Cytokines, Estrogens, and Osteoporosis
It is well established that a decline in circulating levels of 17p-estradiol is a major contributing factor in the development of osteoporosis in postmenopausal women. Until recently, specific mechanisms by which estradiol might influence bone metabolism were largely unknown. Recent studies suggest that estradiol influences the production and/or modulates the activity of several cytokines involved in regulating bone remodeling.
Normal bone remodeling involves a regulated balance between the processes of bone formation and bone resorption. Osteoclast-mediated bone resorption involves two processes: the activation of mature, functional osteo-clasts and the recruitment and differentiation of osteoclast precursors. In addition to PTH, the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF) are involved in the activation of mature osteoclasts to cause bone resorption. For maturation of osteoclast precursors, the cytokines macrophage-colony stimulating factor (M-CSF) and inter-leukin-6 (IL-6) appear to be involved. Estradiol plays a role in bone remodeling by suppressing the formation of these cytokines. As a result of its ability to interact with bone cells and their precursors to regulate local paracrine signaling mechanisms, estradiol produces anti-osteoporotic effects in bone.
When estradiol is present, as in a premenopausal state, it acts as a governor to reduce cytokine production and limit osteoclast activity. When estradiol levels are reduced, the governor is lost, secretion of these cytokines increases, and osteoclast formation and activity increase, resulting in increased bone resorption.
Current research efforts attempt to define more clearly the specific source(s) and roles of the cytokines involved. The elucidation of these factors might allow the development of diagnostic tools, such as the assessment of cytokine levels, to monitor osteoporosis. In addition, such knowledge should facilitate the development of drugs that might interfere with cytokine action and potentially be of value in the treatment of osteoporosis.
The primary cause of osteomalacia and rickets is a deficiency in vitamin D activity. Vitamin D may be deficient in the diet; it may not be adequately absorbed by the small intestine,- it may not be converted into its hormonally active form,- or target tissues may not adequately respond to the active hormone (Table 36.3). Dietary deficiency is generally not a problem in the United States, where vitamin D is added to many foods,- however it is a major health problem in other parts of the world. Because the liver and kidneys are involved in converting vitamin D3 into its hormonally active form, primary disease of either of these organs may result in vitamin D deficiency. Impaired vitamin D actions are somewhat rare but can be produced by certain drugs. In particular, some anticonvulsants used in the treatment of epilepsy may produce osteomalacia or rickets with prolonged treatment.
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