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Terapêutica biológica com antiTNF-α na doença de Crohn : efeito sobre o metabolismo ósseo
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A doença de Crohn (DC) tem sido associada a diminuição da densidade mineral óssea (DMO) e aumento do risco de fractura, com 22 a 55% dos doentes a apresentarem osteopenia e 3 a 6% osteoporose. O TNF-α, activador da osteoclatogénese, está aumentado na DC, colocando-se a hipótese desta citocina inflamatória representar uma via patológica comum à inflamação intestinal e às alterações ósseas na DC. O objectivo desta revisão é verificar se os antagonistas do TNF-α, eficazes na indução e manutenção da remissão da DC, têm um efeito positivo sobre o metabolismo ósseo. De facto, tem sido constatada uma melhoria significativa dos marcadores de formação óssea (b-ALP, OC, P1NP), com diminuição dos marcadores de reabsorção óssea (sNTx, bCL). A melhoria dos marcadores de formação óssea e da DMO por antagonistas do TNF-α parece ser independente da corticoterapia e da resposta terapêutica na DC de comportamento inflamatório, mas dependente da resposta terapêutica na DC fistulizante. A OPG, produzida pelos osteoblastos, está aumentada nos indivíduos com DC, reflectindo provavelmente um mecanismo contra-regulatório de protecção à perda acelerada de massa óssea. Após infliximab e adalimumab, os níveis de OPG diminuíram paralelamente ao aumento da formação óssea e da DMO. Estudos in vitro mostraram um efeito directo do adalimumab nos osteoblastos, com estímulo à síntese de b-ALP, marcador de diferenciação precoce dos osteoblastos. Isto sugere que a terapêutica com antagonistas do TNF-α tem um efeito directo nos osteoblastos humanos in vitro e que o aumento dos marcadores de formação óssea identificados in vivo são provavelmente o reflexo deste efeito benéfico. Para concluir, apesar da evidência disponível na literatura apontar para um efeito benéfico dos antiTNF-α na remodelagem óssea e na DMO, há pouca evidência disponível que sustente a redução do risco de fractura com estes agentes, sendo necessários estudos adicionais.
Crohn’s disease (CD) has been associated with a reduced bone mineral density (BMD) and a higher risk of bone fracture with 22 to 55% of patients presenting with ostepenia and 3 to 6% presenting with osteoporosis. TNF-α, an osteoclastogenesis activator, shows increased levels in CD, leading to the belief that it may represent a common pathway between intestinal inflammation and bone disease in CD. The goal of this review is to establish whether TNF-α antagonists, which are effective in inducing and maintaining remission in active CD, are effective in improving markers of bone formation. There was a significant improvement in markers of bone formation (b-ALP, OC, P1NP) and a decrease in bone reabsorption markers (sNTx, bCL). The improvement of bone formation markers and BMD after the use of TNF-α antagonists seems to be independent of corticoid use and of luminal CD response, but dependent on fistulising CD response. OPG, produced by osteoblasts, is increased in patients with CD, probably reflecting a contra-regulatory mechanism in response to accelerated bone loss. After infliximab and adalimumab therapy, OPG levels decreased and there was a simultaneous increase in bone formation and BMD. In vitro studies showed a direct effect of adalimumab on osteoblasts, which started secreting higher levels of b-ALP, a marker of early osteoblastic differentiation, indicating an improvement in their function. This suggests that treatment with TNF-α antagonists has a direct effect on human osteoblasts in vitro and that the rise in bone formation markers detected in vivo is a reflection of this beneficial effect. In conclusion, despite the available evidence pointing towards a beneficial effect of TNF-α antagonists on bone remodelling and BMD, there is little evidence available to support fracture risk reduction and additional studies are needed.
Crohn’s disease (CD) has been associated with a reduced bone mineral density (BMD) and a higher risk of bone fracture with 22 to 55% of patients presenting with ostepenia and 3 to 6% presenting with osteoporosis. TNF-α, an osteoclastogenesis activator, shows increased levels in CD, leading to the belief that it may represent a common pathway between intestinal inflammation and bone disease in CD. The goal of this review is to establish whether TNF-α antagonists, which are effective in inducing and maintaining remission in active CD, are effective in improving markers of bone formation. There was a significant improvement in markers of bone formation (b-ALP, OC, P1NP) and a decrease in bone reabsorption markers (sNTx, bCL). The improvement of bone formation markers and BMD after the use of TNF-α antagonists seems to be independent of corticoid use and of luminal CD response, but dependent on fistulising CD response. OPG, produced by osteoblasts, is increased in patients with CD, probably reflecting a contra-regulatory mechanism in response to accelerated bone loss. After infliximab and adalimumab therapy, OPG levels decreased and there was a simultaneous increase in bone formation and BMD. In vitro studies showed a direct effect of adalimumab on osteoblasts, which started secreting higher levels of b-ALP, a marker of early osteoblastic differentiation, indicating an improvement in their function. This suggests that treatment with TNF-α antagonists has a direct effect on human osteoblasts in vitro and that the rise in bone formation markers detected in vivo is a reflection of this beneficial effect. In conclusion, despite the available evidence pointing towards a beneficial effect of TNF-α antagonists on bone remodelling and BMD, there is little evidence available to support fracture risk reduction and additional studies are needed.
Descrição
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2017
Palavras-chave
Doença de Crohn Antagonistas TNF-α Osteoblastos Marcadores de remodelagem óssea Densidade mineral óssea Terapêutica biológica