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.
Elisabetta Romagnoli, Jessica Pepe, Sara Piemonte, Cristiana Cipriani and Salvatore Minisola
Salvatore Minisola, Elisabetta Romagnoli, Liliana Scarnecchia, Rossana Rosso, Maria T Pacitti, Antonella Scarda and Gianfranco Mazzuoli
Minisola S, Romagnoli E, Scarnecchia L, Rosso R, Pacitti MT, Scarda A, Mazzuoli G. Serum carboxyterminal propeptide of human type I procollagen in patients with primary hyperparathyroidism: studies in basal conditions and after parathyroid surgery. Eur I Endocrinol 1994;130:587–91. ISSN 0804-4643
This study was carried out in order to evaluate serum carboxy-terminal propeptide of human type I procollagen (PICP) in patients with primary hyperparathyroidism and to examine its changes following parathyroidectomy. Seventeen patients (four males and 13 famels, aged 53.8 ± 3.1 sem years) were studied in basal conditions; six patients also were investigated after successful parathyroid surgery. Mean serum PICP values of patients with primary hyperparathyroidism (194.5 ± 27 sem μg/l) were significantly higher (p < 0.001) with respect to those found in normal subjects. However, deviations from the norm (Z score values) were significantly less with respect to deviations of serum osteocalcin, alkaline phosphatase and urinary hydroxyproline/creatinine ratio. Following parathyroidectomy, it was possible to observe a discrepancy between markers of bone resorption and those of bone formation. The former tend to decrease, while the latter either do not show any significant change (serum alkaline phosphatase and serum osteocalcin) or increase (serum procollagen). The results of our investigation indicate that in basal conditions the assay of serum procollagen may be of clinical value but it would be better to use it in combination with other biomarkers of skeletal remodelling. The results obtained after parathyroidectomy are the opposite of those obtained following parathyroid hormone infusion and should be ascribed to the effect of acute hormone deficiency on collagen synthesis. The positive biochemical uncoupling following surgery might lend support to the rise of bone mineral density consistently reported in the first few months following parathyroidectomy.
S Minisola, Istituto di II Clinical Medica, Policlinico Umberto I, Via del Policlinico 155, 00161 Rome, Italy
Jessica Pepe, Cristiana Cipriani, Chiara Sonato, Orlando Raimo, Federica Biamonte and Salvatore Minisola
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.
Salvatore Minisola, Cristiana Cipriani, Daniele Diacinti, Francesco Tartaglia, Alfredo Scillitani, Jessica Pepe and David Scott-Coombes
Primary hyperparathyroidism (PHPT) is one of the most frequent endocrine diseases worldwide. Surgery is the only potentially curable option for patients with this disorder, even though in asymptomatic patients 50 years of age or older without end organ complications, a conservative treatment may be a possible alternative. Bilateral neck exploration under general anaesthesia has been the standard for the definitive treatment. However, significant improvements in preoperative imaging, together with the implementation of rapid parathyroid hormone determination, have determined an increased implementation of focused, minimally invasive surgical approach. Surgeons prefer to have a localization study before an operation (both in the classical scenario and in the minimally invasive procedure). They are not satisfied by having been referred a patient with just a biochemical diagnosis of PHPT. Imaging studies must not be utilized to make the diagnosis of PHPT. They should be obtained to both assist in determining disease etiology and to guide operative procedures together with the nuclear medicine doctor and, most importantly, with the surgeon. On the contrary, apart from minimally invasive procedures in which localization procedures are an obligate choice, some surgeons believe that literature on parathyroidectomy over the past two decades reveals a bias towards localization. Therefore, surgical expertise is more important than the search for abnormal parathyroid glands.
Simona De Geronimo, Elisabetta Romagnoli, Daniele Diacinti, Emilio D’Erasmo and Salvatore Minisola
Objective: To evaluate the prevalence of vertebral (vFr) and non-vertebral (nvFr) fractures in postmenopausal women with primary hyperparathyroidism (PHPT).
Materials and Methods: We studied 98 patients with PHPT, divided into ‘mild’ (M, n = 25) and ‘non-mild’ (NM, n = 73) sub-groups, according to recently published guidelines (2002), and 89 healthy women (C) matched for age, years since menopause and body mass index. vFr was evaluated according to a visual semiquantitative method; bone mineral density (BMD) at the lumbar spine (LS), and femoral sites (femoral neck, FN and total femur, FT) was measured by dual energy X-ray absorptiometry. Volumetric BMD of the third lumbar vertebra (vBMDL3) was also calculated.
Results: The prevalence of vFr was significantly higher (P < 0.001) in both M and NM PHPT patients compared with C; this prevalence did not differ between M and NM patients. BMD was significantly lower (P < 0.05) in NM patients compared with both C and M patients. BMD at LS in M patients was also significantly higher with respect to C. Similar results were also obtained for vBMDL3; in M patients, vBMDL3 was also significantly higher compared to C. When M and NM patients were subdivided according to the presence or lack of vFr, no difference was found between fractured and unfractured patients for either BMD or vBMDL3 values.
Conclusions: The risk of vFr is higher in postmenopausal patients with mild PHPT even if BMD appears well preserved. This finding suggests that other factors, such as bone quality, seem to be relevant in determining fracture risk, especially when gonadal function is lacking.
Salvatore Minisola, Luciano Colangelo, Cristiana Cipriani, Jessica Pepe, Dana Paulina Cook and Chantal Mathieu
Few topics have elicited more emotion than the issue of screening for vitamin D status and the discussion on the need for global supplementation with vitamin D metabolites. The importance of the problem is highlighted by the USPSTF posted draft research plan with the aim of making an update recommendations statement, possibly next year. Here, we discuss two different viewpoints on screening for vitamin D status: for and against. In the literature there are scientifically sound opinions supporting pro and cons positions. However, we believe that the best way to definitively elucidate this issue is the implementation of a randomized controlled trial evaluating clinical outcomes or harms in persons screened versus those not screened for vitamin D deficiency. The feasibility of such a trial is probably questionable owing to uncertainties still present concerning threshold for vitamin D sufficiency and end points (that is, for example, improved bone mineral density, reduced risk of falls and so on) to be reached.
Sara Piemonte, Elisabetta Romagnoli, Cristiana Cipriani, Federica De Lucia, Roberta Pilotto, Daniele Diacinti, Jessica Pepe and Salvatore Minisola
Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by hypophosphatemia and inappropriately normal or low 1,25-dihydroxyvitamin D.
Here, we report a 6-year postoperative follow-up of a patient with oncogenic osteomalacia with a distinctive skeletal manifestation. The latter was characterized by an almost linear lytic lesion of a few millimeters with irregular borders, mainly involving the trabecular compartment but extending into cortical shell, located in the middle third of the right fibula. Six years after tumor resection, a sclerotic repair with a complete recovery was observed. Furthermore, we monitored a striking increase in bone mineral density throughout the observation period, reaching a peak of 73% over basal values at lumbar spine after 2 years; at total femur and radius, the peak was 47.5 and 4.6% respectively, after 4 years from tumor resection.
We report for the first time that an osteolytic lesion may be part of the skeletal involvement in tumor-induced osteomalacia.
Cristiana Cipriani, Vincenzo Carnevale, Federica Biamonte, Sara Piemonte, Jessica Pepe, Luciano Nieddu, John P Bilezikian and Salvatore Minisola
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.
A retrospective study was conducted for investigating the hospital care for PHPT in Italy.
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.
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).
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.
Jessica Pepe, Daniele Diacinti, Emanuela Fratini, Italo Nofroni, Antonella D’Angelo, Roberta Pilotto, Claudio Savoriti, Luciano Colangelo, Orlando Raimo, Mirella Cilli, Cristiana Cipriani and Salvatore Minisola
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.
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.
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/cm2, 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.
We found a higher prevalence and severity of AAC in PHPT related to parathyroid hormone effect.
Antonio Stefano Salcuni, Vincenzo Carnevale, Claudia Battista, Serena Palmieri, Cristina Eller-Vainicher, Vito Guarnieri, Flavia Pugliese, Giuseppe Guglielmi, Gaetano Desina, Salvatore Minisola, Iacopo Chiodini and Alfredo Scillitani
Patients with primary aldosteronism (PA) have a high prevalence of osteoporosis (OP) and fractures (Fx). We evaluated the presence of PA in patients admitted to our metabolic bone disease outpatient clinic.
Study conducted on an in- and outpatient basis in a referral Italian endocrinology unit.
A total of 2632 patients were evaluated. 2310 were excluded because they were taking drugs known to affect bone or mineralocorticoids metabolism or were diagnosed to have a secondary cause of osteoporosis. The remaining 322 subjects (304 females, 18 males) took part in the study. Bone mineral density (BMD) and thoracic and lumbar spine vertebral morphometry were performed by dual X-ray absorptiometry. All patients were screened for PA with aldosterone-to-renin ratio. In those who had positive results, confirmatory tests were performed.
Among 322 subjects, 213 were osteoporotics and 109 were not. PA was diagnosed in eleven out of 213 osteoporotic patients (5.2%) and one out of 109 non-osteoporotic subjects (0.9%, P = 0.066). PA was observed in the 26.1% of patients with the concomitant presence of osteoporosis, hypertension and hypercalciuria. Compared with patients without PA, patients with PA had mean values of urinary calcium excretion, 4.8 ± 2.5 mmol/day vs 7.6 ± 3.2 mmol/day, P < 0.001 and serum PTH levels, 5.4 pmol/L vs 7.3 pmol/L, P < 0.01, significantly higher.
PA should be considered among the causes of secondary OP.