Abstract
Vitamin D3 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 D3 on bone remodeling as potential limiting factors to broader use of vitamin D3 in the clinic. Vitamin D3 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 D3 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 D3 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 D3 to treat immune disorders and suggest the need for co-treatment with an antiresorptive agent to counteract hypercalcemia and deterioration of bone.
Highlights
The anti-proliferative, pro-differentiating and immunosuppressive effects of hormone 1,25dihydroxyvitamin D3 (Vit D3, calcitriol) are well defined[1]; in order to achieve maximal immunosuppressive activities, concentrations of vitamin D3 are required that may be associated with hypercalcemia
TPTx rats seems to be more sensitive to vitamin D3 and calcium treatment compared to intact animals with an average increase in serum calcium of 56% in TPTx compared to a 12% average increase in intact rats
Similar to results obtained in intact rats, administration of calcium lactate alone did not change any of the measured parameters of calcium metabolism
Summary
The anti-proliferative, pro-differentiating and immunosuppressive effects of hormone 1,25dihydroxyvitamin D3 (Vit D3, calcitriol) are well defined[1]; in order to achieve maximal immunosuppressive activities, concentrations of vitamin D3 are required that may be associated with hypercalcemia. Vitamin D3 has effects on skeletal bone remodeling and at high doses can increase bone resorption and release of calcium thereby contributing to systemic hypercalcemia and hypercalcuria. It is estimated that 99% of the total body calcium resides within the crystalline structure in bone while the remaining 1% is rapidly exchanged between bone and extra-cellular fluids. The skeleton includes both cortical bone that primarily provides mechanical support and protection of vital organs and cancellous bone that has both a metabolic and a mechanical role. Bone resorption is the process of calcium release from bone matrix and is carried out by osteoclasts, multinucleated cells derived from hematopoietic precursors in the bone marrow and other hematopoietic organs. M.D., Ph.D., Pfizer Inc, Comparative Medicine, Eastern Point Road 8274-1312, Groton, CT 06340
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