Bone health and body composition in transgender adults before gender-affirming hormonal therapy: data from the COMET study.

PURPOSE: Preliminary data suggested that bone mineral density (BMD) in transgender adults before initiating gender-affirming hormone therapy (GAHT) is lower when compared to cisgender controls. In this study, we analyzed bone metabolism in a sample of transgender adults before GAHT, and its possible correlation with biochemical profile, body composition and lifestyle habits (i.e., tobacco smoke and physical activity). METHODS: Medical data, smoking habits, phospho-calcic and hormonal blood tests and densitometric parameters were collected in a sample of 125 transgender adults, 78 Assigned Females At Birth (AFAB) and 47 Assigned Males At Birth (AMAB) before GAHT initiation and 146 cisgender controls (57 females and 89 males) matched by sex assigned at birth and age. 55 transgender and 46 cisgender controls also underwent a complete body composition evaluation and assessment of physical activity using the International Physical Activity Questionnaire (IPAQ). RESULTS: 14.3% of transgender and 6.2% of cisgender sample, respectively, had z-score values < -2 (p = 0.04). We observed only lower vitamin D values in transgender sample regarding biochemical/hormonal profile. AFAB transgender people had more total fat mass, while AMAB transgender individuals had reduced total lean mass as compared to cisgender people (53.94 ± 7.74 vs 58.38 ± 6.91, p < 0.05). AFAB transgender adults were more likely to be active smokers and tend to spend more time indoor. Fat Mass Index (FMI) was correlated with lumbar and femur BMD both in transgender individuals, while no correlations were found between lean mass parameters and BMD in AMAB transgender people. CONCLUSIONS: Body composition and lifestyle factors could contribute to low BMD in transgender adults before GAHT.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

Italian association of clinical endocrinologists (AME) position statement: drug therapy of osteoporosis.

Treatment of osteoporosis is aimed to prevent fragility fractures and to stabilize or increase bone mineral density. Several drugs with different efficacy and safety profiles are available. The long-term therapeutic strategy should be planned, and the initial treatment should be selected according to the individual site-specific fracture risk and the need to give the maximal protection when the fracture risk is highest (i.e. in the late life). The present consensus focused on the strategies for the treatment of postmenopausal osteoporosis taking into consideration all the drugs available for this purpose. A short revision of the literature about treatment of secondary osteoporosis due both to androgen deprivation therapy for prostate cancer and to aromatase inhibitors for breast cancer was also performed. Also premenopausal females and males with osteoporosis are frequently seen in endocrine settings. Finally particular attention was paid to the tailoring of treatment as well as to its duration.

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.

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.

Baseline characteristics of the population enrolled in the Italian Observational Study on Severe Osteoporosis (ISSO).

OBJECTIVES: Baseline characteristics of the population enrolled in the ISSO study, designed to evaluate the incidence of vertebral and non-vertebral fractures in Italian patients with severe osteoporosis treated according to clinical practice over 24 months observation. METHODS: Prospective observational study in 783 post-menopausal women and men entering 18-month treatment with teriparatide in a community setting at 57 centres in Italy. Characterisation included demographics, fracture risk factors, bone mineral density, fracture status, Health-Related Quality of Life (HRQoL) measured by the European Quality of Life Questionnaire, EQ-5D, and back pain assessed by VAS. RESULTS: Most patients were elderly women (90.5%), mean age±SD was 72.9±8.8 years. Nearly all (91.3%) had experienced ≥ 1 vertebral fracture (mean±SD, 3.6±2.2 per patient), 37.5% had ≥ 1 non-vertebral fracture (mean±SD, 1.4±0.7 per patient). Nearly all patients were suffering from back pain (94.9%), which had significantly restricted their daily activities (51.7%) and had likely or very likely been caused by vertebral fractures (29.2% and 55.8%, respectively). Mean EuroQoL EQ-5D index value was 0.58±0.25 and VAS score 49.2±23.6. Non-vertebral fractures, back pain and multiple vertebral fractures were associated with lower HRQoL (EuroQoL-5D Index both p<0.001, EQ-5D VAS score p=0.025 and p<0.016, respectively). Many patients were physically inactive (81.1%). One third (34.7%) of population had co-morbidities and 60.5% were on chronic concomitant treatments. Few subjects reported a maternal history of osteoporosis (15.5%), regular consumption of alcohol (13.3%) or were current smokers (11.5%). Nearly two-thirds (71.5%) had already been treated for osteoporosis, mainly with bisphosphonates. Calcium and vitamin D supplements were taken by 13% and 15.5% of the total population, respectively. CONCLUSIONS: At enrollment, the population of ISSO study mostly consisted in aging women, who had osteoporosis with high fracture risk, poor HRQoL and suffered from significant back pain. Most of them had already been treated by bisphosphonates but without calcium and vitamin D supplements. Back pain, as well as non-vertebral and multiple vertebral fractures, were associated with lower HRQoL.

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.

Role of biochemical markers of bone remodeling in clinical practice.

Bone tissue is subject to remodeling throughout the lifetime of an individual. Through a continuous remodeling cycle, actuated via the so-called 'bone remodeling units', old bone is resorbed by osteoclasts with the formation of cavities that are subsequently filled by osteoblasts. Bone loss observed in old age and in women after menopause is due to an imbalance between bone resorption and formation. Biochemical markers provide a dynamic view of the remodeling process, which covers rate of turnover and pathogenesis, and should improve fracture risk prediction. Furthermore, they can be used to monitor the short-term effects of therapy, and indicate if an excessive slowing of the remodeling process is occurring. When searching for markers of bone remodeling, biochemists have focused mainly on skeletal molecules that can be dosed in plasma and/or urine, as indicators of osteoblast function (i.e. bone alkaline phosphatase, osteocalcin, procollagene I C- and N-terminal propeptides) or osteoclast function (i.e. pyridinium crosslinks, collagen I C- and N-terminal telopeptides). The clinical significance of any marker for bone remodeling depends on two fundamental characteristics: specificity and variability. If the objective is to monitor therapeutic efficacy, it seems most rational to use a resorption marker for drugs that act principally on osteoclast, such as estrogens or bisphosphonates, while for drugs that act principally on osteoblast, such as PTH-peptides a marker for bone formation would be more appropriate.

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.

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.

Use of quantitative ultrasonography in differentiating osteomalacia from osteoporosis: preliminary study.

The aim of this work was to use ultrasonographic technology to differentiate osteoporosis from osteomalacia on the basis of different patterns of the graphic trace. Three patients with osteomalacia and three with osteoporosis, all with the same lumbar spine bone mineral density, were studied. The velocity of the ultrasound beam in bone was measured by a DBM Sonic 1,200/I densitometer at the proximal phalanges of the hands in all the patients. The ultrasound beam velocity was measured when the first peak of the waveform reached a predetermined minimum amplitude value (amplitude-dependent speed of sound) as well as at the lowest point prior to the first and second peaks, before they reached the predetermined minimum amplitude value (first and second minimum speeds of sound). The graphic traces were further analyzed by Fourier analysis, and both the main frequency (f0) and the width of the peak centered in the f0 (full width at half maximum) were measured. The first and second minimum speeds of sound were significantly lower in the patients with osteomalacia than in the osteoporosis group. The first minimum speed of sound was 2,169 +/- 73 m/s in osteoporosis and 1,983 +/- 61 m/s in osteomalacia (P < 0.0001); the second minimum peak speed of sound was 1,895 +/-59 m/s in osteoporosis and 1,748 +/- 38 m/s in osteomalacia (P < 0.0001). The f0 was similar in the two groups (osteoporosis, 0.85 +/- 0.14 MHz; osteomalacia, 0.9 +/- 0.22 MHz; P = 0.72), and the full width at half maximum was significantly higher in the osteomalacia patients (0.52 +/- 0.14 MHz) than in the osteoporosis patients (0.37 +/- 0.15 MHz) (P = 0.022). This study confirms that ultrasonography is a promising, noninvasive method that could be used to differentiate osteoporosis from osteomalacia, but further studies should be carried out before this method can be introduced into clinical practice.

Use of ultrasonography in the diagnosis of osteomalacia: preliminary results on experimental osteomalacia in the rat.

This study was performed to investigate the ability of ultrasonographic technique to distinguish osteomalacia from normal bone with the same mineral content. Ten rats with experimentally induced osteomalacia (group A) and 12 control rats having similar body size and weight (group B) were studied. Histomorphometric analysis confirmed the presence of osteomalacia in two rats from group A and showed normally mineralized bone in two rats from group B. Whole body bone mineral density, measured by dual-energy x-ray absorptiometry, was similar in the two groups (86 +/- 6 mg/cm2 in group A and 89 +/- 4 mg/cm2 in group B). The velocity of the ultrasound beam in bone was measured by densitometer at the first caudal vertebra of each rat. The velocity was measured when the first peak of the waveform reached a predetermined minimum amplitude value (amplitude-dependent speed of sound) as well as at the lowest point of this curve before it reaches the predetermined minimum amplitude (first minimum speed of sound). Although the amplitude-dependent speed of sound was similar in the two groups (1381.9 +/- 11.8 m/s in group A and 1390.9 +/- 17.8 m/s in group B), the first minimum speed of sound was clearly different (1446.1 +/- 8.9 m/s in group A and 1503.3 +/- 10.9 m/s in group B; P < 0.001). This study shows that ultrasonography could be used to identify alterations in bone quality, such as osteomalacia, but further studies need to be carried out before this method can be introduced into clinical practice.