Salvatore Minisola

Short and Long-Term Variations in Serum Calciotropic Hormones after a Single Very Large Dose of Ergocalciferol (Vitamin D2) or Cholecalciferol (Vitamin D3) in the Elderly

CONTEXT In humans, few studies have compared the potencies of ergocalciferol and cholecalciferol in improving and maintaining vitamin D status. OBJECTIVE Our objective was to evaluate the effects of a single very large dose of both calciferols on serum changes of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], ionized calcium, and parathyroid hormone (PTH) at baseline, and at 3, 7, 30, and 60 d. DESIGN This was a prospective randomized intervention study. SETTING The study was performed in a nursing home residence. PARTICIPANTS A total of 32 elderly female patients (age range 66-97 yr), with vitamin D deficiency was included in the study. INTERVENTION Participants were randomized into four groups of eight to receive a single dose of 300,000 IU ergocalciferol or cholecalciferol by oral (os) or im route. RESULTS 25(OH)D levels sharply increased at d 3 only when vitamins were given os. The 30-d basal difference in serum 25(OH)D was significantly greater after cholecalciferol os administration (47.8 +/- 7.3 ng/ml) compared with other forms (D(3) im: 15.9 +/- 11.3; D(2) os: 17.3 +/- 4.7; D(2) im: 5 +/- 4.4; all P < 0.001). The area under the curve (AUC) of the serum 25(OH)D against time (AUC(60)) was: D(3) os, 3193 +/- 759 ng x d/ml vs. D(2) os, 1820 +/- 512, P < 0.001; and D(3) im, 1361 +/- 492 vs. D(2) im, 728 +/- 195, P < 0.01. 25(OH)D significantly influences PTH levels at 3 (P < 0.03), 7 (P < 0.01), 30 (P < 0.01), and 60 d (P < 0.05). At 60 d, the form of vitamin (cholecalciferol) significantly lowers PTH levels (P = 0.037). CONCLUSIONS Cholecalciferol is almost twice as potent as ergocalciferol in increasing serum 25(OH)D, when administered either by mouth or im. 25(OH)D plays a role in modulating serum PTH.

Determinants of adherence to osteoporosis treatment in clinical practice

IntroductionPoor adherence to prescribed treatments is widespread in clinical practice and this can lead to potentially life-threatening events. This problem is apparently very common for osteoporosis treatment but the causes of discontinuation and low compliance are complex and poorly defined.MethodsGlobal adherence to osteoporosis treatment was specifically addressed in a nation-wide survey carried out in 9851 postmenopausal women referred to 141 Italian centres for osteoporosis management for a follow-up assessment, at least one year after having been prescribed a treatment with one of the following drugs: calcium±vitamin D supplements alone (CaVitD), hormone replacement therapy (HRT), raloxifene 60 mg (RLX), intramuscular clodronate 100 mg/7-14 days (CLOD), risedronate 5 mg/day (RIS) and alendronate 10mg/daily (ALN10) or 70 mg once weekly (ALN OW).ResultsOverall 19.1% of the patients discontinued the prescribed drug before attending the bone mass re-evaluations, more than half of them within the first 6 months. The discontinuation rate was significantly different between the treatments. The medications most frequently interrupted within one year were CLOD (28.7%; p<0.01 versus any other treatment), while by far the least interrupted was ALN-OW (6.9%; p<0.001 versus any other treatment). The most frequent reasons for discontinuation were drug related side effects, insufficient motivation to treatment and fear of side effects. The prevalence of the reasons for discontinuation were different among treatments: safety concerns were very common for HRT, lack of motivation was the most common cause for CaVitD and CLOD, and drug related side effects for RIS, ALN and RLX. Persistence to treatment was significantly higher in patients with previous vertebral fractures, densitometric osteoporosis, on corticosteroid or anti-inflammatory treatments. A significantly increased risk of treatment interruption was found among patients on benzodiazepine or gastro-protective agents and in patients in whom a bone measurement was not readily available. The highest compliance to recommended dosing was observed with ALN OW and HRT (p<0.001 versus any other) and the lowest for CaVitD (p<0.01 versus any other). Poor treatment compliance (<50% drug taken) was significantly related to benzodiazepine and gastroprotective use, while a significantly better compliance was associated with recognized risk factors for osteoporosis: early menopause, low bone mass values values, previous vertebral fractures. The poorest adherence was observed when treatments were prescribed by General practitioners (GPs), and orthopaedic surgeons (p<0.01 versus global mean).ConclusionsThe results of this large survey of Italian osteoporotic women indicates that the most important determinant of both persistence and compliance to treatment is the type of drug prescribed with a definite advantage of ALN-OW. Treatment compliance is particularly poor for CaVitD and this emphasizes the need for new ways to supplement at least vitamin D. The main reasons for discontinuation are side effects and lack of motivation while the best treatment adherence was observed in patients with severe and well documented osteoporosis.

Effects of salmon calcitonin in postmenopausal osteoporosis: A controlled double-blind clinical study

SummaryIn this paper we present the results of a 12-month double-blind clinical multicenter study assessing the effects of synthetic salmon cacitonin (CT) administration in a group of white postmenopausal osteoporotic women. Treated patients were given 100 MRC units of synthetic salmon CT injected i.m. in the morning every other day. Control patients received a placebo injection. All patients received 500 mg of elementary calcium p.o., b.i.d. Bone mineral content (BMC) was measured at the extreme distal radius of the nondominant arm by a dual photon bone densitometer which utilizes two radionuclides,241Am and125I, with energies of about 60 keV and 30 keV respectively. Biochemical parameters of calcium-phosphorus metabolism were also measured. After 12 months of treatment a significant mean increment of BMC and nondialyzable OHPr/creatinine values and a significant decrease of total OHPr/creatinine values were observed in the treated group, while controls showed a significant decrease in BMC values. These results, together with the observation that in some patients the decrease in total OHPr/creatinine values was not accompanied by an increment of BMC, show that long-term salmon CT treatment may be of benefit in postmenopausal osteoporosis and that the effects of CT on bone mass may be due not only to the inhibition of bone resorption but also to the stimulation of bone formation.

Longitudinal Evaluation of Vitamin D Status in Healthy Subjects from Southern Italy: Seasonal and Gender Differences

Abstract: Vitamin D status is currently considered among the relevant determinants of skeletal integrity. Since vitamin D levels present seasonal variations, we longitudinally studied young healthy men and women in order to investigate the related physiologic modifications of both calcium homeostasis and bone remodeling. Thirty-two men (mean age 39.4 ± 7.8 years) and 58 premenopausal women (aged 36.9 ± 6.4 years) from southern Italy were studied. In all subjects the following parameters were measured both in winter and in summer: serum calcium, phosphorus, creatinine, total alkaline phosphatase activity, 25-hydroxyvitamin D (25OHD), parathyroid hormone (PTH), osteocalcin (BGP), together with urinary calcium (Ca/Cr), total pyridinoline (Pyr/Cr) and deoxypyridinoline (d-Pyr/Cr), corrected for creatinine excretion. In both sexes 25OHD levels were significantly higher in summer, while PTH values were lower, than in winter. The prevalence of hypovitaminosis D, defined by concentrations of 25OHD lower than 30 nmol/l, was 17.8% in winter and 2.2% in summer in the whole sample, while it was 27.8% and 3.4%, respectively, among female subjects. Indeed male subjects did not display hypovitaminosis D, having throughout the year significantly higher calcium and 25OHD levels together with lower PTH values, than the women. Moreover, alkaline phosphatase total activity was more elevated in men both in winter and in summer. In women, during winter, bone remodeling markers levels were higher while urinary calcium levels were lower than in summer. In the whole sample serum 25OHD correlated positively with serum calcium and inversely with PTH. The seasonal percentage variations in PTH were inversely correlated with those of Ca/Cr. Our results show a relatively high prevalence of subclinical vitamin D deficiency among young healthy women from southern Italy. Significant gender-specific differences have been demonstrated in both calcium homeostasis and skeletal remodeling indexes; the seasonal fluctuations in the vitamin D–PTH axis are accompanied by cyclical variations of bone turnover rate, which were more pronounced in women.

Fat-free mass and fat mass reference values by dual-energy X-ray absorptiometry (DEXA) in a 20–80 year-old Italian population

BACKGROUND & AIMS To establish reference values for limb composition, fat-free mass (FFM) and fat mass (FM) in Italian adults for gender-specific age brackets 20-80 years old and to assess age-related regional changes in body composition. METHODS A multicenter, retrospective study was conducted on 1571 healthy subjects, 1240 women and 331 men. Regional FFM and FM were measured by dual-energy X-ray absorptiometry. FM was expressed as % of limb weight. RESULTS FFM in men diminished with age in both arms and legs, with reference ranges (25th -75th percentile) of 3.8-4.6 kg and 10.4-12.2 kg, respectively for 20-29 year-olds, and 3.1-3.9 kg and 8.2-10.4 kg for 70-79 year-olds. Womens arm FFM remained stable with aging (reference values 1.7-2.2 kg), decreasing in their legs (6.2-7.2 kg for 20-29 year-olds, 5.5-6.5 kg for 70-79 year-olds). Limb FM% increased with age in both genders: the reference values were 9-15% (arms) and 12-21% (legs) for 20-29 year-old men, and 19-26% and 19-29%, respectively, for 70-79 year-olds; for womens arms, they were 25-36% for 20-29 year-olds and 36-48% for 70-79 year-olds, while their leg FM remained the same with aging, i.e. 32-40%. CONCLUSIONS These data complete the published reference values for whole body composition, enabling physiological or pathological changes in limb composition to be identified in Caucasian populations living in the Mediterranean area.

Current Issues in the Presentation of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Fourth International Workshop

OBJECTIVE This report summarizes data on traditional and nontraditional manifestations of primary hyperparathyroidism (PHPT) that have been published since the last International Workshop on PHPT. PARTICIPANTS This subgroup was constituted by the Steering Committee to address key questions related to the presentation of PHPT. Consensus was established at a closed meeting of the Expert Panel that followed. EVIDENCE Data from the 5-year period between 2008 and 2013 were presented and discussed to determine whether they support changes in recommendations for surgery or nonsurgical follow-up. CONSENSUS PROCESS Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was undertaken. After extensive review and discussion, the subgroup came to agreement on what changes in the recommendations for surgery or nonsurgical follow-up of asymptomatic PHPT should be made to the Expert Panel. CONCLUSIONS 1) There are limited new data available on the natural history of asymptomatic PHPT. Although recognition of normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism) is increasing, data on the clinical presentation and natural history of this phenotype are limited. 2) Although there are geographic differences in the predominant phenotypes of PHPT (symptomatic, asymptomatic, normocalcemic), they do not justify geography-specific management guidelines. 3) Recent data using newer, higher resolution imaging and analytic methods have revealed that in asymptomatic PHPT, both trabecular bone and cortical bone are affected. 4) Clinically silent nephrolithiasis and nephrocalcinosis can be detected by renal imaging and should be listed as a new criterion for surgery. 5) Current data do not support a cardiovascular evaluation or surgery for the purpose of improving cardiovascular markers, anatomical or functional abnormalities. 6) Some patients with mild PHPT have neuropsychological complaints and cognitive abnormalities, and some of these patients may benefit from surgical intervention. However, it is not possible at this time to predict which patients with neuropsychological complaints or cognitive issues will improve after successful parathyroid surgery.

Subclinical Hypercortisolism among Outpatients Referred for Osteoporosis

Context The Cushing syndrome is a well-recognized secondary cause of osteoporosis. Contributions The researchers looked for hypercortisolism in asymptomatic patients referred for osteoporosis testing. They identified 7 patients with the condition. Six had functioning adrenal masses and 1 had an adrenocorticotropic hormonesecreting pituitary adenoma. The prevalence of subclinical hypercortisolism among patients with T-scores of 2.5 or less and vertebral fractures was 10.8%. Caution The findings come from a referral setting and might not apply to patients in the community. Implication Subclinical hypercortisolism may be more common than is generally recognized in patients with osteoporosis. The Editors Hypercortisolism is a frequent cause of secondary osteoporosis (1). Overt endogenous hypercortisolism (Cushing syndrome) is a well-recognized cause of osteoporosis (2), but because its prevalence in the general population is low (1 per 500000 persons) (2), its contribution to osteoporosis in general populations is trivial. The terms subclinical Cushing syndrome and subclinical hypercortisolism describe altered adrenocorticotropic hormone (ACTH)cortisol homeostasis without the classic signs or symptoms of the Cushing syndrome (3). Subclinical hypercortisolism is more common than overt hypercortisolism, with an estimated prevalence of about 0.8 per 1000 individuals in the general population (3); however, this prevalence is probably underreported because of the lack of symptoms or signs in these patients (37). Several cross-sectional and longitudinal studies have suggested that these patients are at high risk for complications of hypercortisolism, such as diabetes and osteoporosis (816). Recent studies have indicated that subclinical hypercortisolism is more prevalent than previously thought in patients with type 2 diabetes (1719). However, studies on the prevalence of subclinical hypercortisolism in patients with osteoporosis are lacking. Some evidence suggests that osteoporotic fractures may be the presenting manifestations of otherwise-asymptomatic hypercortisolism (20). Moreover, a recent paper showed a difference in cortisol secretion between healthy participants and patients with established osteoporosis, possibly due to mild autonomous cortisol hypersecretion in some individuals (21). Thus, the prevalence of subclinical hypercortisolism in patients with osteoporosis may be underestimated. We therefore designed a study to assess the prevalence of subclinical hypercortisolism in patients referred to our outpatient clinics for evaluation of osteoporosis. Methods Setting and Participants The study was done at the Casa Sollievo della Sofferenza Scientific Institute, San Giovanni Rotondo, Foggia, Italy, and the San Giuseppe-Fatebenefratelli Hospital, Fatebenefratelli Research Association, Milan, Italy, from January 2005 to December 2005. We recruited 219 consecutive patients (200 women and 19 men) referred to our outpatient clinics for prevention or diagnosis and treatment of osteoporosis and who met the following inclusion criteria: 1) absence of any known secondary causes of osteoporosis (that is, past or current thyrotoxicosis, bowel disease, precocious or surgical menopause, chronic renal failure, chronic hepatic disease, eating disorders, or rheumatologic or hematologic disease); 2) absence of depression and alcoholism, which may enhance cortisol secretion; 3) no administration of drugs influencing bone, cortisol, and dexamethasone metabolism or cortisol secretion; and 4) no signs or symptoms of cortisol excess, including moon facies, striae rubrae, skin atrophy, or buffalo hump. All participants signed consent forms, and local ethical committees approved the study in accordance with the second Declaration of Helsinki. Testing Sequence The Figure shows the study flow diagram. All patients had spinal and femoral dual-energy x-ray absorptiometry and spinal radiography. They had outpatient testing for secondary causes of osteoporosis (general chemistry profile, calcium homeostasis measurements [serum calcium, phosphorus, alkaline phosphatase total activity, 24-hour urinary calcium], thyroid-stimulating hormone, antigliadin antibodies, and serum testosterone in men) and blood for cortisol measurement drawn at 8:00 a.m. after a 1-mg overnight dexamethasone suppression test. Participants with altered thyroid-stimulating hormone levels were tested for free thyroxine, antithyroglobulin, and antithyroperoxidase antibodies; those with high serum calcium levels were tested for serum parathyroid hormone. In patients with normal antigliadin antibodies but clinical suspicion of celiac disease, antiendomysial antibodies were also measured. Figure. Study flow diagram. All patients were subdivided on the basis of bone mineral density (BMD) (T-score of 2.5 or less [low BMD] or greater than 2.5 [normal BMD]) and vertebral fractures. ACTH = adrenocorticotropic hormone; Fx+ = presence of vertebral fractures; Fx = absence of vertebral fractures. Participants with serum cortisol levels greater than 50.0 nmol/L after the 1-mg overnight dexamethasone suppression test were hospitalized for further diagnostic investigations (case participants). Those with cortisol levels less than 50.0 nmol/L had no further evaluation, but antiosteoporotic therapy was started in those with osteoporosis. Among hospitalized patients, catheters were inserted in the forearm vein on the day of admission, and blood testing began the day after to avoid stress-related hypopituitaryadrenal axis activation due to venipuncture. Because inpatient status can in theory increase cortisol secretion (19), a control group of inpatients was recruited to estimate the prevalence of subclinical hypercortisolism in hospitalized participants (control participants). This group comprised 56 age- and sex-matched inpatients without diabetes, osteoporosis, or vertebral fractures who were consecutively hospitalized from January 2005 to December 2005. All hospitalized participants had serum cortisol levels measured at 9:00 a.m. after 2 days of low-dose (0.5 mg every 6 hours) dexamethasone suppression and at midnight, 2 measurements of 24-hour urinary free cortisol, and measurement of ACTH at 8:00 a.m. Subclinical hypercortisolism was diagnosed if participants had incomplete suppression of cortisol (>50.0 nmol/L) after the low-dose dexamethasone suppression test and a 24-hour urinary free cortisol level greater than 165.6 nmol/d (normal range, 22.2 to 165.6 nmol/d) and/or midnight cortisol level greater than 207 nmol/L (normal range, 0.0 to 138.5 nmol/L) (3, 7, 8, 2123). The cutoff value of 165.6 nmol/d for urinary free cortisol corresponds to the 97th percentile value of 70 healthy control participants (20 men and 50 women; age, 35 to 65 years; body mass index, 20 to 40 kg/m2) who were recruited in our center as a reference population for urinary free cortisol. The cutoff value of 207.0 nmol/L for midnight cortisol is the standard for diagnosing hypercortisolism when overt Cushing syndrome is clinically suspected (2). Terzolo and colleagues (24) proposed a cutoff value of 148.8 nmol/L for diagnosing subclinical hypercortisolism, but we used the greater value because we lack reference midnight cortisol values in our center and wanted to increase specificity. Participants with subclinical hypercortisolism and an ACTH level of 2.2 pmol/L or less (normal range, 1.1 to 11.0 pmol/L) had abdominal computed tomography. Patients with subclinical hypercortisolism and ACTH levels greater than 2.2 pmol/L had abdominal computed tomography, nuclear magnetic resonance of the pituitary region, and additional biochemical tests (serum cortisol measurement after 8-mg overnight dexamethasone suppression and serum ACTH and cortisol measurement after stimulation with corticotropin-releasing hormone). Whole-body computed tomography was done when an ectopic source of ACTH hypersecretion was suspected (25). Subclinical hypercortisolism in patients with type 2 diabetes can be attributed mainly to adrenal masses (19). Because incidentally discovered adrenal lesions (adrenal incidentalomas) are frequently found in otherwise-healthy persons (4), we performed abdominal computed tomography in a subset of patients who tested positive after the 1-mg overnight dexamethasone suppression test but were classified as having no subclinical hypercortisolism. Testing Procedures In all patients, bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (Hologic Discovery, Bedford, Massachusetts) at the spine (in vivo precision at L1 to L4, 1.0%) and total and femoral neck (in vivo precision, 1.8% and 2.3%, respectively). Individual BMD values were expressed as SD units (T-scores) relative to the reference population of our center, which included 382 healthy female participants (26). Conventional spinal radiographs in lateral (T4 to L4) and anteroposterior (L1 to L4) projections were obtained in all participants by using a standard technique. Two trained radiologists who were blinded to BMD and hormonal data independently reviewed the radiographs. Vertebral fractures were diagnosed on visual inspection by using the semiquantitative method described by Genant and colleagues (27), in which fractures assessed on lateral thoracolumbar spine radiographs were defined as a reduction of more than approximately 20% in anterior, middle, or posterior vertebral height. Fractures were graded by severity and were graded as I, II, or III on the basis of the height reduction (20% to 25%, 25% to 40%, or >40%, respectively). The radiologists discussed questionable cases for consensus on a diagnosis; the interrater reliability between the 2 radiologists was good (= 0.85). The 2-day, low-dose dexamethasone suppression test was done after ACTH, 24-hour urinary free cortisol, and midnight cortisol levels were measured. Every 6 hours, 0.5 mg of dexamethasone was administrated orally, and serum cortisol was measured at 9:00 a.m., 4

Fracture Incidence and Characterization in Patients on Osteoporosis Treatment: The ICARO Study

None of the available osteoporosis therapies have been shown to completely abolish the risk of fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that observed in randomized clinical trials, and it was significantly related to poor compliance and lack of supplementation with calcium and vitamin D.

Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients

The present study aimed to investigate the prevalence and seasonal variation of hypovitaminosis D (defined as serum 25-hydroxyvitamin D level below 30 nmol/l) among healthy subjects and hospitalized patients living in central Italy. We studied 297 subjects, 131 in February 1997 and 166 in July 1997, subdivided into four groups: (a) young healthy blood donors; (b) healthy postmenopausal women; (c) inpatients with various medical diseases and (d) inpatients engaged in long-term rehabilitation programmes because of various neurological disorders. In all subjects and patients serum levels of 25-hydroxyvitamin D were measured by radioimmunoassay. We found a significant seasonal variation (P < 0.0001) of serum 25-hydroxyvitamin D levels, mean values being higher in summer in all groups, except in patients with a longer hospitalization time (group (d)). In each group, a significantly higher prevalence of hypovitaminosis D was found in winter compared with summer time (P < 0.001), being unexpectedly high in postmenopausal women (winter 32% and summer 4.5%); furthermore, in both seasons, inpatients were characterized by the highest incidences of hypovitaminosis, particularly those in group (d) (winter 82.3% and summer 57.8%). The results of the present study emphasize the importance of 25-hydroxyvitamin D measurement, and the need to increase vitamin D intake in Italy; foodstuff fortification and supplement use must be considered in order to prevent negative effects of vitamin D deficiency on skeletal integrity.

Clinical usefulness of serum tartrate-resistant acid phosphatase activity determination to evaluate bone turnover

The study was carried out to evaluate the clinical validity and usefulness of serum tartrate-resistant acid phosphatase (TRAP) activity determined using an improved spectrophotometric assay. Enzyme activity was measured in 84 normal subjects and in 109 patients with common metabolic bone diseases. Mean values of serum TRAP activity in male subjects (n = 19; 10.4 +/- 2.15 U l-1) were not significantly different from those found in female subjects (n = 65; 10.8 +/- 1.8 U l-1). In the latter group mean values were significantly raised in post-menopausal subjects (10.5 +/- 2.0 U l-1; p less than 0.01) compared with mean values in pre-menopausal women (8.45 +/- 1.8 U l-1). We found a significant inverse correlation between serum TRAP activity values and bone mineral density (BMD) measured both at an ultradistal radial point (n = 33, r = -0.506; p less than 0.01), and at the lumbar spine (n = 57, r = -0.261; p less than 0.05). Mean serum TRAP activity values in patients with metabolic bone diseases were: primary hyperparathyroidism, n = 30: 14.2 +/- 4.89 U l-1, p less than 0.001 vs normal subjects; chronic maintenance haemodialysis, n = 19: 17.4 +/- 6.7, p less than 0.001; metastatic cancer, n = 13: 21.2 +/- 6.3, p less than 0.001; post-surgical hypoparathyroidism, n = 10: 9.9 +/- 1.8, NS; involutional osteoporosis, n = 20: 12.5 +/- 2.3 p less than 0.001; Pagets disease, n = 10: 16.8 +/- 3.5, p less than 0.001; osteomalacia, n = 7: 19.5 +/- 3.31, p less than 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)