Pathogenesis of osteoporosis in children

Bone tissue is a dynamic system in which the processes of resorption of the old bone and the formation of a new bone, which constitutes a cycle of bone tissue remodeling, occur simultaneously throughout life.

In childhood, bone is subjected to more intensive remodeling, especially during periods of vigorous growth. The most intensive processes of growth and mineralization of bone occur in the periods of early age, prepubertal. In the pubertal and post-pubertal periods, there is also a significant growth of the skeleton, the bone mass continues to increase.

Intensive growth with simultaneous histological maturation creates a special position for the child's bone, in which she is very sensitive to any adverse effects (eating disorders, motor conditions, muscle tone, medications, etc.).

The constantly occurring processes of resorption and the formation of new bone tissue are regulated by various factors.

They include:

• calcium-regulating hormones (parathyroid hormone, calcitonin, active metabolite of vitamin D ₃ -calcitrol);
• other hormones (glucocorticosteroids, adrenal androgen, sex hormones, thyroxine, somatotropic hormone, insulin);
• growth factors (insulin-like growth factors - IRF-1, IRF-2, growth factor of fibroblasts, transforming growth factor beta, growth factor of platelet origin, epidermal growth factor);
• local factors produced by bone cells (interleukins, prostaglandins, osteoclastactivating factor).

Significant progress in understanding the mechanisms of osteoporosis development was achieved thanks to the discovery of new members of the tumor necrosis factor-a (osteoprotegerin) ligand family, new receptors (nuclear transcription factor activation receptors). They play a key role in the formation, differentiation and activity of bone cells and can be molecular mediators of other mediators of bone tissue remodeling.

Violation of the production of the above factors, their interaction, sensitivity to the corresponding receptors leads to the development of pathological processes in the bone tissue, the most frequent of which is osteoporosis with subsequent fractures.

Reduction of bone mass in osteoporosis occurs due to imbalance of bone remodeling processes.

In this case, 2 main pathological characteristics of bone metabolism are distinguished:

• osteoporosis with a high intensity of bone metabolism, in which enhanced resorption is not compensated by a normal or increased process of bone formation;
• osteoporosis with low bone turnover, when the resorption process is at a normal or slightly elevated level, but there is a decrease in the intensity of the process of bone formation.

Both types of osteoporosis can develop as different situations in the same patient.

The most severe variant of secondary osteoporosis in children develops in the treatment of glucocorticosteroids. At the same time, the duration of therapy with glucocorticosteroids, the dose, the age of the child, the severity of the underlying disease, the presence of additional risk factors for the development of osteoporosis are of great importance. It is suggested that children do not have a "safe" dose of glucocorticosteroids for impact on bone tissue.

Glucocorticoid osteoporosis is caused by the biological effects of the natural hormones of the adrenal cortex - glucocorticosteroids, which are based on the molecular interactions of glucocorticosteroids with the corresponding receptors on bone tissue cells.

The main feature of glucocorticosteroids is a negative effect on both processes, which are the basis of bone tissue remodeling. They weaken the formation of bone and accelerate bone resorption. The pathogenesis of steroid osteoporosis is multicomponent.

On the one hand, glucocorticosteroids have a direct inhibitory effect on the function of osteoblasts (bone cells responsible for osteogenesis):

• slow the maturation of osteoblast precursor cells;
• inhibit the osteoblast-stimulating effect of prostaglandins and growth factors;
• increase the inhibitory effect of parathyroid hormone on mature osteoblasts;
• promote apoptosis of osteoblasts, suppress the synthesis of bone morphogenic protein (an important factor of osteoblastogenesis).

All this leads to a slowing down of bone formation.

On the other hand, glucocorticosteroids have an indirect stimulating effect on bone resorption:

• slow the absorption of calcium in the intestines, affecting the cells of the mucosa;
• reduce the reabsorption of calcium in the kidneys;
• lead to a negative balance of calcium in the body and transient hypocalcemia;
• this, in turn, stimulates the secretion of parathyroid hormone and enhances the resorption of bone tissue.

The loss of calcium is due mainly to the suppression of vitamin D synthesis and the expression of its cellular receptors.

The double effect of glucocorticosteroids on the bone causes the rapid development of osteoporosis, and as a consequence, the increased risk of fractures during the first 3-6 months of treatment with glucocorticosteroids. The greatest loss of bone tissue (from 3-27 to 30-50%, according to different authors) in adults and children also develops in the first year of use of glucocorticosteroids. Although the subsequent decrease in BMD is less pronounced, the negative dynamics persists throughout the period of glucocorticosteroids. In children, this effect is exacerbated by age-related bone tissue, as glucocorticosteroids act on the growing bone. For glucocorticoid damage to the skeleton in childhood is typical delay in linear growth.

With the development of osteoporosis, both cortical and trabecular bone tissue suffer. The backbone is almost 90% composed of trabecular tissue, in the thigh bone its content does not exceed 20%. The structural differences between the cortical and trabecular bone are the degree of their mineralization. Cortical bone is calcified on average by 85%, trabecular bone by 17%.

Structural features of the bone determine its functional differences. Cortical bone performs mechanical and protective functions, trabecular - metabolic (homeostatic, maintaining a constant concentration of calcium and phosphorus remodeling).

Remodeling processes are more active in the trabecular bone, so the signs of osteoporosis, especially when using glucocorticosteroid drugs, appear earlier in the vertebrae, later in the neck of the femur. Thinning of trabeculae and disturbance of their structure is regarded as the main defect in osteoporosis, as in the conditions of disturbed remodeling sufficient formation of new qualitative bone tissue is impossible, bone loss occurs.

Cortical bone is thinner due to resorptive cavities, which leads to porosity of bone tissue. Loss of bone mass, porosity, the appearance of micro-fractures - the basis for bone fractures directly in childhood and / or in the future period of life.

[1], [2], [3], [4], [5], [6], [7], [8],