High serum osteopontin levels are associated with prevalent fractures and worse lipid profile in post-menopausal women with type 2 diabetes.

PURPOSE: Patients with type 2 diabetes (T2DM) have increased fracture risk. Osteopontin (OPN) is a protein involved in bone remodeling and inflammation. The aim of this study was to evaluate the association of OPN with fracture prevalence and with metabolic parameters in post-menopausal women with T2DM. METHODS: Sixty-four post-menopausal women with T2DM (age 67.0 ± 7.8 years, diabetes duration 8.9 ± 6.7 years), enrolled in a previous study, were followed up (3.6 ± 0.9 years). Previous fragility fractures were recorded. The FRAX score (without BMD) was calculated and biochemical parameters (plasma glucose, HbA1c, lipid profile and renal function) were assessed. Serum 25OH-vitamin D, calcium, PTH and OPN were evaluated at baseline. The association between OPN and fracture prevalence at baseline was evaluated by a logistic model. RESULTS: OPN levels were higher in patients with previous fractures (n.25) than in patients without previous fractures at baseline (n.39) (p = 0.006). The odds of having fractures at baseline increased by 6.7 (1.9-31.4, 95% CI, p = 0.007) for each increase of 1 ng/ml in OPN levels, after adjustment for vitamin D and HbA1c levels. Fracture incidence was 4.7%. Higher OPN associated with a decrease in HDL-cholesterol (p = 0.048), after adjustment for age, basal HDL-cholesterol, basal and follow-up HbA1c and follow-up duration. 25OH-vitamin D associated with an increase in FRAX-estimated probability of hip fracture at follow-up (p = 0.029), after adjustment for age, 25OH-vitamin D and time. CONCLUSIONS: In post-menopausal women with T2DM, OPN might be a useful marker of fracture and worse lipid profile.

Bone involvement and mineral metabolism in Williams' syndrome.

CONTEXT: The previous studies suggested a possible increased risk of hypercalcaemia and reduced bone mineral density (BMD) in Williams' syndrome (WS). However, an extensive study regarding bone metabolism has never been performed. OBJECTIVE: To investigate bone health in young adults with WS. DESIGN: Cross-sectional study. SETTINGS: Endocrinology and Metabolic Diseases and Medical Genetic Units. PATIENTS: 29 WS young adults and 29 age- and sex-matched controls. MAIN OUTCOME MEASURES: In all subjects, calcium, phosphorus, bone alkaline phosphatase (bALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHVitD), osteocalcin (OC), carboxyterminal cross-linking telopeptide of type I collagen (CTX), 24-h urinary calcium and phosphorus, femoral-neck (FN) and lumbar-spine (LS) BMD and vertebral fractures (VFx) were assessed. In 19 patients, serum fibroblast growth factor-23 (FGF23) levels were measured. RESULTS: WS patients showed lower phosphorus (3.1 ± 0.7 vs 3.8 ± 0.5 mg/dL, p = 0.0001) and TmP/GFR (0.81 ± 0.32 vs 1.06 ± 0.25 mmol/L, p = 0.001), and an increased prevalence (p = 0.005) of hypophosphoremia (34.5 vs 3.4%) and reduced TmP/GFR (37.9 vs 3.4%). Moreover, bALP (26.3 ± 8.5 vs 35.0 ± 8.0 U/L), PTH (24.5 ± 12.6 vs 33.7 ± 10.8 pg/mL), OC (19.4 ± 5.3 vs 24.5 ± 8.7 ng/mL), and FN-BMD (- 0.51 ± 0.32 vs 0.36 ± 0.32) were significantly lower (p < 0.05), while CTX significantly higher (401.2 ± 169.3 vs 322.3 ± 122.4 pg/mL, p < 0.05). Serum and urinary calcium and 25OHVitD levels, LS-BMD and VFx prevalence were comparable. No cases of hypercalcemia and suppressed FGF23 were documented. Patients with low vs normal phosphorus and low vs normal TmP/GFR showed comparable FGF23 levels. FGF23 did not correlate with phosphorus and TmP/GFR values. CONCLUSIONS: Adult WS patients have reduced TmP/GFR, inappropriately normal FGF23 levels and an uncoupled bone turnover with low femoral BMD.

Voltage-Gated Sodium Channels: Evolutionary History and Distinctive Sequence Features.

Voltage-gated sodium channels (Nav) are responsible for the rising phase of the action potential. Their role in electrical signal transmission is so relevant that their emergence is believed to be one of the crucial factors enabling development of nervous system. The presence of voltage-gated sodium-selective channels in bacteria (BacNav) has raised questions concerning the evolutionary history of the ones in animals. Here we review some of the milestones in the field of Nav phylogenetic analysis and discuss some of the most important sequence features that distinguish these channels from voltage-gated potassium channels and transient receptor potential channels.

Bone damage in type 2 diabetes mellitus.

This review focuses on the mechanisms determining bone fragility in patients with type 2 diabetes mellitus (T2DM). Despite bone mineral density (BMD) is usually normal or more often increased in these patients, fracture incidence is high, probably because of altered bone "quality". The latter seems to depend on several, only partly elucidated, mechanisms, such as the increased skeletal content of advanced glycation end-products causing collagen deterioration, the altered differentiation of bone osteogenic cells, the altered bone turnover and micro-architecture. Disease duration, its severity and metabolic control, the type of therapy, the presence or absence of complications, as like as the other known predictors for falls, are all relevant contributing factors affecting fracture risk in T2DM. In these patients the estimate of fracture risk in the everyday clinical practice may be challenging, due to the lower predictive capacity of both BMD and risk factors-based algorithms (e.g. FRAX).

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.

Vitamin D and parameters of calcium homeostasis in inpatients with and without Type 2 diabetes mellitus.

AIM: We investigated inpatients with and without Type 2 diabetes mellitus, aged over 60 yr, to compare their vitamin D status and calcium homeostatic parameters. MATERIALS AND METHODS: We studied 140 patients consecutively admitted to our Internal Medicine Unit during the year 2010 (61 from November to April, 79 from May to October). The sample encompassed 70 patients with and 70 without diabetes. At admission we measured serum calcium (Ca), phosphate (P), sodium (Na), potassium (K), creatinine (Cr), alkaline phosphatase total activity (AP), albumin adjusted serum calcium (Caalb adj), 25 hydroxy-vitamin D (25OHD), PTH, and 24-h urinary Na/Cr (uNa/Cr), K/Cr (uK/Cr), Ca/Cr (uCa/Cr), P/Cr (uP/Cr) ratios, and calcium excretion (Ca ex). RESULTS: 25OHD levels of patients with and without diabetes did not significantly differ. In patients without diabetes recruited from November to April, 25OHD levels were significantly lower than those from May to October, whilst patients with diabetes did not show a significant seasonal variation. PTH had opposite non-significant seasonal variations, and negatively correlated with 25OHD in both groups of patients. This correlation was lost after adjusting for age and body mass index in patients with diabetes. These inpatients had higher serum P and lower uP/Cr, according to lower PTH. Their serum glucose negatively correlated with uCa/Cr and Ca ex, contrary to inpatients with other diseases. Instead, uCa/Cr and Ca ex correlated with uNa/Cr only in patients without diabetes. CONCLUSIONS: Inpatients with diabetes did differ from those with other disorders for vitamin D status and calcium-phosphate homeostatic mechanism.

Carboxyl-terminal parathyroid hormone fragments: biologic effects.

Carboxyl-terminal PTH fragments (C-PTH), are generated by both direct secretion from parathyroids in relation to serum calcium levels and catabolism of PTH operated by the Kupffer cells in the liver. These molecular fragments have been till recently regarded as inert byproducts of PTH metabolism, since they do not interact with the PTH/PTH-related peptide (rP) receptor, which mediates the classical hormone actions. Current findings instead indicate that C-PTH would interact with a putative C-PTH receptor. This way, C-PTH seem to exert specific effects on calcium homeostasis and bone metabolism, opposite to those of the synthetic agonist of PTH/PTHrP receptor (i.e. PTH 1-34). In vitro and in vivo data actually indicate that C-PTH, by interacting with specific receptors, could have an anti-calcemic action, as well as a pro-apoptotic effect on both osteocytes and osteoclasts. This in turn could result in a reduced activity of the latter cells, with a consequent inhibition of bone resorption.

Sporadic and hereditary primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, particularly frequent in post-menopausal women. It is characterized by hypercalcemia with inappropriately high spontaneous plasma PTH. Singlegland adenoma is the most common cause (75- 85%). PHPT is usually a sporadic disease but in approximately <5% of cases, a familial hyperparathyroid syndrome is diagnosed. Familial hyperparathyroidism is a clinically and genetically heterogeneous group of disorders including: multiple endocrine neoplasia (MEN) type 1, MEN type 2A, MEN4, benign familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism. These syndromes show mendelian inheritance patterns and the main genes for most of them have been defined. The classic form of PHPT, which presents with hypercalcemia, kidney stones, and bone disease, is no longer common. Currently, there is an increasing interest in the subtle manifestations of PHPT, particularly the cardiovascular and neuropsychiatric manifestations. Parathyroidectomy is the definitive cure for PHPT even though patients with the asymptomatic form of the disease can be followed conservatively.

[Guidelines on prevention and treatment of vitamin D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS)]. / Linee guida su prevenzione e trattamento dell'ipovitaminosi D con colecalciferolo. SIOMMMS.

The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has elaborated the following guidelines about the definition, prevention and treatment of inadequate vitamin D status. The highlights are presented here. Daily vitamin D allowance ranges from 1,500 IU (healthy adults) to 2,300 IU (elderly with low calcium intake). Since the average Italian diet includes around 300 IU/day, subjects with no effective sun exposure should be supplemented with 1,200-2,000 IU vitamin D per day. The serum 25-hydroxy-vitamin D [25(OH)D] levels represents the most accurate way to assess vitamin D repletion, even though there are still no standardized assay methods. Conditions of "deficiency" and "insufficiency" are defined by the following ranges of 25(OH)D levels: less than 20 ng/ml and 20-30 ng/ml, respectively. In Italy, approximately 50% of young healthy subjects have vitamin D insufficiency during the winter months. The prevalence of deficiency increases with ageing, affecting almost all elderly subjects not on vitamin D supplements. When a condition of deficiency has been identified, a cumulative dose of 300,000-1,000,000 IU, over 1-4 weeks is recommended. In subjects recently treated for deficiency-insufficiency, a maintenance dose of 800-2,000 IU/day (or weekly equivalent) is recommended. In patients on daily doses over 1,000 IU, 25(OH)D levels should be checked regularly (e.g. once every two years). The highest tolerated daily dose has been identified as 4,000 IU/day. Vitamin D supplementation should be carefully monitored in patients at higher risk of vitamin D intoxication (granulomatosis) or with primary hyperparathyroidism. In pregnant women, vitamin D supplements should be given as in non-pregnant women, but bolus administration (i.e.: single dose >25,000 IU) should be avoided.

Prevalence of less severe hypercortisolism in fractured patients admitted in an outpatient clinic for metabolic bone diseases.

PURPOSE: To evaluate the prevalence of less severe hypercortisolism (LSH) in fractured patients, and its association with hypertension, hyperglicemia, dyslipidemia, and obesity. METHOD: From July 2015 to October 2018 we enrolled all fractured patients admitted in our outpatient center for metabolic bone diseases, after exclusion of patients with secondary osteoporosis apart from diabetes and taking drugs known to affect bone metabolism. In all enrolled patients we collected data regarding gonadal status, history of diabetes, high blood pressure, dyslipidemia, and measured blood pressure, lipid profile, fasting glycaemia. Bone mass was measured with DXA at lumbar spine and femoral neck and the presence of fractures was evaluated with X-ray of thoracic and lumbar spine. All patients performed twice, 1 mg overnight dexametasone suppression test (DST) and, as confirmatory, 2day low-dose DST for diagnosing hypercortisolism. RESULTS: We enrolled 101 fractured patients (75 females, 26 males), aged 65 ± 10.3 years. Five out of 101 (5.0%) patients were diagnosed as LSH. Fifty-five (54.5%) out of 101 were hypertensive, 57 (56.4%) dyslipidemic, 17 (16.8%) hyperglicaemic, 28(27.7%) obese patients. LSH tended to be associated to blood hypertension [5/5 vs 50/96 (Fisher exact test, p = 0.06) hypertensive patients]. Four out five LSH patients were hypogonadic. CONCLUSIONS: Our study confirms that a nonnegligible percentage of fractured subjects actually presents an unrecognized hypercortisolism. Accordingly, regardless of age, we suggest to screen for hypercortisolism all patients with established osteoporosis and in particular hypertensive subjects.

Structural aspects of the solvation shell of lysine and acetylated lysine: A Car-Parrinello and classical molecular dynamics investigation.

Lysine acetylation is a post-translational modification, which modulates the affinity of protein-protein and/or protein-DNA complexes. Its crucial role as a switch in signaling pathways highlights the relevance of charged chemical groups in determining the interactions between water and biomolecules. A great effort has been recently devoted to assess the reliability of classical molecular dynamics simulations in describing the solvation properties of charged moieties. In the spirit of these investigations, we performed classical and Car-Parrinello molecular dynamics simulations on lysine and acetylated-lysine in aqueous solution. A comparative analysis between the two computational schemes is presented with a focus on the first solvation shell of the charged groups. An accurate structural analysis unveils subtle, yet statistically significant, differences which are discussed in connection to the significant electronic density charge transfer occurring between the solute and the surrounding water molecules.

Skeletal involvement in adult patients with endogenous hypercortisolism.

Overt endogenous glucocorticoid excess is a well-recognized cause of bone loss and osteoporotic fractures. Cortisol excess inhibits bone formation, increases bone resorption, impairs calcium absorption from the gut, and affects the secretion of several hormones (in particular gonadotropins and GH), cytokines, and growth factors, influencing bone metabolism. The glucocorticoid excess mainly affects trabecular bone, leading to vertebral fractures in up to 70% of patients. Osteoporotic fractures may be the presenting symptom of an otherwise silent glucocorticoid excess and can precede the diagnosis of hypercortisolism by up to 2 yr. The removal of glucocorticoid excess leads to a recovery of bone mass which is, however, often incomplete and delayed, although it reduces the risk of osteoporotic fractures. Bisphosphonate therapy has been suggested to be useful in maintaining bone mass in these patients. Subclinical hypercortisolism, a condition of impaired hypothalamic- adrenal-axis homeostasis without the classical signs and symptoms of glucocorticoid excess, is a recently defined entity, which has been shown to be associated to increased bone resorption, bone loss, and high prevalence of vertebral fractures regardless of gonadal status. However, data about the effect of this subtle glucocorticoid excess on bone are still scarce and conflicting. Moreover, it is not yet known whether removing the cause of subclinical hypercortisolism leads to a recovery of bone mass and reduces the risk of osteoporotic fractures. Finally, recent data suggest that subclinical hypercortisolism is a common and underrated finding in patients with established osteoporosis. In summary, it is crucial to evaluate the risk of osteoporosis and fractures in patients with glucocorticoid excess; on the other hand, it also seems advisable to screen for glucocorticoid excess patients with osteoporotic fractures without known secondary causes of osteoporosis.

Skeletal turnover, bone mineral density, and fractures in male chronic abusers of alcohol.

BACKGROUND: Chronic alcohol abuse is a risk factor for osteoporosis and fractures, whose pathogenesis is still unclear. We investigated the influence of alcoholism and other risk factors on calcium and skeletal metabolism, bone mineral density (BMD), and fractures. MATERIALS AND METHODS: In 51 chronic male alcoholics without liver failure and 31 healthy controls, serum total and ionised calcium, phosphate, creatinine, 25-hydroxy vitamin D (25OHD), PTH, total (ALP) and bone-specific (BALP) alkaline phosphatase, osteocalcin (BGP), carboxy-terminal telopeptide of type I collagen (beta-CTx), osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B ligand (RANKL) were assessed. In patients only, we also measured serum testosterone, 17-beta estradiol, LH, and IGF-I. BMD was measured by dual energy x-ray absorptiometry at lumbar spine (LS-) and femur [neck (FN-) and total hip (TF-)]. Vertebral fractures were identified by a semiquantitative method on thoraco-lumbar spine x-ray, non-vertebral fractures (as life-style factors) by history. RESULTS: Alcoholics were leaner, had significantly higher ALP and BALP, and lower BGP and 25OHD levels than controls. No significant difference in other calcium and bone metabolism parameters was found. OPG/RANKL ratio was significantly higher in alcoholics. Beta-CTx negatively correlated with abuse duration. OPG positively correlated with daily alcohol assumption and with indexes of liver cytolysis. Though LS-, FN- and TF-BMD of alcoholics and controls did not significantly differ, patients had a much higher prevalence of vertebral fractures. The same was found considering both vertebral and non-vertebral fractures. CONCLUSIONS: Ethanol-induced skeletal damage seems mainly dependent on negative effects on bone formation. Lifestyle factors and traumas likely contribute to the high fracture incidence of alcohol abusers, independently of BMD.

Platelet activation in patients with colorectal cancer.

Aspirin may reduce the risk of colorectal neoplasia at doses similar to those recommended for the prevention of cardiovascular disease. Thus, we aimed to address whether enhanced platelet activation, as assessed by the measurement of the urinary excretion of 11-dehydro-TXB(2) (a major enzymatic metabolite of TXB(2)), occurs in patients with colorectal cancer. In 10 patients with colorectal cancer, the urinary excretion of 11-dehydro-TXB(2) was significantly higher than in 10 controls, matched for sex, age and cardiovascular risk factors [1001(205-5571) versus 409(113-984) pg/mg creatinine, respectively, median (range), P<0.05]. The administration of aspirin 50 mg daily for 5 consecutive days to colorectal cancer patients caused a cumulative inhibition of platelet cyclooxygenase (COX)-1 activity either ex vivo, as assessed by the measurement of serum TXB(2) levels, or in vivo, as assessed by urinary 11-dehydro-TXB(2) excretion. In conclusion, enhanced platelet activation occurs in colorectal cancer patients. Permanent inactivation of platelet COX-1 by low-dose aspirin might restore anti-tumor reactivity.

[Primary hyperparathyroidism]. / Iperparatiroidismo primitivo.

Primary hyperparathyroidism (PHPT) is characterized by excessive PTH secretion in respect to calcium homeostasis needs, due to parathyroid adenoma (80% of cases), hyperplasia (15-20%), or carcinoma (1-2%). In familial forms of PHPT, several mutations have an established role: menin gene for MEN type 1, RET for MEN type 2a, calcium-sensing receptor gene for familial hypocalciuric hypercalcemia, parafibromin gene for PHPT-jaw tumour and carcinoma. Etiology of sporadic adenomas (80% of PHPT cases) is less defined, being most commonly found a mutation of menin gene or activation of PRAD1 oncogene. In recent years, the classical features of the disease became less common. Typically, bone involvement is now represented by a reduced bone mass at skeletal sites more rich in cortical tissue. Prominently trabecular skeletal sites are relatively spared, because of the anabolic effects of a slight PTH excess on trabecular tissue. PHPT patients may have increased fracture risk, though it is not clear why bone damage is more severe in a subgroup of patients. Clinical features of hypercalcemia may be fatigue, anorexia, thirst, and polyuria. Vague neurological and psychiatric symptoms, such as weakness, anxiety, depression, paresthesias, and muscular cramps may ameliorate after parathyroidectomy. Recent reports indicate increased cardiovascular mortality in PHPT patients. Diagnosis is based on the detection of hypercalcemia, together with inappropriately high serum PTH levels. Preoperative localization of the diseased glands is mandatory in persistent or recurrent PHPT, as like as when minimally invasive surgery is planned. High resolution ultrasonography and SPECT double-phase 99m Tc-sestamibi scintigraphy are the most commonly employed techniques. Intraoperatory PTH assay may confirm successful surgery when serum concentrations decrease more than 50%. Surgical therapy is indicated in patients with renal or skeletal complications, such as in those with previous parathyrotoxic crisis. Many surgeons in recent years adopted minimally invasive parathyroidectomy. Medical treatment is an option for patients unwilling or unfitted for surgery because of severe concomitant diseases. Employed therapy includes estrogens, SERMs, bisphosphonates and calcimimetics.

Skeletal involvement in female acromegalic subjects: the effects of growth hormone excess in amenorrheal and menstruating patients.

Bone involvement is a common clinical feature in acromegalic patients, though previous studies gave divergent results possibly because of the different gonadal status of the patients studied. To study the influence of estrogen milieu in these patients, we evaluated 23 acromegalic patients with active disease, subdivided into two groups: menstruating and amenorrheal patients, comparable for duration and activity of disease. Forty-two matched women served as controls. Skeletal involvement was studied by measuring: (a) the main biomarkers of bone turnover: serum alkaline phosphatase total activity (AP), bone GLA protein (BGP), serum carboxy-terminal propeptide of type I collagen (PICP), serum type I cross-linked N-telopeptide (ICTP), and urinary pyridinoline and deoxypyridinoline corrected for creatinine (Pyr/Cr, D-Pyr/Cr) and urinary calcium/creatinine ratio (Ca/Cr); (b) bone mineral density (BMD), as measured by quantitative computed tomography both at lumbar spine and distal radius, and by dual X-ray absorptiometry both at lumbar spine and at three femoral sites (Ward's triangle, femoral neck, and great trochanter). AP, BGP, ICTP, Pyr/Cr, D-Pyr/Cr were significantly higher in patients than in controls, independent of the menstrual pattern. Higher PICP levels were found in the whole group and in menstruating acromegalics when compared with control women; no difference was found in amenorrheal patients, who in turn showed higher urinary Ca/Cr values. When patients were considered all together, BMD at spine, femoral neck, and trochanter was higher than in controls. In contrast, when the gonadal status was taking into account and, menstruating and amenorrheal subjects were considered separately, BMD at spine, but not in other sites, was significantly higher in menstruating patients than in controls. In contrast, no difference of BMD values at any site was observed between amenorrheal patients and controls. The mean BMD Z scores allowed us to detect an unequal involvement of different skeletal sites. Our results show that bone turnover is increased in acromegalic women and suggest that GH anabolic effect on bone is more evident in the presence of estrogens and that different skeletal sites may be affected differently by hormone excess.

Bone loss rate in adrenal incidentalomas: a longitudinal study.

Although by definition patients with adrenal incidentalomas (AI) do not have evident clinical syndromes, they may frequently suffer from subclinical hypercortisolism (SH). This is of some importance because of evidence that SH may lead to clinical complications, including bone loss. Thus, the understanding of bone involvement due to SH may be extremely important in the management of AI. Unfortunately, the available data on bone mineral density (BMD) in AI patients come from cross-sectional studies, which, to further complicate our understanding, are also conflicting, probably due to a different selection of patients and/or the variability in cortisol secretion (CS) often described in AI. To gain further insight about this topic, we performed a longitudinal study evaluating the rate of spinal and femoral bone loss levels in 24 females with AI. AI subjects were subdivided in two groups on the basis of the median of urinary cortisol secretion (UFC): group I (n = 12; UFC, <140.4 nmol/24 h) and group II (n = 12; UFC, >140.4 nmol/24 h). Spinal BMD was measured by both single energy quantitative computed tomography (L1-L4) and dual energy x-ray absorptiometry (DXA; L2-L4), and femoral BMD was determined by DXA. Bone loss rate was expressed as the change in z-score per yr. The spinal bone loss rate was higher (P < 0.005) in group II than in group I when measured by both quantitative computed tomography (-0.19 +/- 0.14 vs. 0.00 +/- 0.15) and DXA (-0.19 +/- 0.17 vs. 0.00 +/- 0.11). Moreover, CS and spinal bone loss rate were significantly correlated when patients were considered together. In conclusion, our data show that 1) AI patients with higher CS have increased lumbar trabecular bone loss rate than those with lower CS; and 2) the degree of spinal bone loss rate is related to the degree of CS. Thus, lumbar spine (LS) BMD has to be evaluated for well balanced decision-making on the treatment of choice for AI female patients.

Altered bone mass and turnover in female patients with adrenal incidentaloma: the effect of subclinical hypercortisolism.

The strategy of treatment for patients with adrenal incidentalomas (AI) may depend upon the presence of hormonal hypersecretion. Although alterations of bone turnover have been recently reported, data on bone mineral density (BMD) are not available in AI patients. We evaluated bone turnover and BMD in 32 female AI patients and 64 matched controls. Spinal and femoral BMD were similar in patients and controls. Serum bone GLA protein (6.8+/-3.5 vs. 8.8+/-3.2 ng/mL; P<0.005) and PTH (48.8+/-15.1 vs. 37.2+/-10.9 pg/mL; P<0.0001) were different in patients and controls. Patients were then subdivided into 2 groups: with (n = 8; group A) or without (n = 24; group B) subclinical hypercortisolism. PTH was higher (P<0.05) in group A than in group B and in both groups than in controls (57.1+/-13.6, 46.0+/-14.8, and 37.2+/-10.9 pg/mL, respectively), and bone GLA protein was lower in group A than in group B and controls (3.8+/-2.3, 7.5+/-3.1, and 8.8+/-3.2 ng/mL, respectively; P<0.05). Serum type I cross-linked C telopeptide and fasting urinary deoxypyridinoline/ creatinine were not different in the three groups. BMD at each site was lower (P<0.05) in group A than in group B and controls. Bone mass and metabolism are altered in AI patients with subclinical hypercortisolism and should be taken into account, therefore, when addressing the treatment of choice for these patients.

Alterations of bone turnover and bone mass at different skeletal sites due to pure glucocorticoid excess: study in eumenorrheic patients with Cushing's syndrome.

The aim of the present investigation was to study the effect of glucocorticoid excess on bone mass and turnover not influenced by other diseases known to affect skeleton and/or by different gonadal status and sex. We studied several markers of bone turnover and bone mineral density (BMD) by both quantitative computed tomography (at spine and forearm) and dual x-ray absorptiometry (at spine and three femoral sites) in 18 eugonadal female patients affected by Cushing's syndrome (CS) compared to 24 eugonadal healthy female subjects matched for age and body mass index. In CS patients, serum bone Gla protein, a marker of osteoblastic function, was reduced (3.28 +/- 2.3 vs. 6.47 +/- 2.5; P < 0.01), and bone resorption was increased, as indicated by increased urinary hydroxyproline (36.6 +/- 12 vs. 29.0 +/- 9.1, P < 0.05) and urinary deoxypyridinoline (22.1 +/- 8.0 vs. 16.4 +/- 6.3; P < 0.05). BMD was significantly (P < 0.05 or P < 0.01) reduced at all sites, except cortical forearm, in CS patients compared to controls. By comparing z-scores of reduced BMD in CS patients, spinal trabecular BMD was found to be the most severely affected. Furthermore, disease activity, as measured by urinary free cortisol, was significantly correlated with bone Gla protein (r = -0.57; P < 0.02), urinary hydroxyproline (r = 0.57; P < 0.02), urinary deoxypyridinoline (r = 0.48, P < 0.05), and BMD measured at spine and femur. Our results show that compared to matched control subjects, female eumenorrheic CS patients have reduced osteoblastic function, increased bone resorption, and reduced BMD, and that the severity of these abnormalities is statistically related to the severity of disease activity, as indicated by urinary free cortisol. Moreover, our data suggest a site and tissue specificity of the effect of glucocorticoid excess on bone mass.

Parathyroid storm: immediate recognition and pathophysiological considerations.

A 56-year-old white man was referred for evaluation of severe hypercalcemia following a three-week history of progressive weakness, nausea, and depression. Initial laboratory results showed serum total and ionized calcium (Ca++) values of 5.3 and 2.6 mmol/l, respectively. A short intact PTH assay was immediately performed and an extremely high value was obtained in just 30 min (1315 ng/l, normal values 6.4-70.4). The patient was therefore treated with saline solution and with salmon calcitonin (1200 IU/day, half by continuous i.v. infusion and half by i.m. route) for 10 days. There was a sudden decrease of both Ca++ and intact PTH during the first six days; then there was a trend to reach a steady-state until parathyroidectomy was performed. After withdrawal of calcitonin therapy it was possible to observe a positive uncoupling between bone formation (serum alkaline phosphatase and osteocalcin) and resorption (serum tartrate-resistant acid phosphatase) markers. On day 35 the patient underwent neck exploration, and an enlarged lower left parathyroid gland was removed that on macroscopic examination revealed the presence of a haemorrhagic cyst; microscopic appearance was suggestive of a previous glandular infarction. This is the first time the daily clinical course of a parathyroid crisis has been documented. Furthermore, changes of biomarkers of bone turnover following calcitonin therapy show that high doses of the hormone may cause a prolonged positive uncoupling of the two processes of bone remodeling.