Treatment with intermittent calcitriol and calcium reduces bone loss after renal transplantation

BACKGROUND: Bone loss occurs during the first 6 months after renal transplantation (RT), and corticosteroid therapy plays an important role. Although calcium plus vitamin D administration prevents corticosteroid-induced osteoporosis, its use in RT recipients is limited by the risk of hypercalcemia. METHODS: This double-blind, randomized, and controlled prospective intervention trial examined the effect of intermittent calcitriol (0.5 microg/48 h) during the first 3 months after RT, plus oral calcium supplementation (0.5 g/day) during 1 year with calcium supplementation alone. The primary outcome measure was the change in bone mineral density (BMD) at 3 and 12 months after RT; we also explored whether the effect of calcitriol on BMD was different among vitamin D receptor (VDR) genotypes (BsmI). Forty-five recipients were randomized to calcitriol therapy (CT) and 41 were randomized to placebo (PL). RESULTS: Both groups had a similar degree of pre-existing hyperparathyroidism (197 +/- 229 vs. 191 +/- 183 pg/mL), but a more pronounced decrease of parathyroid hormone (PTH) levels after RT was observed in CT patients (at 3 months: 61.4 +/- 42.2 vs. 85.7 +/- 53.1 pg/mL, P= 0.02; at 12 months: 67.3 +/- 33.7 vs. 82.6 +/- 37 pg/mL; P= 0.08). CT patients preserved their BMD at the total hip significantly better than those on PL (3 months: 0.04 +/- 3.3 vs. -1.93 +/- 3.2%, P= 0.01; 12 months: 0.32 +/- 4.8 vs. -2.17 +/- 4.4%, P= 0.03); significant differences were noted at the intertrochanter, trochanter, and Ward's triangle. Differences did not reach significance at the femoral neck. Two CT patients (4.4%) and 4 PL patients (9.8%) developed a hypercalcemic episode during the first 3 months after RT. The effect of CT on BMD at 3 months was more prominent in recipients with the at-risk allele of the VDR gene (P= 0.03). CONCLUSION: Therapy with low-dose calcium supplements during 1 year, plus intermittent calcitriol for 3 months after RT, is safe, decreases PTH levels more rapidly, and prevents bone loss at the proximal femur; a more pronounced effect is seen in recipients with at least one at-risk allele of the VDR genotype.     

Melatonin attenuates posttransplant lung ischemia-reperfusion injury

BACKGROUND: Melatonin, a pineal hormone, is a free radical scavenger and an antioxidant. The purpose of this study was to assess the protective effect of melatonin on posttransplant lung ischemia-reperfusion injury. METHODS: Rat single-lung transplantation was performed in two (n = 10) experimental groups after 18 hours of cold (4 degrees C) ischemia. Group I animals consisted of the ischemic control group. In group II, donor and recipient animals were treated with intraperitoneal injection of 10 mg/kg melatonin 10 minutes before harvest and reperfusion, respectively. After 2 hours of reperfusion, oxygenation, plasma, and bronchoalveolar lavage nitrite levels were measured. Lung tissue was assessed for thiobarbituric acid reactive substances and myeloperoxidase activity. Peak airway pressure was recorded throughout the reperfusion period. RESULTS: The melatonin-treated group showed significantly better oxygenation (321.8+/-33.8 mm Hg versus 86.1+/-17.4 mm Hg; p < 0.001), reduced lipid peroxidation (0.65+/-0.3 nmol/g versus 1.63+/-0.8 nmol/g; p = 0.032), and reduced myeloperoxidase activity (0.56+/-0.1 deltaOD x mg(-1) x min(-1) versus 1.01+/-0.2 deltaOD x mg(-1) x min(-1); p = 0.032). Bronchoalveolar lavage nitrite levels in the transplanted lungs were significantly lower in group II than in group I (0.34+/-0.06 micromol/L versus 1.65+/-0.6 micromol/L; p = 0.016). In group II significant reduction in peak airway pressure was noted compared with group I (p = 0.002). CONCLUSIONS: In this model, exogenously administered melatonin effectively protected lungs from reperfusion injury after prolonged ischemia.     

Effect of calcitriol on bone loss after cardiac or lung transplantation.

Rapid bone loss after cardiac and lung transplantation results in an increased risk of osteoporotic fracture. This study examined the efficacy of treatment with calcitriol (1,25-dihydroxyvitamin D3) in preventing bone loss in patients undergoing cardiac or lung transplantation. In this 2-year double-blind, stratified study, 65 patients undergoing cardiac or single lung transplantation were randomly allocated to receive either placebo or calcitriol (0.5-0.75 microg/day), the latter for either 12 months or 24 months. All patients received 600 mg calcium/day. Bone mineral density (BMD) was measured every 6 months for 2 years by dual-energy X-ray absorptiometry. There was no significant difference between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporine over the 2 years. Bone loss at the proximal femur was significantly reduced or prevented at all three sites by treatment with calcitriol for 2 years compared with treatment with calcium alone. Treatment with calcitriol for 12 months followed by calcium for 12 months resulted in similar proximal femoral bone loss to that seen in those patients treated with calcium for 24 months, suggesting calcitriol prophylaxis needs to be continued beyond 12 months. At the lumbar spine, there were no significant differences in BMD between groups. Over a period of 2 years, 22 new vertebral fractures/deformities occurred in 4 patients treated with calcium alone compared with one new vertebral fracture in 1 patient treated with calcitriol. Because the sample size was too low to provide reliable interpretation of vertebral fracture rates, this difference is likely a chance result. Mild hypercalcemia was common with calcitriol therapy, as was mild hypercalciuria (59% of patients vs. 10% controls), but there were no significant differences between groups in serum creatinine after 2 years. These data suggest calcitriol has a role in reducing proximal femur bone loss after cardiac or lung transplantation but treatment needs to be continued beyond 1 year.     

22-Oxacalcitriol attenuates bone loss in nonobese type 2 diabetes

Active vitamin D is a major therapeutic agent for bone disease. Although some studies have reported that vitamin D ameliorates bone disease related to diabetes, the mechanism remains unclear. Our study investigated the effect of the vitamin D receptor activator 22-oxacalcitriol (OCT) on bone disease in a rat model of diabetes. OCT was administered at a dose of 0.2 μg/kg three times per week for 10 weeks. We performed blood and urine analyses, single energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and oxidative stress assessment in rats at 30 weeks of age. OCT did not affect hemoglobin A1c or serum calcium levels. Bone mineral density (BMD), bone volume in the cortical and trabecular bones, and bone turnover were decreased in rats with diabetes. OCT treatment increased BMD and bone formation and tended to increase bone volume in the trabecular bone, but did not change bone volume in the cortical bone or bone resorption. The urinary oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG) excretion and the number of 8-OHdG-positive cells in bone were increased in rats with diabetes, and OCT treatment suppressed these increases. Our data suggest that OCT attenuated bone loss in a rat model of diabetes. This attenuation may be partially mediated by improved bone formation resulting from the antioxidative effect of OCT.     

The efficacy of calcitriol therapy in the management of bone loss and fractures: a qualitative review

Summary  

Osteoporosis, a skeletal disorder characterized by a reduction in bone strength, increases fracture risk. Primary osteoporosis is usually a result of reduced bone mineral density as a consequence of natural aging. Secondary osteoporosis is usually a result of a disease, such as cystic fibrosis, or medical treatment, such as corticosteroids or cancer treatment.     

Calcium regulation and bone mass loss after total gastrectomy in pigs.

OBJECTIVE: Total gastrectomy often results in postgastrectomy bone disease with decreased bone mass and increased fracture risk. To further elucidate the mechanisms of postgastrectomy bone disease, the authors investigated calcium metabolism and bone mineral density after total gastrectomy in pigs. SUMMARY BACKGROUND DATA: Postgastrectomy bone disease can present as osteomalacia, osteoporosis in excess of normal aging, or a combination of both. The underlying mechanisms are insufficiently understood and need further investigation. METHODS: Growing minipigs were gastrectomized and compared with fed-matched, sham-operated control p gs for 1 year. Calcium absorption, serum calcium, parathyroid hormone, 25-(OH)-vitamin D, 1,25-(OH)2-vitamin D, alkaline phosphatase, and computed tomography bone mineral density were measured in three monthly intervals. RESULTS: Total gastrectomy resulted in impaired calcium absorption, reduced serum calcium and 25-(OH)-vitamin D, increased parathyroid hormone and 1,25-(OH)2-vitamin, and reduced bone mineral density compared with fed-matched, sham-operated control pigs. CONCLUSIONS: The authors data indicate that a reduced serum calcium activates counter-regulatory mechanisms, resulting in calcium mobilization from the bone. Possibly, calcium and vitamin D supplementation after total gastrectomy might prevent postgastrectomy bone mass loss.     

Connexin 43 deficiency attenuates loss of trabecular bone and prevents suppression of cortical bone formation during unloading

Connexin 43 (Cx43) is the most abundant gap junction protein in bone and has been demonstrated as an integral component of skeletal homeostasis. In the present study, we sought to further refine the role of Cx43 in the response to mechanical unloading by subjecting skeletally mature mice with a bone‐specific deletion of Cx43 (cKO) to 3 weeks of mechanical unloading via hindlimb suspension (HLS). The HLS model was selected to recapitulate the effects of skeletal unloading due to prolonged bed rest, reduced activity associated with aging, and spaceflight microgravity. At baseline, the cortical bone of cKO mice displayed an osteopenic phenotype, with expanded cortices, decreased cortical thickness, decreased bone mineral density, and increased porosity. There was no baseline trabecular phenotype. After 3 weeks of HLS, wild‐type (WT) mice experienced a substantial decline in trabecular bone volume fraction, connectivity density, trabecular thickness, and trabecular tissue mineral density. These deleterious effects were attenuated in cKO mice. Conversely, there was a similar and significant amount of cortical bone loss in both WT and cKO. Interestingly, mechanical testing revealed a greater loss of strength and rigidity for cKO during HLS. Analysis of double‐label quantitative histomorphometry data demonstrated a substantial decrease in bone formation rate, mineralizing surface, and mineral apposition rate at both the periosteal and endocortical surfaces of the femur after unloading of WT mice. This suppression of bone formation was not observed in cKO mice, in which parameters were maintained at baseline levels. Taken together, the results of the present study indicate that Cx43 deficiency desensitizes bone to the effects of mechanical unloading, and that this may be due to an inability of mechanosensing osteocytes to effectively communicate the unloading state to osteoblasts to suppress bone formation. Cx43 may represent a novel therapeutic target for investigation as a countermeasure for age‐related and unloading‐induced bone loss. © 2012 American Society for Bone and Mineral Research.     

Protective effect of short-tem calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation.

Bone loss is most rapid in the immediate period after cardiac or lung transplantation. This randomized study compared the efficacy of 6 months of treatment with either calcitriol (1,25-dihydroxyvitamin D3; 0.5 microg/day) or two cycles of etidronate plus calcium in preventing bone loss in 41 patients undergoing cardiac or lung transplantation. Patients were followed for 18 months after cessation of treatment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). There were no significant differences between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporin over the 2 years. Bone loss did not differ between groups after 6 months and, despite 6 months prophylaxis with either agent, bone loss was significant in both groups at 6 months and 12 months. However, compared with an untreated reference group, both therapies offered significant protection at 6 months and etidronate provided significant protective carryover after therapy had been discontinued. These data suggest short-term prophylaxis with calcitriol or cyclical etidronate is partially effective in reducing bone loss after cardiac or lung transplantation but treatment needs to be continued for a longer term.     

Calcium,cells and bone

Journal of Bone and Mineral Metabolism -     

Calcium urolithiasis and bone change

Bone mineral contents of calcium urolithiasis patients (105 males and 52 females) were measured by the microdensitometry (MD) method, and the patients were divided into the MD normal group and the MD abnormal group. The patients were also divided into the group (21 males and 3 females) treated with thiazides for 1 year or more and the nontreated group to examine various factors in blood and urine. [Nontreated group] The rate of MD abnormality was higher in younger males. The rate tended to increase with age in females. Alkaline phosphatase values were significantly higher in MD abnormal group males than in MD normal group males. Urinary calcium excretion and PTH values were significantly higher in MD abnormal group females than in MD normal group females. Comparison of hypercalciuria and normocalciuria revealed no significant difference between the MD normal rate and the MD abnormal rate. Comparison of single of stone formers and recurrent stone formers also revealed no significant difference between the MD normal rate and the MD abnormal rate. [Treated group] PTH and alkaline phosphatase values were significantly higher in the treated group than in the nontreated group. Alkaline phosphatase values were significantly higher in the MD abnormal group. From the viewpoint of stone recurrence prevention, the monitoring of bones where the majority of calcium in the body is present is considered important besides behavior of calcium in blood and urine.     

Assessment of bone density and bone loss

Osteoporosis International - Dual-energy X-ray absorptiometry has become the standard for the evaluation of osteoporosis. It is useful both for identifying those people who are going to be at risk...