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Non-classical actions of the vitamin D endocrine system
ABSTRACTS / Bone 40 (2007) S8–S21
results of prevention and treatment measures are still lacking. Most clinicians would agree that the basis of treatment in young patients is to correct the daily intake of calcium and to give supplements of vitamin D. In many cases, this seems to help the growing skeleton to restore its equilibrium. Regular physical activity is an essential stimulus for bone remodeling, and is particularly important in growing subjects: specific programs may be required for patients with diseases affecting mobility. All interventions must be tailored on the patient’s condition and needs, considering the patient’s quality of life as the primary goal. Long-term corticosteroid use should be prudent and wise: the minimum effective dose and the shorter duration are essential. In severe cases, particularly in the presence of fractures, bisphosphonates can be effective. In some cases, such as idiopathic juvenile osteoporosis, spontaneous resolution is frequent, and aggressive drug use is controversial. No consensus statements or guidelines for the diagnosis and treatment of osteoporosis in the young are available. Further research, specifically focused on the young is needed. International collaboration and multicenter studies should be encouraged to put together large samples, particularly in relatively rare diseases. doi:10.1016/j.bone.2007.04.136
Steroid-induced osteoporosis in children N. Bishop University of Sheffield, Sheffield, United Kingdom In children, as in adults, steroids are given mainly to children with underlying inflammatory disorders. These disorders may themselves predispose to reduced bone mass with increased risk of fracture, both as a result of the effects of inflammatory mediators on bone metabolism, and because of associated factors such as reduced mobility, altered nutrition and disordered puberty. The use of oral steroids is associated with an increase in the risk of fractures in the treated childhood population generally, but there are specific instances where steroids may not have these effects. The use of inhaled steroids is also associated with increased fracture risk, but not greater than that associated with the use of inhaled beta agonists. This review will summarise the current state of knowledge relating to steroid action on skeletal homeostasis at both a biological and functional level. doi:10.1016/j.bone.2007.04.137
Non-classical actions of the vitamin D endocrine system R. Bouillon Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium Ligand activated VDR regulates about 3% the mouse genome. Its classical function is to regulate calcium and
S9
bone homeostasis. 1,25-(OH)2D is essential for transepithelial calcium transport in the intestine (by an epithelial calcium channel, TRPV6) and in the kidney (TRPV5). Normal osteoclastogenesis and bone resorption as well as bone mineralisation are possible in the absence of VDR when VDR KO men or animals receive a high calcium diet. VDR.1α,25-(OH)2D3 also have major effects on many other non-classical target tissues as demonstrated in VDR KO mice and man (keratinocytes and hair follicles: alopecia; high renin hypertension; muscle cell maturation defect; differentiation of dendritic/immune and mast cells). Finally all VDR positive cells react to VDR.1,25-(OH)2D by inhibition of proliferation regulated by a coherent action on cell cycle genes. Vitamin D deficiency rickets was rapidly eradicated by widespread vitamin D supplementation. Vitamin D deficiency is still widespread in the elderly population and contributes to osteoporotic fractures. Animal studies support human epidemiological data of a possible link between poor vitamin D status and autoimmune diseases (type 1 diabetes, MS, IBD) and major cancers (breast, prostate, colon cancer). The optimal vitamin D status is not well defined but levels b10 ng/ml are certainly deficient, 25OHD above 20 ng/ml are desirable for optimal bone health. Whether higher levels would be beneficial for general health will require large scale intervention studies. Out of more than 3000 synthetic analogues of vitamin D some show selective receptor modulating activity (antiproliferative and anticancer effects or immune modulator effects, with minimal calcemic activity). The mode of action of superagonistic and/or selective activation of VDR is not completely understood but involves extra- and intracellular pharmacokinetics, VDR stability and above all selective recruitment of coactivators. The clinical use of vitamin D analogues is presently limited but likely to expand rapidly. doi:10.1016/j.bone.2007.04.138
Fractures in childhood chronic disease: Lessons from population-based cohorts Jon M. Burnham Jr., MD MSCE Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA It is crucial to understand the nature of fracture risk associated with chronic childhood diseases in order to target high-risk populations for trials of bone-protective therapies. The study of fractures in childhood illnesses relies on the availability of a valid source of fracture data and careful attention to the variation in fracture risk that occurs according to sex, age, socioeconomic factors, and geographic region. Populationbased studies of illness-related fractures both maximize the available sample size of subjects with uncommon diseases, and simultaneously account for the dramatic variation in fracture risk related to demographic factors.
results of prevention and treatment measures are still lacking. Most clinicians would agree that the basis of treatment in young patients is to correct the daily intake of calcium and to give supplements of vitamin D. In many cases, this seems to help the growing skeleton to restore its equilibrium. Regular physical activity is an essential stimulus for bone remodeling, and is particularly important in growing subjects: specific programs may be required for patients with diseases affecting mobility. All interventions must be tailored on the patient’s condition and needs, considering the patient’s quality of life as the primary goal. Long-term corticosteroid use should be prudent and wise: the minimum effective dose and the shorter duration are essential. In severe cases, particularly in the presence of fractures, bisphosphonates can be effective. In some cases, such as idiopathic juvenile osteoporosis, spontaneous resolution is frequent, and aggressive drug use is controversial. No consensus statements or guidelines for the diagnosis and treatment of osteoporosis in the young are available. Further research, specifically focused on the young is needed. International collaboration and multicenter studies should be encouraged to put together large samples, particularly in relatively rare diseases. doi:10.1016/j.bone.2007.04.136
Steroid-induced osteoporosis in children N. Bishop University of Sheffield, Sheffield, United Kingdom In children, as in adults, steroids are given mainly to children with underlying inflammatory disorders. These disorders may themselves predispose to reduced bone mass with increased risk of fracture, both as a result of the effects of inflammatory mediators on bone metabolism, and because of associated factors such as reduced mobility, altered nutrition and disordered puberty. The use of oral steroids is associated with an increase in the risk of fractures in the treated childhood population generally, but there are specific instances where steroids may not have these effects. The use of inhaled steroids is also associated with increased fracture risk, but not greater than that associated with the use of inhaled beta agonists. This review will summarise the current state of knowledge relating to steroid action on skeletal homeostasis at both a biological and functional level. doi:10.1016/j.bone.2007.04.137
Non-classical actions of the vitamin D endocrine system R. Bouillon Laboratory for Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium Ligand activated VDR regulates about 3% the mouse genome. Its classical function is to regulate calcium and
S9
bone homeostasis. 1,25-(OH)2D is essential for transepithelial calcium transport in the intestine (by an epithelial calcium channel, TRPV6) and in the kidney (TRPV5). Normal osteoclastogenesis and bone resorption as well as bone mineralisation are possible in the absence of VDR when VDR KO men or animals receive a high calcium diet. VDR.1α,25-(OH)2D3 also have major effects on many other non-classical target tissues as demonstrated in VDR KO mice and man (keratinocytes and hair follicles: alopecia; high renin hypertension; muscle cell maturation defect; differentiation of dendritic/immune and mast cells). Finally all VDR positive cells react to VDR.1,25-(OH)2D by inhibition of proliferation regulated by a coherent action on cell cycle genes. Vitamin D deficiency rickets was rapidly eradicated by widespread vitamin D supplementation. Vitamin D deficiency is still widespread in the elderly population and contributes to osteoporotic fractures. Animal studies support human epidemiological data of a possible link between poor vitamin D status and autoimmune diseases (type 1 diabetes, MS, IBD) and major cancers (breast, prostate, colon cancer). The optimal vitamin D status is not well defined but levels b10 ng/ml are certainly deficient, 25OHD above 20 ng/ml are desirable for optimal bone health. Whether higher levels would be beneficial for general health will require large scale intervention studies. Out of more than 3000 synthetic analogues of vitamin D some show selective receptor modulating activity (antiproliferative and anticancer effects or immune modulator effects, with minimal calcemic activity). The mode of action of superagonistic and/or selective activation of VDR is not completely understood but involves extra- and intracellular pharmacokinetics, VDR stability and above all selective recruitment of coactivators. The clinical use of vitamin D analogues is presently limited but likely to expand rapidly. doi:10.1016/j.bone.2007.04.138
Fractures in childhood chronic disease: Lessons from population-based cohorts Jon M. Burnham Jr., MD MSCE Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA It is crucial to understand the nature of fracture risk associated with chronic childhood diseases in order to target high-risk populations for trials of bone-protective therapies. The study of fractures in childhood illnesses relies on the availability of a valid source of fracture data and careful attention to the variation in fracture risk that occurs according to sex, age, socioeconomic factors, and geographic region. Populationbased studies of illness-related fractures both maximize the available sample size of subjects with uncommon diseases, and simultaneously account for the dramatic variation in fracture risk related to demographic factors.