while another 30 women received placebo . On day 5, both groups were treated with zoledronic acid and received 500 mg of calcium carbonate MDV3100 and 400 IU of cholecalciferol twice daily starting from the day of infusion for at least 10 days. On day 5 and then on day 6 and day 7, the following inflammation markers were evaluated by routine procedures: erythrocyte sedimentation rate , C reactive protein , and a1 acid glycoprotein . On day 5, calcium and creatinine were measured by routine procedures. Serum 25D levels were assayed by HPLC . Zoledronic acid was administered in about 30 min at a constant speed soon after sampling on day 5. Patients were instructed to monitor body temperature every 4 h during the day and to write down values in a diary for 2 days.
On day 5 and the following DNA-PK Inhibitors 2 days, women were interviewed by the same physician, to detect symptoms attributable to APR: fever, musculoskeletal , gastrointestinal , eye inflammation, and other were conventionally five symptom clusters; and the occurrence of any postdose adverse event falling within these clusters during the period of study was defined as constituting an APR . During the observation period, the onset of fever reduced inflammation indices and the amount of musculoskeletal pain; the latter is the most commonly reported APR event and is often experienced as a generalized discomfort. All components of APR have their highest onset rate in the first 2 days from zoledronic acid infusion; thus, observing a different severity of pain score between groups within this period is clinically relevant.
The inflammatory response is probably not just delayed but reduced in vitamin D group as we reported a rise in serum markers of inflammation in both groups already on day 6. We used a single high pericardium dose of cholecalciferol because it is an inactive precursor of calcitriol and is safe and well tolerated; synthesis of 1a,25 dihydroxyvitamin D3 requires a 25 hydroxylation followed by a 1a hydroxylation catalyzed by cytochrome P 450 enzymes in the liver and kidney, respectively. Renal production of 1,25 dihydroxyvitamin D3 is tightly regulated by plasma parathyroid hormone levels and serum calcium and phosphorus levels . 1a Hydroxylase is also expressed in immune cells such as monocytes and macrophages in response to activation by IFN c or Toll like receptor signaling ; hence, conversion of 25D3 to 1,252D3 takes place in monocytes and 1,252D3 regulates the expression of vitamin D–responsive genes by binding VDR in an intracrine manner.
Cipriani demonstrated that a single oral dose of 60 IU of cholecalciferol is able to rapidly enhance 25D and, in particular, a sharp and significant increase was observed after 3 days. Moreover, the potency and safety of a single, large, oral 30 IU dose of cholecalciferol in enhancing serum 25D levels was previously reported . In our study, patients receiving 30 IU of cholecalciferol 5 days before zoledronic acid infusion showed a marked rise of 25D, which is a reliable indicator of vitamin D status. Notably, the highest value recorded of serum 25D was below the threshold of 400 ng/mL, which has recently been reported to cause no symptoms in sporadic cases of vitamin D intoxication . In the placebo group three cases of fever D due to reduced sun exposure . Vitamin D inhibits also the prostaglandin pathway by inhibiting the expression of COX/PG endoperoxidase synthase 2 , the inducible ratelimiting enzyme that catalyzes the conversion.