25-Hydroxycholecalciferol response to single oral cholecalciferol loading in the normal weight, overweight, and obese.

UNLABELLED: After a single cholecalciferol load, peak serum 25-hydroxycholecalciferol (25OHD) is lower in individuals with a higher body mass index (BMI), probably due to it being distributed in a greater volume. Its subsequent disappearance from the serum is slower the higher the individual's BMI, probably due to the combination of a larger body volume and a slower release into the circulation of vitamin D stored in adipose tissue. INTRODUCTION: The aim of the study is to examine 25-hydroxycholecalciferol (25OHD) response to a single oral load of cholecalciferol in the normal weight, overweight, and obese. METHODS: We considered 55 healthy women aged from 25 to 67 years (mean ± SD, 50.8 ± 9.5) with a BMI ranging from 18.7 to 42 kg/m(2) (mean ± SD, 27.1 ± 6.0). The sample was divided into three groups by BMI: 20 were normal weight (BMI ≤ 25 kg/m(2)), 21 overweight (25.1 ≤ BMI ≤ 29.9 kg/ m(2)), and 14 obese (BMI ≥ 30 kg/m(2)). Each subject was given 300,000 IU of cholecalciferol orally during lunch. A fasting blood test was obtained before cholecalciferol loading and then 7, 30, and 90 days afterwards to measure serum 25OHD, 1,25 dihydroxyvitamin D [1,25 (OH)2D], parathyroid hormone (PTH), calcium (Ca), and phosphorus (P). Participants' absolute fat mass was measured using dual energy X-ray absorptiometry (DEXA). RESULTS: The fat mass of the normal weight subjects was significantly lower than that of the overweight, which in turn was lower than that of the obese participants. Serum 25OHD levels increased significantly in all groups, peaking 1 week after the cholecalciferol load. Peak serum 25OHD levels were lower the higher the individuals' BMI. After peaking, the 25OHD levels gradually decreased, following a significantly different trend in the three groups. The slope was similar for the overweight and obese, declining significantly more slowly than in the normal weight group. In the sample as a whole, there was a weakly significant negative correlation between fat mass and baseline 25OHD level, while this correlation became strongly significant at all time points after cholecalciferol loading. CONCLUSIONS: The lower peak 25OHD levels seen in the obese and overweight is probably due to the cholecalciferol load being distributed in a larger body volume. The longer persistence of 25OHD in their serum could be due to both their larger body volume and a slower release into the circulation of the vitamin D stored in their adipose tissue.

Improving adherence to and persistence with oral therapy of osteoporosis.

UNLABELLED: Osteoporosis treatment has low adherence and persistence. This study evaluated if greater patient involvement could improve them. At 12 months, only 114 out of 344 participants were "fully adherent and persistent" (all drug doses taken throughout the study). Only frequency of drug administration had a significant influence on adherence. INTRODUCTION: Osteoporosis affects millions of individuals worldwide. There are now several effective drugs, but adherence to and persistence with treatment are low. This 12-month multicenter, prospective, randomized study evaluated the efficacy of two different methods aimed at improving adherence and persistence through greater patient involvement, compared with standard clinical practice. METHODS: Three hundred thirty-four post-menopausal women, receiving an oral prescription for osteoporosis for the first time, were recruited and randomized into three groups: group 1 (controls, managed according to standard clinical practice) and groups 2 and 3 (managed with greater patient and caregiver involvement and special reinforcements: group 2, instructed to use several different "reminders"; group 3, same "reminders" as group 2, plus regular phone calls from and meetings at the referring Center). All enrolled women had two visits (baseline and 12 months). RESULTS: Of 334 enrolled women, 247 (74%) started the prescribed therapy. Of those who started, 219 (88.7%) persisted in therapy for at least 10 months. At final evaluation, only 114 women were considered as "fully adherent and persistent" (all doses taken throughout the 12 months). There were no significant differences regarding "full adherence" among the three randomized groups. The frequency of drug administration had a significant influence: weekly administration had a >5-fold higher adherence and monthly administration an 8-fold higher adherence (p < 0.0001) than daily administration. CONCLUSIONS: The special effort of devising and providing additional reminders did not prove effective. Additional interventions during the follow-up, including costly interventions such as phone calls and educational meetings, did not provide significant advantages.

Effect of a single injection of testosterone enanthate on 17ß estradiol and bone turnover markers in hypogonadal male patients.

PURPOSE: Several clinical studies testify the critical role played by estrogens in male bone metabolism. The aim of our study is to assess the effect of a single injection of testosterone enanthate in a group of hypogonadal men on 17ß estradiol serum levels and some bone metabolic parameters. METHOD: Twenty-one hypogonadal males were given one testosterone enanthate injection (250 mg). Blood samples were drawn before the injection and after 1, 2 and 3 weeks. The following variables were measured: Total testosterone (TT), 17ß estradiol (17ß E2), Sex hormone binding globulin, total alkaline phosphatase, osteocalcin, and C-telopeptide of type I collagen (CTx). RESULTS: After testosterone injection, both TT and 17ß E2 increased, peaking 1 week after the injection. Individual observation of the response of 17ß E2 to testosterone showed that a subgroup (n = 9) failed to respond with any increase in 17ß E2 at any of the weekly tests (group E2-), while the remainder (n = 12) showed a significant increase in 17ß E2, which reached a mean value three times higher than at baseline (group E2+). The E2- patients reached a TT peak lower than that observed in the E+ group. CTx serum levels declined progressively in the E2+ group, reaching the significance (p = 0.03) at the end of the study, while it did not change in E- group. CONCLUSION: This study suggests that a single injection of testosterone might have different effects on the production of endogenous estrogens, and a significant reduction of bone resorption parameters takes place only in the patients who show a significant increase of 17ß estradiol in response to testosterone administration.

Low serum 25-hydroxyvitamin D levels are associated with left ventricular hypertrophy in essential hypertension.

BACKGROUND AND AIM: Low serum 25-hydroxyvitamin D [25(OH)D] levels may have an important role in predisposing to hypertension and myocardial disease. We investigated the relationship between 25(OH)D and left ventricular (LV) structure and function, assessed by echocardiography, in a series of patients with essential hypertension (EH). METHODS AND RESULTS: Sixty-two newly diagnosed never-treated patients (32 male/30 female), aged 18-65 years, with grade 1-2 hypertension, no diabetes, no obesity, no hyperlipidemia, and no cardiopulmonary, renal, or hepatic disease, were studied. Twenty-four healthy normotensive sex-, age-, BMI-matched subjects served as controls. Hypertensive patients with 25(OH)D deficiency, defined as serum 25(OH)D levels <50 nmol/L, had higher prevalence of LV hypertrophy (LVH) than their 25(OH)D-sufficient counterparts (57.1 vs 17.6%, P = 0.02); no differences between the two groups were found in blood pressure levels as well as in other biochemical and hormone parameters. There was an inverse correlation between LV mass index and 25(OH)D levels (r = -0.366, P < 0.003) and a direct correlation between LV mass index and BMI (r = 0.333, P < 0.006) in the entire hypertensive population. The two variables remained independently associated with LVH at multivariable logistic regression analysis (OR 1.05, P < 0.005 and OR 1.25, P = 0.03, respectively). Prevalence of 25(OH)D deficiency was similar in EH patients and controls (45.1 vs 41.6%, P = 0.89), whereas no correlation between echocardiographic parameters and hormone levels was found. CONCLUSIONS: In the absence of major cardiovascular risk factors, 25(OH)D deficiency is a frequent finding in EH patients and is independently associated with LVH.

Calcium metabolism & hypercalcemia in adults.

Calcium is essential for many metabolic process, including nerve function, muscle contraction, and blood clotting. The metabolic pathways that contribute to maintain serum calcium levels are bone remodeling processes, intestinal absorption and secretion, and renal handling, but hypercalcemia occurs when at least 2 of these 3 metabolic pathways are altered. Calcium metabolism mainly depends on the activity of parathyroid hormone (PTH). Its secretion is strictly controlled by the ionized serum calcium levels through a negative feed-back, which is achieved by the activation of calcium-sensing receptors (CaSRs) mainly expressed on the surface of the parathyroid cells. The PTH receptor in bone and kidney is now referred as PTHR1. The balance of PTH, calcitonin, and vitamin D has long been considered the main regulator of calcium metabolism, but the function of other actors, such as fibroblast growth factor-23 (FGF-23), Klotho, and TPRV5 should be considered. Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia, accounting for more than 90% of cases. Uncontrolled hypercalcemia may cause renal impairment, both temporary (alteration of renal tubular function) and progressive (relapsing nephrolithiasis), leading to a progressive loss of renal function, as well as severe bone diseases, and heart damages. Advances in the understanding of all actors of calcium homeostasis will be crucial, having several practical consequences in the treatment and prevention of hypercalcemia. This would allow to move from a support therapy, sometimes ineffective, to a specific and addressed therapy, especially in patients with chronic hypercalcemic conditions unsuitable for surgery.

Malignant hypercalcemia.

Malignancy-associated hypercalcemia (MAH) is one of the clinical emergencies in medical oncology, arising early or, more often, during the late phases of disease. Prevalence cannot be estimated accurately because previous figures of 5-30% of all cancer patients have progressively reduced thanks to the widespread use of bisphosphonates for the prevention of skeletal events. The classic distinction of humoral vs. osteolytic hypercalcemia is still relevant from an etiological point of view, but should not be considered as a rigid alternative since both mechanisms may be active in the same patients and the activation of the RANKL pathway is a common pathogenetic mechanism. Parathyroid hormone-related protein mimics the effects of PTH on the bone and kidney (tubular calcium resorption) and may represent an attractive druggable target, but additional agents (cytokines or other mediators) as well as ectopic production of 1,25(OH)2D3 may give an important contribution to humoral hypercalcemia. Conversely, bone invasion by cancer cells determines massive bone reabsorption due to the release of proteolytic enzymes and pro-osteolytic agents with paracrine activity on adjacent bone and stromal cells. When cancer patients develop headache, confusion, de-hydration and tremors hypercalcemia should be suspected although slow rise of calcium levels may produce more indolent symptoms. Bisphosphonates (with or without hydration and diuretics) may efficiently control MAH but only if an active treatment for the underlying cancer is promptly started. The anti-RANKL monoclonal antibody denosumab represents a novel agent able to revert the vicious cycle of bone metastases and data from phase III studies are currently showing promising activity in reverting bone resorption with manageable toxicity.

Endocrine therapy of breast cancer.

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.

Bone organic matrix components: their roles in skeletal physiology.

Bone matrix is composed mainly of inorganic materials, while the bone organic compartment is a minor and complex structural entity, surrounding and supporting cells. Three major classes of biomolecules are involved in this organic part: structural proteins, specialized proteins, and proteoglycans. This review will briefly summarize our knowledge about the role and regulation of these specific bone components.

Statins, fracture risk, and bone remodeling.

Statins inhibit HMG-CoA reductase and reduce the intracellular formation of mevalonate. They are chemical compounds able to reduce total cholesterol by 15-40% and LDL cholesterol by 20-60%, and to increase HDL cholesterol by 5-15%. They also reduce triglycerides by 10- 30%. Statins, blocking the mevalonate pathway, inhibit the prenylation of proteins, which is essential to perform their biological function. A great deal of research has documented the positive effect of statins on bone formation and the importance of bone morphogenetic protein-2 (BMP-2) in mediating this effect. Statins are also able to decrease osteoblast apoptosis. The positive effect of statins on bone formation is accompanied by an inhibition of osteoclast activity, which gives statins the ability to uncouple the bone remodeling processes. Patients taking statins have a higher femoral bone density than those who do not. The lipophilic statins seem to be more effective than the hydrophilic statins in protecting bone. In several clinical trials, but not in all, the use of statins had been associated with a reduction in the fracture risk. In conclusion, statins have a positive effect on bone in vitro, but such an efficacy in humans has yet to be clearly demonstrated. Randomized, controlled trials are needed to provide a satisfactory answer on this issue.

[Guidelines for the diagnosis, prevention and treatment of osteoporosis]. / Linee guida per la diagnosi, prevenzione e terapia dell'osteoporosi Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro - SIOMMMS.

UNLABELLED: The guidelines for the osteoporosis management were first drafted by a working group and then critically evaluated by the board of SIOMMMS. The most relevant points are: DEFINITION: Osteoporosis is defined as a quantitative and qualitative deterioration of bone tissue leading to increased risk of fracture. Postmenopausal and senile osteoporosis are defined as primitive. DIAGNOSIS: The cornerstone for the diagnosis of osteoporosis is the measurement of bone mineral density (BMD) by DXA (dual-energy X-ray absortiometry) at the femoral neck with T-score values <-2.5, following the WHO definition. Other DXA sites or technologies for measuring bone mass are also acceptable when the former is not accessible. A BMD evaluation is recommended to all women above 65 years of age. At younger age or in man the bone assessment is recommended only in subjects with specific risk factors. A control of bone mass measurement is seldom required before 2 years. DIFFERENTIAL DIAGNOSIS: A few biochemical tests such as serum and urinary calcium, protein electrophoresis, serum creatinine and ESR are usually sufficient to exclude most secondary types of osteoporosis. The value of the so called bone turnover markers for the diagnosis and follow-up of osteoporosis remains uncertain. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management. PREVENTION: The osteoporosis prevention should be based on the elimination of specific risk factors such as inadequate calcium and vitamin D intake, smoking and sedentary life. The use of pharmacological agents in subjects with BMD values >-2.5 is usually not justified. Pharmacological intervention: The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk. This is the case only when the risk of fracture is rather high. FRAX is recognized as a useful tool for easily estimate the long-term fracture risk. SIOMMMS with these guidelines is committed to validate and further develop this diagnostic tool.

Osteoporosis treatment and fracture incidence: the ICARO longitudinal study.

UNLABELLED: None of the available osteoporosis therapies completely abolish the risk of fracture. Among 862 patients on treatment with antiresorptive agents (alendronate, risedronate, and raloxifene) for >1 year a fragility fracture was observed in 9.5%/year. This incidence is considerably higher than that observed in randomized clinical trials. INTRODUCTION: Available osteoporosis therapies reduced in randomized controlled trials (RCTs) the risk of fracture by 30-50%. The proportion of patients suffering from new fractures while on active treatment ("inadequate clinical treatment response" or ICR) can be derived from the data of the RCTs, where confounding factors are usually controlled by the exclusion criteria. In the retrospective part of the ICARO study we observed a 8.9% annual incidence of ICR. Here we report the results of the longitudinal part of the study. METHODS: The study includes 862 women with severe postmenopausal osteoporosis. Ninety-two of these patients (10.7%) were defined as having ICR (9.5%/year) during therapy with antiresorptive drugs (alendronate, risedronate, and raloxifene) for at least 1 year. RESULTS: The ICR patients were comparable to patients who did not sustain clinical fractures with regard to body mass index, follow-up duration, number of prevalent vertebral fractures, type of osteoporosis treatment, proportion of patients taking calcium and vitamin D supplements, and compliance with treatment. Those with ICR were significantly older (p=0.032) and more frequently had multiple vertebral deformities (p=0.013). CONCLUSIONS: The incidence of ICR during treatment with antiresorptive agents among patients with severe postmenopausal osteoporosis in a routine setting is considerably higher than that observed in randomized clinical trials.

A 4-year treatment with clodronate plus calcium and vitamin D supplements does not improve bone mass in primary biliary cirrhosis.

INTRODUCTION: International guidelines for managing osteoporosis in cirrhosis or severe cholestasis indicate a <-2.5 t-score as a cut-off for medical treatment, while no treatment is recommended in the case of osteopenia (t-scores ranging from -1.0 to -2.5). AIM: We conducted a prospective study in primary biliary cirrhosis with a view to optimizing the rationale for the medical treatment of bone loss. METHODS: All naïve post-menopausal women with primary biliary cirrhosis were enrolled in the study. Bone metabolism was evaluated by measuring 25-hydroxy-vitamin D, parathyroid hormone, osteocalcin. Bone mineral density was assessed at the lumbar spine by dual-photon X-ray absorptiometry at the baseline and every 2 years for up to 4 years. Patients with either osteopenia or osteoporosis received the following treatment: oral calcium carbonate (1000 mg/day)+vitamin D3 (880 IU/day)+i.m. disodium clodronate 100mg every 10 days for 4 years. RESULTS: Ninety-six patients completed the study: 30 had a normal bone mineral density (group 1), 37 had osteopenia (group 2), 29 had osteoporosis (group 3). No significant differences in biochemical parameters of bone metabolism were observed between the three groups. A total of 288 bone mineral density measurements were taken. Linear regression analysis failed to reveal significant changes in t-score over the follow-up in all groups. CONCLUSIONS: A 4-year treatment with clodronate+calcium/vitamin D3 supplements does not significantly improve osteoporosis or osteopenia in primary biliary cirrhosis women in menopause, but prevents the natural bone loss in these patients. Extensive international trials are warranted to optimize the prevention and treatment of bone loss in primary biliary cirrhosis.

Superiority of alfacalcidol compared to vitamin D plus calcium in lumbar bone mineral density in postmenopausal osteoporosis.

In a randomized multicenter, double-blind, double-dummy, parallel group study a comparison of the efficacy and safety of 1 microg alfacalcidol to 880 IU vitamin D plus calcium carbonate (1 g calcium) once daily per os was performed on 148 postmenopausal osteoporotic Caucasian patients with normal vitamin D serum levels for 18 months. Bone mineral density (BMD) was measured at baseline, 12 and 18 months. Safety parameters were followed during the entire study period. Sixty-nine (90.8%) in the alfacalcidol group and 67 (93.1%) in the vitamin D group were included in the ITT analysis. Lumbar BMD in the alfacalcidol group increased by 0.017 g/cm2 (2.33%) and 0.021 g/cm2 (2.87%) from baseline (P<0.001) at 12 and 18 months, respectively, whereas in the vitamin D plus calcium group the increase was 0.005 g/cm2 (0.70%) from baseline (N.S.) at both 12 and 18 months. The higher changes from baseline in the alfacalcidol group, as compared to the changes in the vitamin D plus calcium group at both 12 and 18 months, were found to be statistically significant (P=0.018, 0.005). A small increase of mean femoral BMD was achieved in both groups (N.S.). Adverse events were similar in both groups. No significant differences were noted between the groups in serum calcium. In conclusion, alfacalcidol was found to be superior in significantly increasing lumbar BMD as compared to vitamin D plus calcium while safety characteristics were found to be similar in both treatments.

Use of quantitative ultrasound of the hand phalanges in the diagnosis of two different osteoporotic syndromes: Cushing's syndrome and postmenopausal osteoporosis.

The aim of this study was to assess the ability of the quantitative ultrasound of the hand phalanges to detect different types of osteoporosis resulting from different pathogenetic mechanisms. For this purpose, postmenopausal and glucocorticoid-induced osteoporosis was studied. Thirteen female patients with Cushing's syndrome (CS) resulting from pituitary-dependent bilateral adrenal hyperplasia (10 patients) and from adrenal adenoma (3 patients), and 32 postmenopausal osteoporotic (OP) women, were examined. The two groups of patients were comparable for body mass index (BMI), but CS patients were significantly younger than OP ones (CS 44.5+/-11.6; OP: 73.9+/-3.6). All the patients had femoral neck bone mineral density (BMD) T-score less than -2.0. Cushing patients had a femoral neck BMD similar to that of OP patients (CS: 603+/-66 mg/cm2; OP: 628+/-69 mg/cm2; p=0.19). In contrast, amplitude-dependent speed of sound (AD-SoS) was significantly higher in CS patients than in OP patients (CS: 1997+/-91 m/s; OP: 1707+/-114 m/s; p<0.0001). By adjusting DXA and ultrasound parameters according to age, femoral neck BMD was significantly lower in CS patients and AD-SoS remained significantly higher than in OP patients. These findings indicate that these two different kinds of osteoporosis can be distinguished by ultrasonography and that ultrasound parameters alone cannot be used for evaluating skeletal status in CS patients.

Short- and long-term changes in bone mineral density of the lumbar spine after parathyroidectomy in patients with primary hyperparathyroidism.

The aims of this study were (1) to analyze whether correlations exist between lumbar spine (LS) bone mineral density (BMD) and the main preoperative biochemical parameters in a large population of patients with primary hyperparathyroidism (HPT); and (2) to evaluate the LS-BMD changes after parathyroidectomy (PTx) at long-term follow-up. Sixty-two patients (median age 57 years, range 23-82 years) with confirmed primary HPT underwent LS osteodensitometry by dual-energy X-ray absorptiometry with BMD measurements at the L2-L4 region before surgery and at 1 year and 2 years after successful PTx. Three groups of patients were considered: Group A (men, n = 14, 22.6%), Group B (premenopausal women, n = 12, 19.3%), and Group C (postmenopausal women, n = 36, 58.1%). There were no linear correlations (P = NS) among the main biochemical parameters, the age of the patients, and their baseline LS-BMD values that were significantly (P < 0.01) lower in Group C patients. At 2-year follow-up the LS-BMD improved by 13.0%, 11.5%, and 11.7% in Groups A, B, and C, respectively (P = NS). In order to compare groups with the same linear relationship between age and LS-BMD, a subgroup of postmenopausal patients aged < or = 60 years (Group C2) was considered. ANOVA showed that the improvement of the LS-BMD at 1- and 2-year follow-up was higher (P = 0.002) in Group B than in Group C2 patients. The result was confirmed by using the Mann-Whitney U-test (P = 0.0078). Improvement of LS-BMD after successful PTx was significantly (P < 0.01) higher in premenopausal women, suggesting a possible role of estrogen hormone in complete bone remodeling.

Phalangeal quantitative ultrasound technology and dual energy X-ray densitometry in patients with primary hyperparathyroidism: influence of sex and menopausal status.

Fifty-one patients with surgically proven primary hyperparathyroidism (PHPT), 11 males and 40 females, mean age+/-SD: 55.9+/-14.1 years, and 58 age- and sex-matched normal subjects were studied. The femoral and L(2)-L(4) bone mineral density (BMD; Hologic QDR 4500 C), as well as quantitative ultrasonometry (QUS; DBM-Sonic 1200) of the phalanges of both hands were measured in patients and controls. QUS measurements included amplitude-dependent speed of sound (AD-SoS), and other parameters derived from the graphic trace: signal dynamics (Sdy), first wave amplitude (FWA), bone transmission time (BTT) and ultrasound bone profile index (UBPI). Patients with PHPT showed significantly lower dual energy X-ray densitometry (DXA) values and QUS parameters compared to controls (lumbar spine Z-score: controls: -0.16+/-1.12, PHPT: -0.70+/-1.14, P=0.016; femoral neck Z-score: controls: -0.28+/-1.74, PHPT: -1+/-1.01, P=0.013; total femur Z-score: controls: -0.33+/-1.12, PHPT: -1.01+/-0.95, P=0.0013; AD-SoS Z-score: controls: -0.89+/-1.22, PHPT: -1.97+/-1.78, P=0.0003; FWA Z-score: controls: 0.36+/-1, PHPT: 0.62+/-0.85, P<0.0001; BTT Z-score: controls: 0.04+/-1.03, PHPT: -0.45+/-1.37, P=0.044; UBPI Z-score: controls: -0.02+/-1.01, PHPT: -0.68+/-1.05, P=0.002; SDy (mV/micros(2)): controls: -295+/-256, PHPT: -498+/-306, P=0.0003). In male patients, BMD values measured on the lumbar spine and femoral regions were similar to those found in male controls, while QUS values were significantly lower (lumbar spine Z-score: controls: -1.05+/-1.41, PHPT: -1.75+/-1.21, P=0.21; femoral neck Z-score: controls: -0.37+/-1.84, PHPT: -1.11+/-1.14, P=0.27; total femur Z-score: controls: -0.16+/-1.59, PHPT: -1.02+/-1.20, P=0.168; AD-SoS Z-score: controls: -0.52+/-1.58, PHPT: -1.57+/-1.77, P=0.149; FWA Z-score: controls: 0.67+/-1.01, PHPT: -0.74+/-0.79, P=0.0016; BTT Z-score: controls: 1.22+/-0.83, PHPT: 0.75+/-1.51, P=0.478; UBPI Z-score: controls: 0.56+/-0.94, PHPT: -0.47+/-1.10, P=0.025; SDy (mV/micros(2)): controls: -167+/-230, PHPT: -485+/-307, P=0.01). Women with PHPT were further divided into two subgroups: premenopause ( n=11) and postmenopause ( n=29). The premenopausal women with PHPT showed significantly lower DXA values than those of the premenopausal control ones, but similar QUS parameters (lumbar spine Z-score: controls: 0.12+/-0.66, PHPT: -0.59+/-0.85, P=0.03; femoral neck Z-score: controls: 0.06+/-2.85, PHPT: -1.48+/-1.05, P=0.11; total femur Z-score: controls: -0.51+/-0.97, PHPT: -1.48+/-0.63, P=0.009; AD-SoS Z-score: controls: 0.78+/-0.89, PHPT: -1.26+/-1.88, P=0.42; FWA Z-score: controls: 1.14+/-0.77, PHPT: 0.12+/-0.80, P=0.007; BTT Z-score: controls: 0.13+/-0.60, PHPT: 0.25+/-1.15, P=0.757; UBPI Z-score: controls: 0.73+/-0.49, PHPT: 0.24+/-0.96, P=0.15; SDy (mV/micros(2)): controls: -118+/-123, PHPT: -271+/-301, P=0.106). The postmenopausal women with PHPT showed both DXA and QUS parameters significantly lower than those found in the postmenopausal controls (lumbar spine Z-score: controls: 0.09+/-0.96, PHPT: -0.31+/-0.96, P=0.004; femoral neck Z-score: controls: -0.38+/-1.01, PHPT: -0.76+/-0.91, P=0.14; total femur Z-score: controls: -0.33+/-0.97, PHPT: -0.81+/-0.92, P=0.057; AD-SoS Z-score: controls: -1.08+/-1.17, PHPT: -2.38+/-1.68, P=0.31; FWA Z-score: controls: -0.013+/-0.81, PHPT: -0.86+/-0.74, P=0.0009; BTT Z-score: controls: -0.58+/-0.68, PHPT: -1.13+/-0.93, P=0.016; UBPI Z-score: controls: -0.62+/-0.83, PHPT: -1.11+/-0.82, P=0.034; SDy (mV/micros(2)): controls: -419+/-242, PHPT: -589+/-269, P=0.012). The relative risk of osteopenia was significantly increased in PHPT patients at several measurement sites. There was a highly significant correlation between spine and femoral BMD and QUS parameters, while PTH serum levels did not correlate with any of the densitometric variables. In conclusion, QUS parameters would seem to be able to distinguish patients with PHPT from normal controls in male subjects and in postmenopausal women, but not in premenopausal women. This would suggest that the higher estrogen levels in premenopausal patients might preserve the bone from significant structural changes. This may also suggest that hyperparathyroidism, in addition to the reduction of bone mineral content, can cause an alteration of bone structure with an additional increase in fracture risk in postmenopausal women. Furthermore, the alterations in QUS parameters in patients who do not show significant changes in DXA measurements suggest an involvement of bone that is independent of mineral content and may be helpful for selecting candidates for surgery, according to NIH criteria.

[Current indications for surgical treatment of asymptomatic primary hyperparathyroidism]. / Attuali indicazioni al trattamento chirurgico dell'iperparatiroidismo primitivo asintomatico.

The clinical picture of hyperparathyroidism has gone toward deep modifications in the last few decades, and currently this disease is more frequently asymptomatic. So, the question is raising concerning which patients have to be operated, due to the substantial benignity of the disease and the lack of well defined symptoms. Classical indications for surgery have been formulated more than a decade ago and are as follows: calcemia higher than 3 mmol/L, previous episode of life threatening hypercalcaemia, reduced creatinine clearance, nephrolithiasis, hypercalciuria, osteoporosis. In the last years other indications have been added, on the basis of clinical and epidemiological studies that have contributed to broaden our knowledgement on the evolution and compliances of the disease. Among these, the following data have to been kept in mind: history of previous atraumatic fractures, vertebral osteopenia (Z-score < -2), vitamin D deficiency, perimenopausal status, neuromuscular or psychical disturbances.

Relationship between serum parathyroid hormone, serum calcium and arterial blood pressure in patients with primary hyperparathyroidism: results of a multivariate analysis.

OBJECTIVE: To evaluate the possible relationship between serum calcium, serum parathyroid hormone (PTH) levels and arterial blood pressure (BP) in patients with primary hyperparathyroidism (HPT). DESIGN: A retrospective population-based study. METHODS: Charts of 194 patients with proven primary HPT were reviewed, and the main clinical and biochemical parameters were recorded. There were 48 men (24.7%) and 146 women (75.3%), with a median age of 59 years (range 23-82 years). Patients who used antihypertensive drugs or hormone replacement therapy had been previously excluded. All patients underwent successful parathyroidectomy, and were cured of their disease. RESULTS: There were no differences (P=NS) between men and women in systolic (143.3+/-19.1 vs 145.4+/-17.1 mmHg) and diastolic (87.1+/-12.3 vs 88.4+/-9.9 mmHg) BP, and in the main biochemical parameters. A significant (P<0.01) correlation was found between (i) serum calcium and serum PTH levels (r=0.39, F=88.36), (ii) age and BP, both systolic (r=0.61, F=118.16) and diastolic (r=0.48, F=64.5), and (iii) body mass index (BMI) and BP (r=0.45 and 0.36 respectively). There was no significant association of serum calcium levels with systolic (r=0.0974, t=1.3422, P=0.18) or diastolic (r=0.1117, t=1.5409, P=0.12) BP, and of serum PTH levels with systolic (r=-0.0349, t=-0.4783, P=0.63) or diastolic (r=-0.0793, t=-1.0913, P=0.28) BP. Multivariate analysis confirmed that none of the independent biochemical parameters significantly correlated with BP, both systolic and diastolic. CONCLUSIONS: In patients with primary HPT there is no relationship between PTH, calcium and BP. Thus, in hyperparathyroid patients, BP should be considered as an independent variable, mainly related to age and BMI.

Bone metabolism and gonad function in male patients undergoing liver transplantation: a two-year longitudinal study.

Osteodystrophy is a major complication of end-stage liver disease, especially in postmenopausal women. Our aim in this study was to evaluate bone metabolism and gonad function in men undergoing orthotopic liver transplantation (OLTx). Twenty-three consecutive men (mean age 48+/-13 years) evaluated for OLTx were studied, assessing the following parameters at baseline and 3, 6, 12 and 24 months after OLTx: lumbar spine (L2-L4) bone mineral density (BMD), parathyroid hormone (PTH), osteocalcin (BGP), 25-hydroxyvitamin D (25OHD), free testosterone (FT) and gonadotropins (FSH, LH). At baseline, 12 patients (52%) had a T-score <-2.5 SD and the mean BMD was 0.806+/-0.11 g/cm2 (range 0.470-1.045 g/cm2). The BMD was lower 3 months after OLTx and significantly higher 12 and 24 months after OLTx. A significant increase in serum BGP was observed at 6, 12 (p<0.05) and 24 months (p<0.005) after OLTx. The mean serum PTH level was 26.6+/-3.1 pg/ml at baseline and increased significantly at 12 and 24 months (to 49.4+/-9.9 and 61.2+/-10.1 pg/ml, respectively; p<0.05). 25OHD serum levels were low at baseline and returned to the normal range after 12 and 24 months (baseline, 8.73+/-1.54 ng/ ml; 12 months, 16.4+/-2.6 ng/ml; 24 months, 17.67+/-3.1 ng/ml; p<0.05). FT was significantly lower at baseline than in a group of 10 healthy controls (5.09+/-10.99. vs 10.3+/-1.1 pg/ml; p<0.0001). After OLTx a significant increase in FT was recorded at 6, (p<0.05) and 24 months (p<0.005). FT was not correlated with BMD, however. After OLTx an increase in FSH and LH was observed (but failed to reach statistical significance) at 3 and 6 months, followed by a slight reduction at 12 and 24 months. Thus a high proportion of men with end-stage liver disease do have osteoporosis. After OLTx, an early recovery of gonad function is observed, followed by an increase in bone mass, which occurs from the sixth month onward.

Recovery of bone mineral density after surgical cure, but not by ketoconazole treatment, in Cushing's syndrome.

The aim of our study was to retrospectively assess the effect of treatment on bone mineral density (BMD) in patients with Cushing's syndrome. Nineteen patients (17 women, 2 men; mean age +/- SD, 41 +/- 10 years; preoperative duration of disease 20 +/- 15 months) were studied. Six patients had a cortisol-producing adenoma and 13 had pituitary-dependent bilateral adrenal hyperplasia. BMD of the lumbar spine (L2-L4) was measured by dual-energy X-ray absorptiometry just before and 1-10 years after adrenalectomy or pituitary adenomectomy. Patients were divided in two groups. The first group of 9 patients (6 adrenal and 3 pituitary adenomas; group A) included those treated successfully by surgery ( > 5 years follow-up in the case of pituitary surgery). The second group of 10 patients (group B) included those treated with the steroidogenesis inhibitor ketoconazole, 300-600 mg/day, after unsuccessful pituitary surgery. In group A, restoration of normal cortisol was associated with a significant increase in BMD (from 829 +/- 112 mg/cm2 to 952 +/- 107 mg/cm2; p = 0.002). In group B, no changes in BMD were observed (from 857 +/- 160 to 847 +/- 163 mg/cm2), in spite of markedly decreased or normalized cortisol levels during ketoconazole treatment. These findings indicate that definitive correction of hypercortisolism restores BMD to normal levels in patients with Cushing's syndrome. In patients treated with ketoconazole after unsuccessful pituitary surgery, even when normalization of cortisol levels was achieved, BMD remained low. This would suggest an interfering effect of this drug on bone metabolism.