Action of Calciotropic Hormones on Bone Metabolism – Role of Vitamin D3 in Bone Remodeling Events

Abstract

Vitamin D 3 is known to have immunosuppressive effects that can be beneficial for treatment of immune disorders and transplant rejection, however therapeutic application is limited due to hypercalcemia and hypercalcuria. The goal of our studies was to explore both the acute and steady state effects of vitamin D 3 on bone remodeling as potential limiting factors to broader use of vitamin D 3 in the clinic. Vitamin D 3 was evaluated for its skeletal effects in both thyroparathyroidectomized (TPTx) and intact rat models. In TPTx rats, deprivation of thyroid and parathyroid hormones and calcitonin creates a low state of bone modeling and remodeling ideal for evaluation of changes imposed by drug intervention. The use of both models allowed for discrimination of individual (TPTx) versus combined (intact) effects of calciotropic hormones on bone and calcium metabolism. Our studies have confirmed the limitations of using vitamin D 3 for treatment/co-treatment of immune disease in humans due to the intrinsic hypercalcemic properties of the hormone, and also highlighted the potential of vitamin D 3 to negatively impact skeletal integrity due to excessive bone remodeling driven by bone resorption. Taken together our data emphasize the importance of including biomarkers of bone remodeling as an integral part of clinical and preclinical studies using vitamin D 3 to treat immune disorders and suggest the need for co-treatment with an antiresorptive agent to counteract hypercalcemia and deterioration of bone.

Oral Administration of Soluble Guanylate Cyclase Agonists to Rats Results in Osteoclastic Bone Resorption and Remodeling with New Bone Formation in the Appendicular and Axial Skeleton

“…In the TPTx rat model, the deprivation of thyroid and parathyroid hormones and calcitonin creates a low state of bone modeling and remodeling. This model is ideal for in vivo screening of bone effects of novel therapies for increased bone formation and/or bone resorption because of the sensitivity, fast readout (as early as 24-48 hr), and small amount of compound needed to effect bone changes in this model (Trechsel, Stutzer, and Fleish 1987;Millest et al 1995;Andresen et al 2006). The model also allows for correlation of pharmacokinetic, pharmacodynamic, and safety endpoints.…”

“…Multiple factors including PTH and CT control bone remodeling, regulation of bone mass, and differentiation and function of osteoclasts and osteoblasts (Andresen et al 2006;Harada and Rodan 2003;Boyle, Simonet, and Lacey 2003). The goal of the TPTx study was to assess the effect of sGCa compounds on bone remodeling in the absence of parathyroid and thyroid hormonal effects to help understand the pathogenesis of the bone changes.…”

“…43, No. 3, 2015 SOLUBLE GUANYLATE CYCLASE AGONISTSTPTx rat study: The TPTx rat model used in this study was described previously by Andresen et al (2006). Study animals were assigned to the following 5 groups: vehicle control (7 control rats dosed with vehicle alone), TPTx vehicle (8 TPTx rats dosed with vehicle alone), TPTx HI-sGCa-D (8TPTx rats dosed with HI-sGCa-D at 500 mg/kg/day), TPTx HD-sGCa-C (8 TPTx rats dosed with HD-sGCa-C at 180 mg/kg/day), and TPTx HD-sGCa-B (8 TPTx rats dosed with HD-sGCa-B at 50 mg/kg/day; Table 1).…”

Influência da vitamina D na atividade osteoclástica em um modelo de cultura de órgãos ósseos

“…Esses achados demonstram que a administração, in vitro, de VitD promove a diferenciação dos osteoclastos a partir de células precursoras e, em altas doses, eleva a reabsorção óssea mediada por osteoclastos. Este último efeito é dependente do aumento da produção de RANKL pelos osteoblastos, fator-chave necessário para a diferenciação e a ativação dos osteoclastos (4) . Além disso, foi demonstrado também que a elevação da atividade osteoclástica in vitro é dose-dependente, ou seja, quanto maior a dose de VitD, maior será o nível de cálcio no meio, e as lacunas de reabsorção serão mais amplas.…”

A 30 Year Old Man with Fever and Indolent Soft Tissue Masses

“…In skeletal tuberculosis, no radiological evidence of pulmonary tuberculosis can be identified in about 50% of cases (Andresen et al, 2006). Therefore, the presence of osteolytic lesions without the evidence of pulmonary involvement does not exclude the diagnosis of osteoarticular tuberculosis.…”