Osteogenic cells are derived from sinusoid vessel walls. When conditions are favourable—a supply of energy, correct concentrations of oxygen and carbon dioxide, the hormone balance on the anabolic and anticatabolic side, the osteogenic factor present—osteogenic precursor cells differentiate to osteoblasts and osteocytes. When the balance is on the catabolic side precursor cells coalesce to form osteoclasts. When catabolic conditions persist osteoclastic activity continues until all the precursor cells are used up. Phagocytic cells can also enlarge and coalesce to form osteoclasts. Parathyroid hormone is needed for coalescence. The formation of these osteoclasts is stimulated by an increased marrow pressure or exposure of dead bone tissue. Corticosteroids prevent initial enlargement of cells. Excess parathyroid hormone stimulates the production and activity of extra phagocytic osteoclasts. The hormone balance may approach the catabolic during later stages of pregnancy and after childbirth, after the menopause, during and after the general hormonal decline in old age, when corticosteroids are given for therapeutic purposes, or as a result of the action of contraceptive agents. The effects of stress (caused by the unpleasant emotions, fear, apprehension frustration, jealousy, anxiety, etc, as well as serious illness or trauma) include a rise in blood cortisol levels. A combination of factors may result in corticosteroid levels exceeding the threshold for thrombus formation. This threshold depends on the other chemicals affecting the pituitary-adrenal system that are present. It is abnormally low for contraceptive agents. These mechanisms of bone formation and removal account for the main types of osteoporosis. A lowered blood flow arises from a decrease or cessation of muscle activity, the effect of catabolic compounds on muscle fibres, or thrombi lodged in vessels supplying muscles and bone. A build-up of pressure stimulates the formation of phagocytic osteoclasts, while until the flow is increased again there is insufficient stimulus for new bone formation. When catabolic conditions prevail, osteogenic precursor cells coalesce to osteoclasts, and when anticatabolic conditions return, more precursor cells are formed that may proceed to osteoblast and bone formation before the next catabolic episode. With an unfortunate timing of alternations this results in considerable bone loss. In pregnancy the loss is temporary, but after the menopause and in old age there may be a permanent decrease of bone tissue. This type of osteoporosis may also be caused by contraceptive agents. It leads to backache, the increased number of fractured wrists in older women, and intracapsular hip fractures. Small thrombi cause irreversible osteoporosis. Blood flow through bone is decreased, and vessels in cortical bone blocked. Bone served by these vessels dies, and with prolonged catabolic conditions a considerable amount of dead bone tissue may be present. After phagocytic removal it is not usually replaced. This type of ‘senile’ osteoporosis, which can cause extracapsular hip fractures, is common in old age. It is also the main mechanism of osetoporosis caused by contraceptive agents. There are racial variations. Negroes are the least susceptible and the Japanese the most susceptible. In elderly people senile osteoporosis is part of a more generalized condition. The liver and brain are also affected—there are considerable individual variations, but symptoms often include depression and sometimes pyschotic episodes. Like diabetes and thyroid deficiency, an anticatabolic deficiency requires continuous therapy. The anticatabolic agent chosen should be one that reverses corticosteroid effects on bone, liver and brain efficiently, and at the same time has a high Cortisol threshold for thrombus formation.
Activation of 4-1BB signaling in bone marrow stromal cells triggers bone loss via the p-38 MAPK-DKK1 axis in aged mice