibit the expression of genes, dependent on vitamin D3, that is, calbindin-membrane calcium-binding protein and the receptor for vitamin D. In the majority of patients undergoing chronic steroid therapy, calcium absorption in the gastrointestinal tract is significantly decreased, while calciuria is increased, which causes a negative calcium balance. This, in turn, leads to hyperstimulation of the parathyroid glands and secondary hyperparathyroidism.[13,14] As a result of negative calcium balance and inhibited osteoblast activity, bone tissue deminaralization foci occur. Therefore, osteomalacia accompanies glucocorticoid-induced osteoporosis. In addition, patients treated with glucocorticoids may demonstrate avascular bone necrosis, which develops mostly in the femoral and humerus head and in the distal femur. This complication occurs as a result of disturbed blood circulation and poor nutrition of bone tissue. The VEGF that is secreted by osteoblasts stimulates vascularization of newly-formed bone. It has been demonstrated that glucocorticoids inhibit the production of the VEGF by osteoblasts, leading to vascular dysfunction and necrosis of newly-formed bone. The foci of aseptic bone necrosis are areas of reduced mechanical resistance, and thus susceptible to fractures. The catabolic effects of steroids also apply to muscular tissue. As a result of reduced muscle mass and strength, the weakened strain is transmitted to the bone during movement and a weaker piezoelectric effect occurs. In addition, an abnormal posture, together with the central obesity, increases the risk of vertebral fractures. Muscle weakness of the lower limbs can lead to falls, increasing the risk of fractures in all locations.
Bone mass loss observed over the course of steroid therapy begins quickly during the first few months (there can be 10% loss of bone mineral density [BMD] per year), then slows down after the first year of treatment to finally stabilize at the annual rate of 2–5%.[15,16] Reconstructed bone tissue differs from that observed in physiological conditions. It is characterized by impaired mineralization, defective protein structure and impaired microarchitecture, and is thus very susceptible to fractures, which heal slowly, often with excessive periosteal reactions.[12,17]
Aging Health. 2012;8(5):471-477. © 2012 Future Medicine Ltd.