Disuse by bed rest, limb immobilization, or space flight causes rapid bone loss by arresting bone formation and accelerating bone resorption. Propranolol (a non-selective β-adrenergic antagonist) has been shown to improve bone properties by increasing bone formation and decreasing bone resorption in an ovariectomy-induced rat model. However, no studies have yet compared the osteoprotective properties of propranolol with well-accepted therapeutic interventions for the treatment and prevention of immobilization/disuse osteoporosis. To clarify this, we investigated the effects of propranolol compared with zoledronic acid and alfacalcidol in a new animal model of immobilization/disuse osteoporosis. Three-month-old male Wistar rats were divided into five groups with six animals in each group: (1) immobilized (IMM) control; (2) normal control; (3) IMM + zoledronic acid (50 μg/kg, intravenous single dose); (4) IMM + alfacalcidol (0.5 μg/kg, per oral daily); (5) IMM + propranolol (0.1 mg/kg, subcutaneously 5 days/week) for 10 weeks. In groups 1 and 3–5, the right hindlimb was immobilized. At the end of treatment, the femurs were removed and tested for bone porosity, bone mechanical properties, and cortical microarchitecture. Treatment with propranolol induced greater reductions in the bone porosity of the right femur and improved the mechanical properties of the femoral mid-shaft femur in comparison to the IMM control. Moreover, treatment with propranolol also improved the microarchitecture of cortical bones when compared with the IMM control, as indicated by scanning electron microscopy. The anti-osteoporotic property of propranolol was comparable with zoledronic acid and alfacalcidol. This study shows that the bone resorption induced by immobilization/disuse in rats can be suppressed by treatment with propranolol.
r e v b r a s r e u m a t o l . 2 0 1 5;5 5(3):240-250 w w w . r e u m a t o l o g i a . c o m . b r a b s t r a c tObjectives: Disuse by bed rest, limb immobilization or space flight causes rapid bone loss. We conducted the present study to investigate the therapeutic effects of zoledronic acid (ZOL), alone and in combination with alfacalcidol (ALF) in a rat model of disuse osteoporosis.Methods: In the present study, 3-month-old male Wistar rats had their right hind-limb immobilized (RHLI) for 10 weeks to induce osteopenia, then were divided into four groups: 1 -RHLI positive control; 2 -RHLI plus ZOL (50 g/kg, i.v. single dose); 3 -RHLI plus ALF (0.5 g/kg, oral gauge daily); 4 -RHLI plus ALF (0.5 g/kg, oral gauge daily) plus ZOL (50 g/kg, i.v. single dose) for another 10 weeks. One group of non-immobilized rats was used as negative control. At the end of the treatment, the femurs were removed and tested for bone porosity, bone mechanical properties, and bone dry and ash weight.Results: Combination therapy with ZOL plus ALF was more effective in decreasing bone porosity than each drug administered as monotherapy in RHLI rats. With respect to improvement in the mechanical strength of the femoral mid-shaft, the combination treatment of ZOL plus ALF was more effective than each drug administered as a monotherapy. Moreover, combination therapy using ZOL plus ALF was more effective in improving dry bone and ash weight, than single-drug therapy using ZOL or ALF in RHLI rats.Conclusions: These data suggest that combination therapy with ZOL plus ALF represents a potentially useful therapeutic option for the treatment of disuse osteoporosis. r e v b r a s r e u m a t o l . 2 0 1 5;5 5(3):240-250 241 Efeito combinado do ácido zoledrônico e do alfacalcidol no tratamento da osteoporose por desuso em ratos Palavras-chave: Osteoporose por desuso Estudo com ratos Ácido zoledrônico Alfacalcidol r e s u m o Objetivos: O desuso pelo repouso no leito, pela imobilização de membros ou por missões espaciais provoca a perda óssea rápida. Fez-se este estudo para investigar os efeitos terapêuticos do ácido zoledrônico (ZOL), isoladamente e em combinação ao alfacalcidol (ALF), em um modelo de rato com osteoporose por desuso.Métodos: Ratos Wistar machos de três meses foram submetidos à imobilização da pata traseira direita (IPTD) por 10 semanas para induzir a osteopenia; em seguida, foram divididos em quatro grupos: 1 -IPTD para controle positivo; 2 -IPTD mais ZOL (50 g/kg, dose única intravenosa); 3 -IPTD mais ALF (0,5 g/kg, via oral diariamente); 4 -IPTD mais ALF (0,5 g/kg, via oral diariamente) mais ZOL (50 g/kg, dose única intravenosa) por outras 10 semanas. Um grupo de ratos não imobilizados foi usado como controle negativo. No fim do tratamento, os fêmures foram removidos e testaram-se a porosidade do osso e suas propriedades mecânicas, além do peso seco e das cinzas do osso.Resultados: A terapia combinada com ZOL mais ALF foi mais eficaz em reduzir a porosidade do osso do que a monoterapia com um dos fármacos administrado isoladame...
These data suggest that combination therapy with ZOL plus ALF represents a potentially useful therapeutic option for the treatment of disuse osteoporosis.
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