Sara Piemonte

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.

MANAGEMENT OF ENDOCRINE DISEASE: Value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation

The growing attention to the role of vitamin D in skeletal and extra-skeletal diseases over the last decade induced an increased demand for vitamin D determination as well as a dramatic rise of sales of vitamin D supplement. However, several critical points in this field remain to be clarified. We lack a clear consensus about the definition of vitamin D deficiency, insufficiency, and sufficiency. The identification of different thresholds defining vitamin D status has relevant implications in clinical practice. In fact, the worldwide prevalence of low vitamin D status is highly varying according to the level of 25(OH)D utilized to define sufficiency. Therefore, the assessment of 25-hydroxyvitamin D levels may have a critical role, but a number of different technical problems associated with its determination may interfere in interpreting the results. The hydrophobic nature of vitamin D and the tight binding to its carrier (vitamin D binding protein), the different forms circulating in blood, and the issue of standardization are among the most important factors influencing the measurement of this metabolite. Another controversial point relies on the conflicting guidance on prevention and treatment of vitamin D deficiency endorsed by different medical and scientific communities. In particular, uncertainty exists about how to replete vitamin D stores, how to maintain normal 25(OH)D levels after repletion, which form of vitamin D is preferable for supplementation, and which route of administration and dosing regimens are advisable. Finally, concerns have been raised regarding vitamin D toxicity and its adverse effects.

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.

Prevalence of Kidney Stones and Vertebral Fractures in Primary Hyperparathyroidism Using Imaging Technology

CONTEXT The fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (PHPT) has recently suggested that skeletal and renal imaging be routinely conducted. So far, no study has systematically assessed this issue. OBJECTIVE The objective was to evaluate the prevalence of kidney stones (KS) and vertebral fractures (VFs) in a cohort of patients with PHPT utilizing noninvasive imaging technology. DESIGN This was a prospective study evaluating patients consecutively diagnosed with PHPT in a single center over a 5-year period (2009-2013). SETTING The setting was a referral center. PATIENTS There were a total of 140 patients with PHPT (127 women [18 premenopausal and 109 postmenopausal] and 13 men; mean age, 63.2 ± 11 y). MAIN OUTCOMES MEASURES Main outcome measures were the prevalence of KS by abdominal ultrasound, osteoporosis by dual-energy x-ray absorptiometry (DXA) (lumbar spine, femoral neck, total hip, and distal 1/3 radius), and VFs by vertebral spine x-ray, with attention to those categorized as symptomatic or asymptomatic. RESULTS Fifty-five percent of all subjects had KS by ultrasound, 62.9% had osteoporosis by T-score at any site, and 35.1% had VFs by x-ray. There was no difference in the incidence of VFs and densitometric osteoporosis between symptomatic and asymptomatic patients (VFs, 34.4 vs 34.7%; osteoporosis by DXA, 59.4 vs 65.8%), whereas more KS were detected in symptomatic (78%) than asymptomatic (35.5%). Twenty-two percent of patients classified as asymptomatic at baseline without osteoporosis by DXA were found to have KS and/or VFs. CONCLUSIONS Nephrolithiasis and VFs are common in asymptomatic subjects with PHPT. The results provide evidence in support of recent recommendations that a more proactive approach be taken to detect silent bone and stone disease in asymptomatic PHPT.

The diagnosis and management of hypercalcaemia.

#### The bottom line Hypercalcaemia is a common finding in the setting of primary care,1 as well as in emergency departments2 and patients admitted to hospital.3 Primary hyperparathyroidism and malignancy are the two most common causes of increased serum calcium levels, together accounting for about 90% of all cases.4 The remaining 10% represent an important figure, and thus the need to consider other disorders in the evaluation of patients with hypercalcaemia. This review aims to give an overview of the diagnosis and clinical management of hypercalcaemia for non-specialist clinicians and health professionals. #### Sources and selection criteria We carried out a search through Medline and PubMed of articles published from 1990 to 2015 using the terms “mild hypercalcaemia” and “severe “hypercalcemia”, “primary hyperparathyroidism”, “hypercalcemia of malignancy”, “parathyroid hormone measurement”, “parathyroidectomy”, and “cinacalcet” and through the National Cancer Institute using the term “hypercalcaemia”. We also retrieved personal archived references to identify …

Vitamin D and its relationship with obesity and muscle

The skin synthesis of vitamin D represents the first step of a metabolic pathway whose features have been extensively studied and clarified in the last decades. In particular, the production of active and inactive forms of the hormone and the actions of the corresponding enzymes have offered new insights into the knowledge of vitamin D metabolism. Additionally, the description of the different organs and tissues expressing the vitamin D receptor and its possible functions, as well as its genetic determinants, have allowed focusing on the interrelationship between vitamin D and many physiological and pathological functions. In this context, many studies reported the association between vitamin D and adipose tissue metabolism, as well as the possible role of the hormone in obesity, weight, and fat mass distribution. Finally, many reports focused on the vitamin D-related effects on skeletal muscle, particularly on the mechanisms by which vitamin D could directly affect muscle mass and strength. This paper is mainly aimed to review vitamin D metabolism and its relationship with obesity and skeletal muscle function.

The combination of FRAX and Ageing Male Symptoms scale better identifies treated HIV males at risk for major fracture.

Osteoporosis and hypogonadism are common in men with HIV infection. Ageing Male Symptoms (AMS) scale measures symptoms related to hypogonadism. FRAX provides 10‐year probability of major fractures. We investigated the role of AMS scale combined with FRAX without bone mineral density (BMD), in identifying HIV men with bone fragility.

Serum sclerostin levels decline in post-menopausal women with osteoporosis following treatment with intermittent parathyroid hormone.

Objective: This study was carried out in order to evaluate the effect of 18-month treatment with PTH (1–34) or PTH (1–84) on serum sclerostin levels in humans. Subjects and methods: We investigated 10 women with severe osteoporosis, previously treated with alendronate and 20 untreated osteoporotic women. Subjects with severe osteoporosis were randomly divided into 2 groups of 5 patients each; the first group was treated with 20 µg of PTH (1–34) and the second one with 100 µg of PTH (1–84) according to an open-label design. Fasting blood samples were collected at baseline and at 2, 4, and 24 h after hormone administration. The same protocol was followed at month 1,6, 12, 18. Serum sclerostin levels were measured at each time point by a sandwich-type enzyme-linked immunosorbent assay. Results: Basal serum sclerostin levels were not significantly different between patients previously treated with alendronate and those never treated. No significant acute change of serum sclerostin levels was observed after PTH administration. Fitting a mixed effect regression model, we found a significant time effect (p=0.0012) using the sclerostin level as the response variable and the month of drug administration as a single covariate. Treatment with both PTH molecules induced a monthly mean reduction of sclerostin levels of 0.1956 pmol/l. Conclusions: Our results indicate that long-term therapy with PTH (1–34) or PTH (1–84) in women with osteoporosis previously treated with alendronate is associated with a reduction in circulating sclerostin levels. This is a putative mechanism through which PTH performs its anabolic action.

Parathyroidectomy eliminates arrhythmic risk in primary hyperparathyroidism, as evaluated by exercise test

OBJECTIVE To investigate whether parathyroidectomy (PTx) reverses risk factors for arrhythmias related to the QT dynamic changes evaluated during bicycle ergometry exercise test (ET). METHODS Twenty-four postmenopausal women with primary hyperparathyroidism (PHPT) (mean age 60.08.4 years) and 30 sex- and age-matched controls underwent ET, echocardiography, and biochemical evaluation. The following stages were considered during ET: rest, peak exercise, and recovery. The patients were randomized to two groups: 12 underwent PTx (group A) and 12 were followed-up conservatively (group B). After 6 months, the patients were studied again. RESULTS Groups A and B showed no differences in mean baseline biochemical values, echocardiographic parameters, and QTC interval. PHPT patients showed an increased occurrence of ventricular premature beats (VPBS) during ET compared with controls (37.0 vs 6.6%, P=0.03). Serum calcium level was a predictor of VPBS (P=0.05). Mean value of QTC was in the normal range at baseline (Group A: 401±16.9; group B: 402.25±13.5 ms) but significantly lower than controls (417.8±25.1 ms, P<0.01). A negative correlation was found between QTc and calcium values (P=0.03). Physiological reduction of QTc interval from rest to peak exercise was not observed in PHPT patients before surgery. After PTx, group A had a significant reduction in VPBs compared with baseline (at baseline, 5 of 12 vs none of 12 patients after PTx, P=0.03) and a restored normal QT adaptation during ET. Group B showed no significant changes after a 6-month period. CONCLUSIONS PTx reduces the occurrence of VPBs and restored the QTc adaptation during ET.

Arrhythmias in primary hyperparathyroidism evaluated by exercise test.

Hypercalcemia induces arrhythmias and shortening of QT. The aim of this study was to investigate risk factors for occurrence of arrhythmias in patients with primary hyperparathyroidism (PHPT) during bicycle ergometer exercise test (ET).