Impairment in muscle strength and its determinants in primary hyperparathyroidism: A study in postmenopausal women.

Neuromuscular impairment is described among the non-classical complications of primary hyperparathyroidism (PHPT). However, the extent of this complications and related mechanisms have not been fully addressed. The study aimed at assessing muscle strength and its main determinants in postmenopausal women with PHPT. We studied 48 postmenopausal women with PHPT (mean age 60.8 ± 5.6 SD years; BMI 25.6 ± 5.5 kg/m2) and 38 healthy postmenopausal women (mean age 58.6 ± 5.9; BMI 25.2 ± 3.5). In all subjects, the maximum voluntary contraction (MVC, Newton, N) was measured by Hand held Dynamometer (Kayser Italia srl, Livorno, Italy) and the lumbar spine, total hip, femoral neck, and non dominant distal one-third radius areal BMD (aBMD) by dual X-ray absorptiometry (DXA) (Hologic, Waltham, MA). Serum ionized calcium (Ca++), parathyroid hormone (PTH), phosphorus (P), and 25-hydroxyvitaminD [25(OH)D] levels were measured in both groups. A subgroup of 30 PHPT women agreed to participate to the follow-up sub-study and were re-assessed 24 months after parathyroidectomy (n = 15) or after baseline evaluation (n = 15). Patients with PHPT had significant lower MVC values compared to healthy women (p < 0.001). As expected, serum Ca++ and PTH levels were higher and P lower in PHPT compared to controls. We observed a significant association between MVC and total hip and one-third radius aBMD (R = 0.320 and 0.370, p < 0.05) and negative association with Ca++ (R = -0.340, p < 0.05) in the PHPT group; MVC was positively associated with one-third radius aBMD (R = 0.360, p < 0.05) and negatively with age, BMI and myostatin (R = -0.390, -0.340 and -0.450, p < 0.05) in the group of healthy women. The linear model using BMI, Ca++, P, 25(OH)D, PTH, myostatin, and aBMD as covariates showed that one-third radius aBMD was positively associated with MVC in PHPT patients (p < 0.02) and in healthy subjects (p < 0.001). Additionally, serum PTH and myostatin were negatively associated with MVC in healthy subjects (p < 0.03 and p < 0.01). The linear model showed that surgery was associated with an increase in MVC (p < 0.05) in PHPT patients after 24 months, all other variables being equal and by controlling for baseline values of MVC. Handgrip strength is significantly impaired in postmenopausal women with PHPT. Some common mechanisms influencing muscle function exist in PHPT and in healthy subjects; they are associated with the reduced aBMD at cortical sites. Hypercalcemia seems to be one of the main determinants of impairment in muscle strength in PHPT, while no role is played by myostatin.

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.

Imaging technologies in the differential diagnosis and follow-up of brown tumor in primary hyperparathyroidism: Case report and review of the literature.

Brown tumors are osteolytic lesions associated with hyperparathyroidism (HPT). They may involve various skeletal segments, but rarely the cranio-facial bones. We report a case of a young boy with a swelling of the jaw secondary to a brown tumor presenting as the first manifestation of primary HPT (PHPT). He was found to have brown tumor located in the skull, as well. Different imaging technologies were employed for the diagnosis and follow-up after parathyroidectomy. We enclose a review of the literature on the employment of such imaging technologies in the differential diagnosis of osteolytic lesions. A multidisciplinary approach comprising clinical, laboratory and imaging findings is essential for the differential diagnosis of brown tumor in PHPT.

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.

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.

Understanding and managing secondary osteoporosis.

INTRODUCTION: The term secondary osteoporosis (SO) identifies a reduction of bone mass related to a well-established disease or pharmacological agent. The identification of the underlying disease often represents a challenging situation in clinical practice. AREAS COVERED: The prevalence of SO in the real world may vary, ranging from 17% to 80%; therefore, search for a form of SO represents a pillar when evaluating patients with osteoporosis. Guidelines for treatment of specific secondary forms of osteoporosis, such as glucocorticoid-induced osteoporosis, have been published even though often neglected in clinical practice. For the majority of SO, there are currently no specific guidelines concerning treatment with only few trials showing the effect of bone-active drugs on fracture risk reduction. EXPERT OPINION: Healthcare professionals should be aware of the secondary forms of osteoporosis, in particular when the reason for reduced skeletal resistance is uncertain or when bone mineral density results are unsatisfactory in a patient compliant to therapy. In a few cases (such as, for example: no response to therapy, better classification of bone involvement in patients with kidney failure, suspicion of rare metabolic bone disease) bone biopsy is needed to investigate the patient. This review highlights recent advances in understanding and managing SO.

Retinal micro-vascular and aortic macro-vascular changes in postmenopausal women with primary hyperparathyroidism.

Aim of the study was to evaluate the micro and macro-vascular changes in patients with primary hyperparathyroidism (PHPT) compared to controls. 30 postmenopausal PHPT women (15 hypertensive and 15 normotensive) and 30 normotensive controls underwent biochemical evaluation of mineral metabolism and measurements of arterial stiffness by 24 hour ambulatory blood pressure monitoring. Retinal microcirculation was imaged by a Retinal Vessel Analyzer. PHPT patients also underwent bone mineral density measurements and kidney ultrasound. PHPT patients had higher mean calcium and parathyroid hormone values compared to controls. Evaluating macro-vascular compartment, we found higher values of 24 hours-systolic, diastolic blood pressure, aortic pulse wave velocity (aPWV) and aortic augmentation index (Aix) in hypertensive PHPT, but not in normotensive PHPT compared to controls. The eye examination showed narrowing arterial and venular diameters of retinal vessels in both hypertensive and normotensive PHPT compared to controls. In hypertensive PHPT, 24 hours systolic blood pressure was associated only with parathyroid hormone (PTH) levels (beta = 0.36, p = 0.04). aPWV was associated with retinal diameter (beta = -0.69, p = 0.003), but not with PTH. Retinal artery diameter was associated with PTH (beta = -0.6, p = 0.008). In the normotensive PHPT, only PTH was associated with retinal artery diameter (beta = -0.60, p = 0.01) and aortic AIx (beta = 0.65, p = 0.02). In conclusion, we found macro-vascular impairment in PHPT and that micro-vascular impairment is negatively associated with PTH, regardless of hypertension in PHPT.

Comparative Effect of rhPTH(1-84) on Bone Mineral Density and Trabecular Bone Score 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. © 2018 American Society for Bone and Mineral Research.

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.

Oral calcidiol is a good form of vitamin D supplementation.

Vitamin D supplementation represents an important topic in the field of metabolic bone disease. Calcidiol, the 25-hydroxy-vitamin D [25(OH)D], is the form of vitamin D most recently introduced in clinical practice. Advantages of the use of calcidiol derive from the pharmacokinetic properties and are related to the possibility of use in patients with liver disease, obese patients, patients with intestinal malabsorption, secondary hyperparathyroidism associated with chronic kidney disease as well as to avoid any possible toxic effect when high doses are used. The ADDI-D study demonstrated the efficacy and safety of calcidiol at the daily dose of 20 or 40 µg and 125 µg/week. In particular, the daily dose of 40 µg can be suggested as an alternative in severely deficient patients, as it has demonstrated to ensure higher vitamin D levels, compared to the 20 µg/day and the weekly 125 µg dose. The last can be an option when issues with compliance to the supplementation are present.

Cardiovascular manifestations of primary hyperparathyroidism: a narrative review.

Data on cardiovascular disease in primary hyperparathyroidism (PHPT) are controversial; indeed, at present, cardiovascular involvement is not included among the criteria needed for parathyroidectomy. Aim of this narrative review is to analyze the available literature in an effort to better characterize cardiovascular involvement in PHPT. Due to physiological effects of both parathyroid hormone (PTH) and calcium on cardiomyocyte, cardiac conduction system, smooth vascular, endothelial and pancreatic beta cells, a number of data have been published regarding associations between symptomatic and mild PHPT with hypertension, arrhythmias, endothelial dysfunction (an early marker of atherosclerosis), glucose metabolism impairment and metabolic syndrome. However, the results, mainly derived from observational studies, are inconsistent. Furthermore, parathyroidectomy resulted in conflicting outcomes, which may be linked to several potential biases. In particular, differences in the methods utilized for excluding confounding co-existing cardiovascular risk factors together with differences in patient characteristics, with varying degrees of hypercalcemia, may have contributed to these discrepancies. The only meta-analysis carried out in PHPT patients, revealed a positive effect of parathyroidectomy on left ventricular mass index (a predictor of cardiovascular mortality) and more importantly, that the highest pre-operative PTH levels were associated with the greatest improvements. In normocalcemic PHPT, it has been demonstrated that cardiovascular risk factors are almost similar compared to hypercalcemic PHPT, thus strengthening the role of PTH in the cardiovascular involvement. Long-term longitudinal randomized trials are needed to determine the impact of parathyroidectomy on cardiovascular diseases and mortality in PHPT.

The Epidemiology of Hypoparathyroidism in Italy: An 8-Year Register-Based Study.

Hypoparathyroidism is a rare endocrine disorder, but few studies have focused on the epidemiology and hospital management of the disease and none has been performed in Italy. We investigated the prevalence of different forms of hypoparathyroidism among hospitalized patients in Italy during an 8-year period. This study is designed as a retrospective register-based study. We retrieved data from the "Record of Hospital Discharge" (SDO) of the Italian Health Ministry, from the year 2006 to 2013 and analyzed the codes corresponding to hypoparathyroidism-related diagnoses. The inpatient prevalence of the disease was also calculated after excluding repeated hospitalizations. Overall, 27,692 hospitalization episodes for hypoparathyroidism were identified during the entire period (72.2% in women and 27.8% in men; mean age 49.5 ± 22.9 years). The mean length of stay was 7.4 ± 9.8 days (25.9% of the episodes requiring less than 3 days of stay). The mean hospitalization rate for hypoparathyroidism was 5.9/100,000 inhabitants per year and there was a significant decrease during the period of 2006-2013 (p < 0.0001). The mean hospitalization rate for postsurgical hypoparathyroidism was 1.4/100,000 inhabitants per year and the trend showed a significant reduction during the years (p < 0.0001). The mean prevalence of hypoparathyroidism among inpatients was 5.3/100,000 inhabitants per year, and there was a significant decrease over the years (p < 0.0001). Hypoparathyroidism, particularly the postsurgical form of the disease, is not an uncommon condition among hospitalized patients in Italy. We observed a tendency to a decrease in the frequency of hospitalization during the period 2006-2013.

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.

Acute effect of zoledronic acid on the risk of cardiac dysrhythmias.

There have been recent concerns regarding the risk of serious adverse events, such as cardiac dysrhythmia and atrial fibrillation (AF), associated with bisphosphonate use in osteoporosis. This open-label, non-randomized, crossover pilot study evaluated short-term effects of zoledronic acid and placebo on the occurrence of cardiac dysrhythmias and prodysrhythmic profile in postmenopausal women with osteoporosis and low risk of cardiac dysrhythmias. Fifteen postmenopausal women (mean age 70.7 ± 6.9 years) with osteoporosis received placebo infusion on day 1 and zoledronic acid 5 mg on day 7. Standard 12-lead resting EKG measured QT parameters at baseline and up to 24 h after infusion. Continuous 24-h EKG assessed dysrhythmic events and heart rate variability (HRV) for 24 h after infusion. There were no statistically significant differences in resting EKG parameters between placebo and zoledronic acid: QTc (404.28 ± 9.28 and 410.63 ± 18.43 ms), no significant differences in mean serum electrolytes at baseline and after infusion, and no significant association between QT/QTc parameters and serum electrolytes before and after each infusion (QTc: 401.83 ± 17.73 for zoledronic acid and 404.65 ± 16.79 for placebo). There was no significant difference in HRV parameters between placebo and zoledronic acid, and no dysrhythmias were recorded at rest or with 24 h EKG monitoring. Zoledronic acid does not produce dysrhythmia or prodysrhythmic effects in the short term. Among possible mechanisms proposed for cardiac dysrhythmias with zoledronic acid, no serum electrolyte or autonomous nervous system balance perturbations have been reported.

Hospital care for primary hyperparathyroidism in Italy: a 6-year register-based study.

OBJECTIVE: Primary hyperparathyroidism (PHPT) is one of the most frequently diagnosed endocrine disorders, but few studies have focused on hospital management of the disease in Europe. We investigated the frequency of hospital admission for diagnosis and surgical treatment of PHPT in Italy. DESIGN: A retrospective study was conducted for investigating the hospital care for PHPT in Italy. METHODS: We retrieved data from the 'Record of Hospital Discharge' of the Italian Health Ministry, from 2006 to 2011, and analyzed the codes corresponding to PHPT-related diagnoses and surgical procedures. RESULTS: Overall, 46 275 hospitalization episodes for PHPT were identified during the entire period (69% in women and 31% in men; mean age 63.3±39.8 years). Patients' mean age significantly increased during the years (P<0.001). The mean length of stay was 8.2±10.5 days (28% of the episodes requiring <3 days of stay). Admissions for surgical procedures were 12 457 accounting for 26.9% of the total hospitalizations. There was a trend to a significant increase in the percentage of surgery (P<0.05). The mean hospitalization rate for PHPT was 12.9/100 000 inhabitants per year and the trend showed a significant decrease during the period of 2006-2011 (P<0.0001). The mean hospitalization rate for PHPT surgery was 3.65/100 000 per year, which significantly increased over time (P<0.001). CONCLUSIONS: PHPT considerably influences the Italian Hospital healthcare system. We observed a tendency to a decrease in the frequency of hospitalization during the period of 2006-2011, most probably because of economic issues, a concomitant increased age of patients, and, interestingly, also a progressive increase in the percentage of surgical treatment among patients admitted for PHPT.