Luciano Nieddu

Long-Term Bioavailability After a Single Oral or Intramuscular Administration of 600,000 IU of Ergocalciferol or Cholecalciferol: Implications for Treatment and Prophylaxis

CONTEXT We previously showed that a single high dose of oral (po) cholecalciferol (D₃) sharply increases serum 25-hydroxyvitamin D [25(OH)D]. OBJECTIVE We evaluated the long-term bioavailability and metabolism of a single po or intramuscular (im) high dose of ergocalciferol (D₂) or D₃. DESIGN This was a prospective intervention study. SETTING The study was conducted in an ambulatory care setting. PATIENTS Participants were 24 subjects with hypovitaminosis D. INTERVENTIONS A single dose of 600,000 IU of po or im D₂ or D₃ was administered. MAIN OUTCOME MEASURES Serum 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)₂D] were measured at baseline and at days 30, 60, 90, and 120 by RIA. Serum 1,25(OH)₂D₂, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], 24,25-hydroxyvitamin D₂ [24,25(OH)D₂], and 24,25-hydroxyvitamin D₃ [24,25(OH)D₃] were measured by liquid chromatography-tandem mass spectrometry in a subgroup of patients receiving the po formulations. RESULTS The areas under the curve of 25(OH)D after D₃ were significantly higher than those after D₂ (P < .0001). Serum 25(OH)D basal difference significantly increased at day 30 with po D₂ and D₃ (P < .01 and P < .0001) and up to day 90 with po D₃ (P < .01). The im formulations produced a slow increased, and values peaked at day 120 relative to the other time points (P < .0001). We found a decrease in 1,25(OH)₂D at day 30 (P < .05) and up to day 120 (P < .001) and an increase in 1,25(OH)₂D₂ at day 30 (P < .01) and up to day 120 (P < .01) after po D₂. Oral D₂ and D₃ produced increases in 24,25(OH)D₂ and 24,25(OH)D₃, respectively, at day 30 (P < .001). CONCLUSIONS A po dose of 600,000 IU of D₂ or D₃ is initially more effective in increasing serum 25(OH)D than the equivalent im dose and is rapidly metabolized. Our RIA assay for 1,25(OH)₂D may not recognize 1,25(OH)₂D₂.

Osteoporosis intervention in ambulatory patients with previous hip fracture: a multicentric, nationwide Italian survey

Our study investigated the patterns of treatment and adherence to prescribed therapies in 2,191 ambulatory patients with previous hip osteoporotic fractures at 207 participating orthopedic centers throughout Italy. All patients who came to the attention of the involved orthopedic surgeons were administered a questionnaire investigating: age, sex, height, weight, date of admission and length of stay in the hospital, other previous clinical fractures, bone density or biochemical testing concerning mineral metabolism, treatment with bone-active drugs in the six months before the fracture, treatment after discharge from the hospital, continuous use of prescribed drugs, pain at the site of hip surgery, and comorbidity. A multivariate logistic regression model was applied, considering a subset of the variables in the questionnaire, in order to determine the factors that significantly influenced discontinuation of treatment after hip fracture. Among the patients, 88.1% were female and 86.2% of the subjects were older than 65. The mean length of hospital stay for hip fracture was 19.0±25.3 days. At the time of interview, the mean time elapsed since hospitalization was 542.9±1,197.3 days. A previous clinical fracture was referred by 20.2% of patients. Before hip fracture occurrence, 52.8% of patients had never received any kind of treatment, and this figure reached 80% if we also included those who had taken only calcium and/or vitamin D. Corresponding proportions after fracture were 22% and 31.3%, respectively. Finally, 52% of patients had stopped treatment given for osteoporosis after a mean period of 1.4 years. According to the results of the logistic regression, increasing age, pain [odds ratio (OR): 1.36; 95% confidence interval (CI): 1.21–1.65] and no use of diagnostic tests (OR: 2.46; CI: 1.79–3.37) showed a positive effect on the probability of quitting the medication. On the other hand, being female reduces by half (OR: 0.49; CI: 0.37–0.45) the probability of quitting medication. Our data showed a low rate of primary prevention, a still insufficient post-fracture therapy, along with a high rate of early discontinuation of osteoporosis medication in patients with previous hip fracture.

Regulation of PTH secretion by 25-hydroxyvitamin D and ionized calcium depends on vitamin D status: a study in a large cohort of healthy subjects

INTRODUCTION Previous papers investigating vitamin D status have often outlined the significant relationships between serum parathyroid hormone (PTH) and 25-hydroxyvitamin D (25OHD), but the influence of ionized calcium levels has not been concomitantly considered. DESIGN Cross-sectional. MATERIALS AND METHODS In 1050 healthy men (547) and women (503), serum ionized calcium (iCa), creatinine (Cr), albumin, 25OHD, and PTH were measured. After conventional analysis, a regression tree was fitted on the data set. RESULTS 25OHD and PTH values showed significant opposite seasonal changes. 25OHD levels negatively correlated with PTH, which in turn negatively correlated with iCa. A regression tree was fitted to the whole data set using PTH as the response variable and 25OHD and iCa as covariates. PTH concentration depended on that of iCa only in subjects with 25OHD levels>16.35 ng/mL, while for 25OHD<16.35 ng/mL it depended on 25OHD values. CONCLUSIONS Our results indicated that PTH levels were highly conditioned by those of 25OHD in subjects with 25OHD values lower than 16.35 ng/mL and by those of iCa only for higher 25OHD concentration.

Mineral metabolism abnormalities in patients with prostate cancer: a systematic case controlled study

PurposeProstate cancer is the most common tumor in men. To the best of our knowledge a systematic assessment of bone and mineral abnormalities has not been performed in prostatic cancer patients consecutively enrolled.MethodsThis study was therefore carried out to investigate changes of skeletal and mineral metabolism in patients with prostate cancer (n  = 69). A population of patients with cancer of various origin was also investigated as a control group (n  = 53), since a comparison with non-prostate cancer patients has not been previously reported.ResultsIn the prostatic cancer group, one patient had extremely high values of C-terminal Fibroblast Growth Factor 23, low values of tubular reabsorption of phosphate and very high values of bone alkaline phosphatase, suggesting the diagnosis of oncogenic osteomalacia. We found nine patients with primary hyperparathyroidism in the group of prostate cancer vs. only one in cancer patients group (p  <  0.026). We stratified the population on the basis of Gleason score, prostate specific antigen and hormonal therapy. Using a generalized linear model with a logit link to predict the probability of developing primary hyperparathyroidism, only Gleason score, C-terminal fibroblast growth factor 23 and hormonal therapy had a significant effect (p  < 0.05). Controlling for other covariates, a rise in fibroblast growth factor 23 increases the odds of developing primary hyperparathyroidism by 2% (p  = 0.017), while patients with higher values of Gleason score have a much greater probability of developing primary hyperparathyroidism (log-odds  =  3.6, p  <  0.01). The probability decreases with higher values of Gleason score while on hormonal therapy; a further decrease was observed in patients on hormonal treatment and lower values of GS. Finally, lower grade of Gleason score without hormonal therapy have a significant protective factor (p  <  0.01) decreasing the odds of developing primary hyperparathyroidism by 8%.ConclusionWe showed a remarkable prevalence of primary hyperparathyroidism in men with prostate cancer; the multivariate analysis demonstrates that higher aggressiveness of prostate cancer, as determined by Gleason score, is a significant predictor of increased risk of developing primary hyperparathyroidism.

Comparative Effect of rhPTH(1-84) on Bone Mineral Density and Trabecular Bone Score in Hypoparathyroidism and Postmenopausal Osteoporosis: rhPTH(1-84) IN HYPOPARATHYROIDISM AND POSTMENOPAUSAL OSTEOPOROSIS

Parathyroid hormone (PTH) (1‐84) improves lumbar spine (LS) areal bone mineral density (aBMD) and trabecular bone score (TBS) in hypoparathyroidism over a 2‐year treatment period. Studies in osteoporosis have shown that with PTH(1‐34) there is a significant increase in LS aBMD and TBS. In this article, we provide new data comparing the effects of the same form of PTH, namely recombinant human PTH, rhPTH(1‐84), on aBMD and TBS in hypoparathyroid and osteoporotic patients over an 18‐month treatment period. We studied 19 premenopausal (mean age 45.8 ± 11.8 years) and 16 postmenopausal (71 ± 8.4 years) hypoparathyroid women and 38 women with postmenopausal osteoporosis (71 ± 8.3 years). DXA (hologic) at LS, femoral neck, total hip, and distal one‐third radius was assessed. Site‐matched LS TBS data were extracted from deidentified spine DXA scans using the TBS iNsight software (version 2.1; Medimaps, Geneva, Switzerland). We observed a significant increase in LS aBMD in premenopausal and postmenopausal hypoparathyroid (3 ± 1.1%, p < 0.02 and 3.1 ± 1.4%, p < 0.05, respectively) and osteoporosis (6.2 ± 1.1%, p < 0.0001) patients after 18 months. There was a significant increase (3 ± 1.5%, p = 0.05) in TBS in premenopausal hypoparathyroid patients. A change in TBS was not observed in either postmenopausal group. One‐third radius aBMD significantly declined in postmenopausal hypoparathyroid (‐3.6 ± 1.1%, p < 0.01) and osteoporosis (‐8 ± 1.4%, p < 0.0001) patients. Overall, there was a significantly greater increase in TBS in premenopausal hypoparathyroid than in osteoporosis patients (p < 0.0001) after adjusting for baseline values, age, BMI, and average daily dose of rhPTH(1‐84). Comparing only postmenopausal women, the LS aBMD increase was greater in osteoporotic than hypoparathyroid subjects (p < 0.01). Our results demonstrate that rhPTH(1‐84) administered for 18 months increases trabecular aBMD in hypoparathyroidism and postmenopausal osteoporosis with greater gains observed in the subjects with osteoporosis. The data suggest different effects of PTH on bone depending on the baseline skeletal structure, skeletal dynamics, compartments, and menopausal status.

Two-hour postload glycemia is associated to an increased risk of NAFLD in healthy subjects with family history of type 2 diabetes: a case control study

Nonalcoholic fatty liver disease (NAFLD) includes steatosis and nonalcoholic steatohepatitis (NASH), which can be complicated by cirrhosis and hepatocellular carcinoma [1]. NAFLD affects over 30 % of the general population and is associated with type 2 diabetes mellitus (T2DM), obesity and metabolic syndrome [2, 3]. NAFLD prevalence in T2DM patients is about 70 % using ultrasonography (US) [4]. NAFLD and T2DM share insulinresistance, which in the liver increases gluconeogenesis and glycogenolysis, resulting in hyperglycemia. The pancreatic beta islet cells adapt to hyperglycemia by increasing insulin secretion. Hyperinsulinemia upregulates several lipogenic transcription factors, promoting hepatic lipid synthesis [5]. The association between NAFLD and T2DM seems to be the result of a “common soil” [3]. Several studies showed that NAFLD predicts T2DM and vice versa, and that each condition may act as a progression factor for the other [4]. There is evidence of a high risk of NASH and its progression to hepatocellular carcinoma in T2DM patients [6]. Conversely, recent studies showed that NAFLD not only predicts diabetes [7], but also contributes to poor glycemic control and chronic complications [8]. Despite its clear link with T2DM, the association of NAFLD with family history of diabetes has been poorly investigated. A recent cross-sectional study in nondiabetic individuals with NAFLD demonstrated that family history of diabetes increased the risk of NASH and fibrosis [9]. The aim of this study was to evaluate the prevalence of NAFLD in healthy first degree relatives of T2DM patients (T2DM-rel) and in healthy subjects without family history of T2DM and to assess the risk factors associated with NAFLD development.