The Mutual Interplay between Bone, Glucose and Lipid Metabolism: The Role of Vitamin D and PTH.

BACKGROUND: We sought to investigate the mutual interplay between bone, glucose and lipid metabolism in a wide cohort of community-based subjects. METHODS: We studied 1240 blood donors (F/M ratio 1/3.2, mean age 41.9 ± 11.7 SD). Serum ionized (Ca++), magnesium (Mg++), 25-hydroxy-vitamin D [25(OH)D], PTH-1-84, 1,25-dihydroxyvitamin D [1,25(OH)2D], total cholesterol (C), HDL-C, triglycerides and glucose were measured and LDL-C levels were calculated in all subjects. RESULTS: 25(OH)D negatively correlated with BMI (R = -0.11), PTH (R = -0.16) (p < 0.0001), total C (R = -0.06, p < 0.05) and triglycerides (R = -0.13, p < 0.0001) and positively with 1,25(OH)2D (R = 0.12) and creatinine (R = 0.17) (p < 0.0001). Serum PTH positively correlated with total C (R = 0.08, p < 0.01), LDL-C (R = 0.1, p < 0.001), triglycerides (R = 0.09, p < 0.01) and glucose (R = 0.15, p < 0.0001) and negatively with HDL-C (R = -0.09, p < 0.01). The odds of showing abnormal serum triglycerides and HDL-C increased as 25(OH)D decreased (p < 0.0001 and p < 0.03) and PTH increased (p < 0.03 and p = 0.05), while the odds of showing abnormal LDL-C levels increased in association with elevated PTH (p < 0.01). CONCLUSION: Vitamin D, PTH, glucose and lipid metabolism are mutually influenced. Hypovitaminosis D predisposes toward worsening lipid profiles through the actions of PTH, while serum PTH levels per se associate with higher glucose and LDL-C levels.

FGF23 functions and disease.

The main function of fibroblast growth factor 23 (FGF23) is the regulation of phosphate metabolism through its action on the sodium-dependent phosphate cotransporters in the proximal renal tubules. Additionally, FGF23 interacts with vitamin D and parathyroid hormone in a complex metabolic pathway whose detailed mechanisms are still not clear in human physiology and disease. More recently, research has also focused on the understanding of mechanisms of FGF23 action on organs and system other than the kidneys and bone, as well as on its interaction with other metabolic pathways. Collectively, the new evidence are successfully used for the clinical evaluation and management of FGF23-related disorders, for which new therapies with many potential applications are now available.

Diagnosis and management of hypocalcemia.

The aim of this clinical narrative review is to summarize and critically appraise the literature on the differential diagnosis of hypocalcemia and to provide its correct management. Calcium is essential for muscle contraction and neurotransmitter release, but clinical manifestations of hypocalcaemia (serum calcium level <8 mg/dl; 2.12 mmol/L) may involve almost any organ and system and may range from asymptomatic to life-threating conditions. Disorders causing hypocalcemia can be divided into parathyroid hormone (PTH) and non-PTH mediated. The most frequent cause of hypocalcemia is postsurgical hypoparathyroidism, while a more comprehensive search for other causes is needed for appropriate treatment in the non PTH-mediated forms. Intravenous calcium infusion is essential to raise calcium levels and resolve or minimize symptoms in the setting of acute hypocalcemia. Oral calcium and/or vitamin D supplementation is the most frequently used as treatment of chronic hypocalcemia. In hypoparathyroidism, providing the missing hormone with the use of the recombinant human (rh) PTH(1-84) has been recently approved both by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This new therapy has the advantage of being effective for correcting serum calcium levels and significantly reducing the daily requirements of calcium and active vitamin D supplements. However, due to the high cost, a strict selection of candidates to this therapy is necessary. More challenging is the long-term hypocalcemia treatment, due to its associated complications. The development of long-acting recombinant human PTH will probably modify the management of chronic hypoparathyroidism in the future.

Controversies Surrounding Vitamin D: Focus on Supplementation and Cancer.

There has recently been a huge number of publications concerning various aspects of vitamin D, from the physiological to therapeutic fields. However, as a consequence of this very fast-growing scientific area, some issues still remain surrounded by uncertainties, without a final agreement having been reached. Examples include the definitions of vitamin D sufficiency and insufficiency, (i.e., 20 vs. 30 ng/mL), the relationship between 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone, (i.e., linear vs. no linear), the referent to consider, (i.e., total vs. free determination), the utility of screening versus universal supplementation, and so on. In this review, the issues related to vitamin D supplementation in subjects with documented hypovitaminosis, and the role of vitamin D in cancer will be concisely considered. Daily, weekly, or monthly administration of cholecalciferol generally leads to essentially similar results in terms of an increase in 25(OH)D serum levels. However, we should also consider possible differences related to a number of variables, (i.e., efficiency of intestinal absorption, binding to vitamin D binding protein, and so on). Thus, adherence to therapy may be more important than the dose regimen chosen in order to allow long-term compliance in a sometimes very old population already swamped by many drugs. It is difficult to draw firm conclusions at present regarding the relationship between cancer and vitamin D. In vitro and preclinical studies seem to have been more convincing than clinical investigations. Positive results in human studies have been mainly derived from post-hoc analyses, secondary end-points or meta-analyses, with the last showing not a decrease in cancer incidence but rather in mortality. We must therefore proceed with a word of caution. Until it has been clearly demonstrated that there is a causal relationship, these positive "non-primary, end-point results" should be considered as a background for generating new hypotheses for future investigations.

Adherence to bisphosphonates in the general population: a study in patients referred to a primary care service.

PURPOSE: The aim of the study was to evaluate the adherence to treatment with bisphosphonates in women with postmenopausal osteoporosis referred to a primary care clinic. METHODS: A total of 7257 outpatients were referred to the primary care service where the study was conducted. We retrieved data of postmenopausal women to which bisphosphonates have been prescribed in the period January 1, 2000-December 31, 2014, and analyzed the group of patients who had discontinued the drug. RESULTS: The total number of women treated with bisphosphonates was 285 (mean age 72 ± 9.8 years). At the time the data were retrieved, 157 (55% of the total) had discontinued therapy. Among them, 119 (41.7%) agreed to participate in the study. They reported the following reasons for treatment discontinuation: withdrawal by another physician (40%), lack of motivation (20%), absence of BMD improvement (14%), uncomfortable way of drug administration (11%), side effects (6%), fear of side effects (1.6%), high number of concomitant medications (0.8%), and others (6.6%). Sixty patients (50.4%) discontinued therapy within 2 years, 27 patients (23%) > 2 and ≤ 5 years and 32 (27%) after 5 years. CONCLUSIONS: Our study demonstrates that more than half of women with postmenopausal osteoporosis referred to a primary care service discontinued bisphosphonates before the clinical effect can be seen and mostly because of advice by physicians not initially prescribing the drug. There is an inappropriate management of bisphosphonate therapy in terms of therapeutic efficacy and strategies aimed at ameliorating clinical management of osteoporosis patients are warranted.

The relative influence of serum ionized calcium and 25-hydroxyvitamin D in regulating PTH secretion in healthy subjects.

BACKGROUND: While the inverse relationship between serum ionized calcium (Ca2+) and PTH is well-established, the relationship between 25(OH)D and PTH showed conflicting results. The study aimed to evaluate the relative contributions of age, sex, serum Ca2+, ionized magnesium (Mg2+), 25(OH)D and 1,25(OH)2D in regulating PTH secretion in healthy subjects. METHODS: This is a secondary analysis of an observational study performed from March 2014 to July 2015 carried out in 2259 blood donors (1652 men and 607 women, age range 18-68 years). Subjects with parathyroid disorders and taking drugs that affect mineral metabolism were excluded. RESULTS: Significant correlations [between Ca2+ and PTH (r = -0.223, p < 0.001), 25(OH)D and PTH (r = -0.178, p < 0.001) and between PTH and age (r = 0.322, p < 0.001)] were found. As a preliminary step to multivariate analysis, a regression tree analysis was performed using PTH as response variable and age, Ca2+, Mg2+, 25(OH)D, 1,25(OH)2D and sex as explanatory variables to determine the effect of each covariate on the response variable. For subjects <38 years, 25(OH)D was the most important parameter in regulating PTH. For subjects ≥38 both 25(OH)D and Ca2+ levels regulated PTH secretion. Subjects with 25(OH)D < 13 ng/mL had average higher PTH; in this group only, subjects with Ca2+ ≥ 1.30 mmol/L had average lower PTH compared to subjects with Ca2+ < 1.30. The multivariate analysis showed that all variables had a significant effect (p < 0.001) on PTH. Anova Type III errors c indicated that 25(OH)D accounted for 32.1% of the total variance in PTH, Ca2+ accounted for 18% of the total variance, BMI for 14.3%, and 1,25(OH)2D for 11.1%. The remaining percentage was attributable to age and sex. This was confirmed by the regression tree approach, where 25(OH)D and Ca2+ accounted for the largest variation in the average levels of PTH. DISCUSSION: Under stable conditions 25(OH)D plays a significant role in regulating PTH secretion. Under conditions of relative vitamin D sufficiency, Ca2+ also plays an important role.

Reduction of arrhythmias in primary hyperparathyroidism, by parathyroidectomy, evaluated with 24-h ECG monitoring.

OBJECTIVE: Hypercalcemia may induce arrhythmias. There are no data on the prevalence of arrhythmias in primary hyperparathyroidism (PHPT) in daily life. Aim of the study was to investigate both the prevalence of arrhythmias in patients with PHPT compared to controls and the impact of parathyroidectomy, evaluated by 24-h electrocardiogram (ECG) monitoring. DESIGN: This is a randomized study. METHODS: Twenty-six postmenopausal women with PHPT and 26 controls were enrolled. PHPT patients were randomized to two groups: 13 underwent parathyroidectomy (Group A) and 13 were followed up conservatively (Group B). After 6 months, patients were studied again. Each patient underwent mineral metabolism biochemical evaluation, bone mineral density measurement, standard ECG and 24-h ECG monitoring. RESULTS: PHPT patients showed higher calcium and parathyroid hormone compared to controls and a higher prevalence of both supraventricular (SVBPs) and ventricular premature beats (VPBs) during 24-h ECG monitoring. Groups A and B showed no differences in mean baseline biochemical values and ECG parameters. Mean value of QTc in PHPT groups was in the normal range at baseline, but significantly shorter than controls. A negative correlation was found between QTc and ionized calcium levels (r = -0.48, P < 0.05). After parathyroidectomy, Group A had a significant reduction in SVPBs and VPBs compared to baseline and restored normal QTc. Group B showed no significant changes after a 6-month period. CONCLUSIONS: The increased prevalence of SVPBs and VPBs is significantly reduced by parathyroidectomy, and it is mainly related to the short QTc caused by hypercalcemia.