The pathogenesis of osteoporosis involves the interplay of many factors that cause bone loss and skeletal microarchitecture
deterioration. In patients at risk of falling this damage significantly increases fragility fracture risk. The many factors that contribute to proper bone growth and
maintenance are described.Adult bone is remodeled by bone multicellular units (BMUs). In this process, hematopoietic cells differentiate into osteoclasts. These osteoclasts begin the resorptive phase of bone remodeling by removing old bone. This phase is followed by a short reversal period wherein resorption ceases but bone formation does not start. Osteoblasts lay down new bone in the formation phase. These cells undergo apoptosis or become incorporated into the new bone as osteocytes. If the activity of BMUs increases the bone will be compromised because the resorption phase is much quicker than the formation phase. Inadequate formation is a hallmark of osteoporosis.Proper growth and maintenance of bone is dependent on estrogen. Bone remodeling increases substantially at the menopause and the rapid increase in bone loss in the few years after menopause is attributed to both an increase in resorption and a decrease in formation. Estrogen remains important for a healthy skeleton in elderly women. In these women, bone is more sensitive to estrogen than are tissues such as the breast or uterus. Proper development of bone in males is also dependent on estrogen.Estrogen acts on cells of the BMU as well as marrow cells to stimulate bone growth. This interaction may involve suppression of the inflammatory response. There is some evidence that estrogen also promotes bone survival by preventing oxidative stress. Estrogen exerts the majority of its cellular effects through activation of the estrogen receptor alpha. Gene
polymorphisms in this receptor reduce fragility and increase bone mineral density. The estrogen receptor-related receptor does not bind estrogen but may also have a role in bone maintenance. It could interact with DNA directly or modulate the effects of the estrogen receptor.Estrogen’s effects on bone are influenced by sex hormone-binding protein and aromatase. Sex hormone-binding protein influences the bioavailability and possibly the uptake of estrogen into bone cells. An important local source of estrogen is aromatase which is responsible for estrogen synthesis in postmenopausal women.Calcium and vitamin D contribute to bone maintenance and a deficiency in either or both causes secondary hyperparathyroidism. Supplementation improves bone strength and reverses the hyperparathyroidism. The effects of vitamin D receptor polymorphisms on bone formation and fragility are controversial, probably because the receptor function and expression are dependent on several factors. Increased parathyroid concentrations in the winter are associated with increased fracture risk, independent of an increase risk of falling.The tumor necrosis factor family of proteins is essential for proper communication between osteoclasts and osteoblasts and ultimately the proper control of bone resorption. Osteoclast precursor cells are differentiated and activated by activation of receptor activator of nuclear factor beta (RANK). Activation of RANK is dependent on its ligand, RANKL, which his produced by osteoblasts. Osteoblasts also block osteoclast activity through secretion of osteoprotegerin. A study in postmenopausal women showed that a monoclonal antibody against RNKL reduced bone resorption. Surface expression of RANKL on bone marrow cells increases during early postmenopause that suggests a role for this signaling in estrogen deficiency-related bone loss. An osteoprotegerin gene polymorphism is associated with osteoporotic fractures. In pathophysiological states T cells produce RANKL.Data from mice suggest that membrane adapter DNAX-activatingprotein 12 and the Fc receptor common chain may also participate in osteoclast-osteoblast interactions. These same models suggest that osteoblast differentiation is dependent on runt-related transcriptionfactor 2 or osterix, a downstream factor. Osteoblast activity is also modulated by WNT signaling. In humans over-expression or gene polymorphisms in a signaling molecule of this pathway, LDL receptor–related protein 5, are associated with increased bone growth and strength. Downregulation or mutations cause osteoportic syndrome and premature osteoporosis respectively.Bone growth is impaired by the age-related reductions in osteoblast replication and differentiation and reductions in growth factors. Gene polymorphisms thatprevent growth factor synthesis result in low bone mineral density and increased fracture risk. In addition, bones respond to interleukins, prostaglandins and other cytokines. The major type of prostaglandin in bone stimulates both bone resorption and formation. Many other factors are involved in bone maintenance. Nitric oxide-releasing drugs increase bone mineral density possibly by inhibiting resorption. Leukotrienes stimulate resorption and inhibit formation. Polymorphisms in the lipoxygenase gene in postmenopausal women influence peak bone density. Defects in thecollagen 1 chain and increased levels of homocysteine have an influence on fracture risk that is independent of bone mineral density. Leptin deficiency is associated with high bone mineral density and mass. Epidemiologic data suggest that leptin improves bone strength through inhibition of the adrenergic system. Finally, inhibition of the cannabinoid type 1 receptor protects mice from overectomized-induced bone loss.Osteoporosis and fracture risk can be predicted by regular bone mineral density determinations, measurement of bone metabolism markers, and an assessment of risk factors. If intervention is necessary, especially in at-risk patients, exercise and supplementation are recommended. The use of bisphosphonates that inhibit osteoclast activity can preserve bone as does low dose parathyroid hormone fragment. Despite our current knowledge there are many challenges to confront with respect to our understanding of bone maintenance, and the diagnosis and treatment of osteoporosis.