Mirella Cilli

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.

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.

Intermittent High Doses of Vitamin D: A Need for Further Studies?

It was with interest that we read the paper by Sanders et al. [1] enlightening the harmful effects of the administration of huge doses of vitamin D. However, we believe that some points need clarification. There are two studies demonstrating a negative effect of so-called intermittent bolus doses of vitamin D on the incidence of fractures [2, 3]. However, we must recognize that these trials, even though randomized, double-blind, and placebo-controlled, lack important information concerning, for example, the distribution of risk factors for falls in the two arms (cognitive impairment, drug use, units of alcohol consumed, and so on). Such information is essential because, as admitted by the authors, the link between high vitamin D serum levels and fractures remains obscure and mainly speculative. We believe that, at least from a theoretical point of view, the concept that the administration of vitamin D follows simple pharmacokinetic rules should be reinforced; these are based on straightforward parameters such as the actual level in the patient, the desired level (however defined), and the time needed to fill the body stores [4]. This approach is unpractical on a population basis, therefore explaining in part the utilization of intermittent large doses to overcome the problem of compliance. We agree that if the issue is not the absolute peak value reached but the fluctuations of serum 25(OH)D levels [1, 5], then there is at least one possibility of overcoming this problem. Indeed, we previously demonstrated [6] that following intramuscular injection of vitamin D, there is a slow increase of total 25(OH)D, contrary to what is observed after oral administration. We have now extended and confirmed these initial results over a longer period of time (C. Cipriani et al., in preparation). The intramuscular route was also used by Smith et al. [3], but paradoxically they were not able to show any significant increase in 25(OH)D in the subgroup of patients in which this metabolite was measured. Finally, we agree that there is an urgent need of randomized controlled trials with physical outcomes as primary end points, using a number of different regimens to definitively solve this hot issue. In this context, the control of all parameters that are considered risk factors for falls and fractures is critical. The results could have a profound impact on public health systems, considering the low cost of such supplementation.

Effect of a single oral dose of 600,000 IU of cholecalciferol on muscle strength: A study in young women

Background: The effect of a single large oral dose of vitamin D on muscle function in young people with vitamin D deficiency has not been investigated so far. Aim: We evaluated the effect of a single oral dose of 600, 000 IU of cholecalciferol on muscle strength. Subjects and methods: Eighteen young women with vitamin D deficiency received a single oral dose of 600, 000 IU of cholecalciferol. We evaluated changes in maximal voluntary contraction (MVC) and speed of contraction (S) in response to cholecalciferol by using an hand held dynamometer at 3, 15, 30, 60 and 90 days, compared to baseline. Results: We observed no significant change in MVC and S values, a significant increase of 25-hydroxyvitamin D [25(OH)D] and 1, 25-dihydroxyvitamin D [1, 25(OH)2D] and a significant decrease in serum parathyroid hormone (PTH) (p<0.001 for all). A significant correlation was found between MVC and S and serum phosphorus (P) after supplementation (p<0.02 and p<0.05, respectively). Conversely, we observed no association between the parameters of muscle strength and 25(OH)D, ionized calcium (Ca2+), PTH and 1, 25(OH)2D. Conclusions: A single dose of 600, 000 IU of cholecalciferol does not directly enhance handgrip strength in young women with vitamin D deficiency. More studies are needed on the indirect effect of the hormone on muscle.

Adipokines and bone metabolism: an interplay to untangle

is probably mediated by the leptin receptor found on osteoblasts and chondrocytes. The indirect effect is mediated by different pathways. Leptin also impacts and regulates osteocalcin, an osteoblast-derived hormone considered a marker of bone formation, which in turn regulates both bone metabolism and insulin sensitivity [4]. Serum leptin levels have been shown to have a strong positive correlation with bone mineral density (BMD) in women, and high levels of leptin were reported to be predictive of low risk of fractures in some but not all studies [4]. Leptin increases osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) alpha superfamily secreted by osteoblasts which acts as a soluble decoy receptor for the activator of nuclear factor kappa B (RANK), a transmembrane protein expressed by osteoclasts. By preventing the soluble receptor activator of nuclear factor kappa B ligand (RANKL) from binding to RANK, OPG protects bone from excessive resorption. Adiponectin levels have been shown to be inversely related to visceral fat and body mass index [5]; serum values vary largely depending also on age, sex, menopausal status and comorbidities [6]. Secretion of adiponectin may be inhibited by cytokines, such as TNF alpha, interleukin 6 and hormones (cortisol and testosterone), which are also involved in bone metabolism. Adiponectin receptors have been demonstrated on osteoblasts, but also on muscle and liver, which are organs that interplay with adipose tissue and bone metabolism [7]. Osteoblasts and marrow adipocytes originate from a common mesenchymal progenitor, and adiponectin has been postulated as a potential factor that may induce osteoblast proliferation and differentiation. Interestingly, osteocalcin may upregulate the expression of the adiponectin gene in adipocytes, thus improving insulin sensitivity. Adiponectin has been studied also in different clinical conditions such as non-alcoholic Recent evidence of increased fracture risk in obese patients has focused the attention on the relationship between adipose and skeletal tissue [1]. Adipocytes secrete a number of bioactive molecules, such as adipokines, which recently have been shown to have a role in bone metabolism. Adipokines are pleiotropic molecules, investigated in many physiological or pathological processes, including inflammation, endothelial damage, atherosclerosis, impaired insulin signaling and hypertension. Adipokine dysregulation has been shown to be a strong determinant of the low-grade inflammatory state of obesity, which promotes a cascade of metabolic alterations leading to cardiovascular complications, insulin resistance or diabetes mellitus [2, 3]. So far, only a few adipokines (adiponectin, leptin, resistin, visfatin and the newly discovered omentin-1) have been studied in the context of bone metabolism. Leptin was the first adipokine discovered. Circulating levels seem to reflect the amount of energy stored in the adipose tissue; however, a wide variability in leptin levels has been reported in individuals with the same body mass index [4]. A number of factors regulate circulating leptin levels in healthy individuals. In addition, leptin also influences several hypothalamic pituitary peripheral neuroendocrine axes, including the thyroid, gonadal, cortisol and growth hormone axes. Leptin exerts its effect on bone metabolism by means of both direct and indirect mechanisms. The direct mechanism

High prevalence of abdominal aortic calcification in patients with primary hyperparathyroidism as evaluated by Kauppila score

OBJECTIVE The prevalence of abdominal aortic calcification (AAC) in primary hyperparathyroidism (PHPT) is unknown. We assessed both prevalence and severity of AAC in PHPT postmenopausal women. METHODS In this study 70 PHPT postmenopausal women and 70 age- and sex-matched controls were enrolled. Each participant underwent biochemical evaluation, lateral spine radiograph, bone mineral density (BMD) measurement (lumbar, femoral, radial sites), and kidney ultrasound. Lateral lumbar films were analyzed in the region of L1-L4 vertebrae and the Kauppila score (a semi-quantitative grading system) was used to assess the severity of AAC. RESULTS There were no differences regarding demographic and cardiovascular risk factors in the two groups. PHPT patients had higher prevalence of kidney stones (30% vs 7%, P=0.0008) and lower radial BMD values (0.558±0.071 vs 0.588±0.082 g/cm(2), P<0.05) compared with controls. PHPT patients showed higher prevalence of AAC (31 vs 18, P=0.03), with more severe calcifications (Kauppila score 7.35±6.1 vs 5.05±3.5, P=0.007). PHPT patients with AAC were older and had been suffering from the disease for a longer period compared with those without ACC. Moreover, PHPT patients with severe AAC had mean higher serum parathyroid hormone levels compared with patients with moderate or mild calcifications. In PHPT patients with AAC, multiple regression analysis, adjusted for age and years since diagnosis, showed that only parathyroid hormone significantly correlated with Kauppila score. CONCLUSION We found a higher prevalence and severity of AAC in PHPT related to parathyroid hormone effect.

Quality of life in patients with primary hyperparathyroidism

The clinical picture of primary hyperparathyroidism (PHPT) has changed over the last three decades and many asymptomatic patients are now diagnosed through the unexpected finding of high serum calcium levels. However, though not yet considered as typical features of the disease and therefore not included in the guidelines for surgery, many data are available on neuropsycological manifestations and their impact on quality of life in asymptomatic patients. PHPT patients indeed show early experience nonspecific symptoms, such as weakness, depression, sleep disturbance, memory loss and anxiety. Although the underlining mechanisms have not been still identified, the prevalence of psychiatric and cognitive deficits has been investigated in many studies, as well as the possible association with quality of life and well-being improvement after surgery. This article aims to review the current knowledge on quality of life in PHPT patients before and after surgery and the possible clinical implications of these findings.

Emerging data on cardiovascular risk in primary hyperparathyroidism.

The cardiovascular risk profile of patients affected by primary hyperparathyroidism (PHPT) has been an issue of debate over the last years. Studies regarding the potential damages caused by increased serum levels of parathyroid hormone (PTH) and/or calcium, have yielded controversial results, suggesting either the presence or the absence of damage [1, 2]. It is interesting to note that the answer to this question is further complicated by the changing clinical presentation of PHPT over the last decade. Indeed, once considered a symptomatic disorder characterized by significant hypercalcemia with kidney stones and/or bone involvement [3– 5], today PHPT is most commonly seen in asymptomatic individuals with milder hypercalcemia, due to the large availability of routine serum calcium measurements and developments in assay systems. A new presentation is now emerging, characterized by normocalcemia and elevated serum parathyroid hormone levels (the so-called ‘‘normocalcemic primary hyperparathyroidism’’). Recently in this Journal, Procopio et al. reported an increased prevalence of intermediate-high cardiovascular risk score (CRS), both in symptomatic and asymptomatic PHPT patients, as compared to healthy controls [6]. Their data are in line with several previous studies that reported an increased coronary artery and cerebrovascular morbidity in PHPT [7, 8]. By means of a multivariate analysis, they also showed that, PHPT status predicts the presence of intermediate-high CRS and metabolic syndrome [9], while elevated calcium levels predict altered glucose tolerance among the components of metabolic syndrome. Procopio et al. added new information on an emerging aspect of patients with this glandular disorder; however, there are also some limitations that should be kept in mind when interpreting the results obtained. For example, the classification of patients is somewhat arbitrary. Asymptomatic patients with complications should no longer be considered as such; indeed, future classifications should be based on the presence or absence of complications. Just to make an example, patients may be asymptomatic, but can be incidentally discovered to have a kidney stone by ultrasound; in such a case she/he is asymptomatic but already has a complication of the disease. In essence, the term asymptomatic does not mean without complications; in this context, also a vertebral fracture may be asymptomatic but represents a complication. Secondly, the paper does not include any follow-up after surgery; this could have added meaningful information about the possible reversible effects of a restored biochemical calcium metabolism on cardiovascular risk factors. The current data conflict on this last issue [10, 11], possibly due to the different timing of surgery. For example in the case of hypertensive patients, it is entirely possible that parathyroidectomy would be effective only if performed in an early phase of the disease, when structural abnormalities are not present. A similar situation can be observed in other endocrine disorders determining arterial hypertension, such as primary hyperaldosteronism [12]. It has been shown that, in the general population, cardiovascular risk factors can result in cardiac organ damage which might be detected by echocardiographic measurements. Conflicting results are present in the current literature in relation to the finding of left ventricular (LV) hypertrophy and LV systolic and diastolic dysfunction in J. Pepe S. Piemonte C. Cipriani M. Cilli S. Minisola (&) Department of Internal Medicine and Medical Disciplines, Sapienza University, Viale del Policlinico 155, 00161 Rome, Italy e-mail: salvatore.minisola@uniroma1.it

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.

A reappraisal of vitamin D effect on non-skeletal targets and mortality

partially protected the mice from developing diabetes but the rate of incidence was still relatively high. Addition of 1,25(OH),D3 to diet prevented the appearance of diabetes. Concerning investigations carried out in human subjects, data from observational studies seem to indicate an association between low vitamin D status and incident diabetes. Both higher plasma 25-hydroxyvitamin D [25(OH)D] concentrations and higher vitamin D intake are associated with lower risk of both types of diabetes and metabolic syndrome [8–10]. Prospective cohort studies, as well as meta-analyses, yield conflicting results [11]; regarding the first type of studies, it is really hard to believe that a single 25(OH)D value may be reflective of chronic exposure for the entire period of the observation. Furthermore, in the majority of investigations, authors are unable to report sun exposure as well as possible over the counter or supplementation use of vitamin D during the period of observation. Discrepant results in observational studies (vs intervention studies) could be ascribed to a number of factors; among them it is worthwhile to recognize reverse causation and residual confounding. The low vitamin D values found in diabetic obese patients, might be, for example, entirely explained by the fact that they have more chronic diseases, spending less time outdoors with limited sun exposure. To overcome some of these potential problems, Afzal and coworkers [12] employed a Mendelian randomization approach to investigate how genetic variants determining low concentrations of calcidiol were associated with diabetes. The Mendelian randomization approach takes advantage of the random assortment of genetic variants occurring during gamete formation, which exploits an equal distribution of confounding factors among different genotypes. This approach may be utilized to evaluate whether genetically affected risk factors are causally related to clinical outcomes. In other words, this approach may be equated to There is an incessant debate in the current literature (with a parallel astonishing increasing number of papers) regarding possible beneficial health effect of adequate vitamin D status and vitamin D supplementation [1]. Indeed, in addition to its positive effects on skeletal [2, 3] and muscle tissue [4], vitamin D has been claimed to be beneficial for patients with cardiovascular, malignant, autoimmune disease or infections, just to list a few of the at least 137 outcomes reported in the literature [5]. The interest in these extra-skeletal effects, also shared by the lay community, mainly stems from the observation that hypovitaminosis D can be easily estimated by blood testing and likewise easily treated by supplementation [6]. Therefore, if an effect on non-skeletal tissues is demonstrated, it could represent a cost-effective public health measure to prevent or retard the progression of a number of diseases. Studies aimed at demonstrating the link between vitamin D and a specific target may be of different kinds (Table 1). The first consideration to be made is that the “in vitro” and animal studies, seem to be more robust than studies in human subjects. Considering, for example, vitamin D concentration and the risk of (both type 1 and type 2) diabetes, De Luca and Cantorna [7] demonstrated that in non-obese diabetic mouse model, vitamin D deficiency markedly accelerated the appearance and increased the incidence of type 1 diabetes. Administration of ordinary vitamin D