Diagnosis and treatment of Paget's disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS).

INTRODUCTION: Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management. METHODS: Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice. RESULTS AND CONCLUSION: Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Reliability of calcium-phosphorus (Ca/P) ratio as a new, accurate and inexpensive tool in the diagnosis of some Ca-P disorders.

PURPOSE: The serum calcium/phosphorus (Ca/P) ratio is an accurate tool to differentiate patients with primary hyperparathyroidism (PHPT) from healthy subjects. However, other disorders of the Ca-P metabolism might impair the Ca/P ratio, such as hypophosphatemia (HypoP) not PHPT related. The aim of this study is to examine the diagnostic value of Ca/P ratio in the diagnosis of PHPT and HypoP not PHPT related. METHODS: Single-center, retrospective, case-control study, including 150 patients with PHPT and 306 patients with HypoP, compared with 150 controls. HypoP patients were enrolled among HIV-infected patients by selecting those with Fanconi-like syndrome due to antiretroviral treatment. Parameters which were measured were serum Ca, P, parathyroid hormone (PTH), 25-OH vitamin D, albumin and creatinine). RESULTS: The Ca/P ratio was significantly higher in PHPT and HypoP patients, compared to controls (p < 0.0001). At receiver operator characteristic (ROC) curve analysis, the cut-off of 3.56 (2.75 SI) for Ca/P ratio was able to identify patients with PHPT and HypoP (sensitivity 95%; specificity 93%). Among patients with Ca/P ratio above 3.56, the thresholds of 10.3 mg/dL (2.6 mmol/L) for serum Ca (sensitivity 93%; specificity 98%) and 80.5 pg/mL for PTH (sensitivity 91%; specificity 91%) were defined for the specific diagnosis of PHPT. CONCLUSIONS: The Ca/P ratio above 3.56 (2.75 SI) is a highly accurate tool to identify PHPT and HypoP not PHPT-related patients. Thanks to its simplicity, this index can be proposed as a screening and first-line examination in the diagnostic work-up when a disorder of Ca-P metabolism is suspected or should be ruled out.

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) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) Position Statement: Clinical Management of Vitamin D Deficiency in Adults

Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25-hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice.

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.

Serum total estradiol, but not testosterone is associated with reduced bone mineral density (BMD) in HIV-infected men: a cross-sectional, observational study.

SUMMARY: By investigating the relationship between serum testosterone, estradiol, and bone mineral density (BMD) in a large cohort of HIV-infected men, estradiol was associated with BMD, relative estrogen deficiency being involved in bone loss in men with hypogonadism, in addition to all HIV-related factors. Increased aromatization in adipose tissue does not counteract HIV-related bone loss. INTRODUCTION: The purpose of this study is to evaluate the relationship between serum testosterone, estradiol, and BMD in a large cohort of HIV-infected men. METHODS: We investigated biochemical, hormonal parameters, and BMD in 1204 HIV-infected men (age 45.64 ± 7.33 years) participating in a cross-sectional, observational study. Among other parameters, the main outcome measures were serum total testosterone and estradiol, gonadotropins, 25-hydroxyvitamin D [25(OH)D], parathormone (PTH), calcium, phosphorous, femoral, and lumbar BMD. RESULTS: In men with HIV, the prevalence of osteoporosis and osteopenia is 15.1 and 63.2% with 25(OH)D insufficiency being very common (60.1%). After age adjustment, BMD is positively associated with estradiol, but not testosterone, at linear (p < 0.001) and stepwise (p < 0.05) multiple regression. Lumbar BMD significantly increases across the estradiol quartiles but not among testosterone quartiles. Femoral and lumbar BMD are significantly higher in men with estradiol ≥ 27 pg/mL than in those with estradiol <27 pg/mL. Apart from estradiol, only age, calcium, and BMI predict BMD at stepwise linear multiple regression, but the strength of this association is weak. CONCLUSIONS: Estradiol, but not testosterone, is associated with BMD in HIV-infected men and exerts a protective role on bone especially when it is above 27 pg/mL. Relative estrogen deficiency is a potential mechanism involved in bone loss in hypogonadal HIV-infected men, in addition to all HIV-related factors. Increased aromatization in adipose tissue does not counteract HIV-related bone loss. Finally, reduced BMD in young-to-middle-aged HIV-infected men might be considered a peculiar hallmark of HIV infection due to its relevant prevalence, representing one of the several pieces composing the complicated puzzle of premature aging related to HIV infection.

Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism.

UNLABELLED: No data on the pharmacological treatment of normocalcemic hyperparathyroidism (NPHPT) are available. We treated 30 NPHPT postmenopausal women with alendronate/cholecalciferol (treated group) or vitamin D alone (control group). Over 1 year, bone mineral density (BMD) increased significantly in treated group, but not in control group. Both treatments did not affect serum or urinary calcium. INTRODUCTION: Normocalcemic primary hyperparathyroidism (NPHPT) is defined by normal serum calcium and consistently elevated PTH levels after ruling out the causes of secondary hyperparathyroidism. It is likely that subjects with NPHPT may develop kidney and bone disease. As no data on the pharmacological treatment of NPHPT are available, we aimed to investigate the effects of alendronate and cholecalciferol on both BMD and bone biochemical markers in postmenopausal women with NPHPT. Safety of vitamin D was evaluated as secondary endpoint. METHODS: The study was a prospective open label randomized trial comparing 15 postmenopausal women with NPHPT (PMW-NPHPT), treated with oral alendronate plus cholecalciferol (treated group) and 15 PMW-NPHPT treated only with cholecalciferol (control group). Blood samples were obtained at baseline and after 3, 6, and 12 months. Bone turnover markers (BTM) were measured at baseline, 3, and 6 months, respectively. BMD was assessed at baseline and after 12 months. RESULTS: After 1 year of treatment, BMD increased significantly at the lumbar, femoral neck, and hip level in the treated group, but not in the control group (p = 0.001). No differences were found between or within groups in serum calcium, PTH, and urinary calcium levels. BTM significantly decreased in the treated group but not in the control group, at 3 and 6 months (p < 0.001), respectively. No cases of hypercalcemia or hypercalciuria were detected during the study. CONCLUSION: The results of this study indicate that alendronate/cholecalciferol increases BMD in postmenopausal women with NPHPT. Alendronate/cholecalciferol or vitamin D alone does not affect serum or urinary calcium.

Role of calcium-sensing receptor in bone biology.

Extracellular calcium concentration changes are recognized by Ca++ sensing receptor (CaR), a member of the G-protein-coupled receptor family. Recently, progress has been made in the understanding of CaR functional role in bone cells, notwithstanding a lack of detailed knowledge about the identity of the cation receptors. It is generally agreed that a high extracellular calcium induces osteoblast proliferation and osteoclastogenesis inhibition. Potential implications that may be considered include a role for CaR in osteogenesis, in serum calcium homeostasis regulation, and as a factor coupling bone formation to resorption in bone remodeling. The localization of CaR in bone cells provides further knowledge of the mechanisms operating in the bone remodeling model; in fact, increased calcium gradient in the site of bone resorption favors osteoblast precursors chemotaxis and inhibits osteoclasts through the increase of [Ca++]e. In vitro data indicate that CaR is a physiological regulator of bone cells, regulating the recruitment, differentiation and survival of osteoblasts and osteoclasts. This leads to the concept that the CaR present in bone cells may be targeted by agonists or antagonists to control bone cell metabolism and bone remodeling.

Asymptomatic primary hyperparathyroidism: surgical and medical management.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, frequently asymptomatic. Notwithstanding, mild PHPT may cause adverse skeletal effects that include high bone remodeling, reduced bone mineral density (BMD), and increased fracture risk. The definitive therapy for symptomatic and asymptomatic PHPT (aPHPT) is parathyroidectomy, which has been shown to increase BMD. In patients who choose not to be treated surgically or have contraindications for surgery, medical therapy should include drugs designed to protect the skeleton and/or to lower serum calcium, such as bisphosphonates, hormone replacement, and/or calcimimetic agents. However, there are currently no fracture data for any of these options. Obviously, there is the need for larger randomized controlled trials with fractures as end-points to evaluate the efficacy of medical treatment.

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.

Salt intake, hypertension, and osteoporosis.

A high salt intake has been correlated with several pathological conditions such as hypertension, cardiovascular disease, renal calcium stones, and osteoporosis. Some of these diseases present a high prevalence in the elderly and common pathogenetic mechanisms are proposed for some of them. A high salt intake has been associated with hypertension as well as osteoporosis and one of the proposed pathogenetic mechanisms is an increased calcium excretion in urine. Urinary calcium loss induces a negative calcium balance that may predispose hypertensive subjects to developing greater bone loss. The gene which encodes for the thiazide- sensitive sodium-chloride cotransporter (NCCT) represents a possible link between hypertension and osteoporosis. Subjects heterozygous for an inactivating mutation of NCCT present a positive effect on bone density as shown by the significantly higher Z-scores at the lumbar spine and total femur. Recent clinical studies also support the benefit of ACE inhibitors in reducing fracture risk or improving bone metabolism. These data suggest that the renin-angiotensin system may be one of the several factors involved in bone metabolism. Hypertension, together with stroke, has been demonstrated to be a risk factor for osteoporosis. Although the risk associated with hypertension was limited in terms of relative risk, it may have a significant impact on the general population owing to the high prevalence of hypertension. The treatment of hypertension may thus be very useful in also giving protection against fractures.

Hyperphosphatemia: effects on bone metabolism and cardiovascular risk.

Hyperphosphatemia indicates a plasma inorganic phosphate (Pi) concentration greater than 5 mg/dl in the adult and 7 mg/dl in adolescent subjects. Pi homeostasis is maintained by several mechanisms (intestinal absorption, renal excretion, balance of Pi exchanges in and out of the cells, hormonal regulation). Most of the Pi, after intestinal absorption, undergoes urinary excretion suggesting that the kidney plays a major role in the maintenance of homeostasis and plasma concentration of the Pi, modifying its reabsorption in the proximal tubule where 3 types of sodium/ phosphate cotransporters have been identified (NPT). NPT2 is crucial for the Pi reabsorption and is modulated by several hormones (PTH and vitamin D3, phosphatonins) and non-hormonal factors. The hyperphospatemia is usually due to a decrease in renal function or a PTH absence (primary or secondary hypoparathyroidism) or phosphatonin deficiency. A correct serum Pi concentration is a critical condition for maintaining the calcium-phosphate (CaxPi) product within a safe range ensuring the physiological processes of bone mineralization; an increase of CaxPi product in extracellular fluids over a critical threshold, may promote processes of extraskeletal calcification. In the last few years several studies have shown that the pathogenetic mechanisms of vascular calcification do not imply a simple deposition of calcium phosphate crystals in the wall of the vessels affected by atherosclerotic lesions, but an active process making vascular smooth cells assume functional characteristics of osteoblasts. The consequences on bone are heterogeneous according to the pathogenetic mechanisms responsible for hyperphosphatemia.

Uselessness of a questionnaire for osteoporosis and role of bone mass measurements in predicting tooth loss.

AIM: We evaluated whether the number of teeth lost is associated with risk factors for osteoporosis and whether bone mass measurements can add further information. METHODS: A total of 455 healthy women were enrolled. All the subjects filled in a questionnaire on risk factors for osteoporosis. The bone mineral density (BMD) was measured both by dual X-ray absorptiometry (DXA) and quantitative ultrasound measurements (QUS). RESULTS: On the basis of the questionnaire score 65.1% of the subjects were in the low risk category, 11% in the moderate risk category, 19.3% in the fairly high risk category and 4.6% in the high risk category. Close relationships (P<0.001) were observed between bone mass loss and the questionnaire risk categories. The number of teeth lost significantly increased from normal to osteoporosis groups. High correlations were also found between osteosonographic parameters and the number of teeth lost. Among questionnaire items a significant positive correlation was found only between the number of teeth lost and both age class (P<0.001) and years since menopause (P<0.001). A multiple regression showed that only age class (P<0.001) and ultrasound bone profile index (UBPI) (P=0.041) were independently linked to tooth loss. CONCLUSIONS: The results obtained showed that age is the main determinant of tooth loss and that QUS adds further information in identifying patients at a higher risk of tooth loss.

Long-term potassium citrate therapy and bone mineral density in idiopathic calcium stone formers.

Several authors have described an association between idiopathic calcium (Ca) stone disease and bone mass reduction. Hypocitraturia is a frequent feature of urolithiasis, and alkaline citrate has been recommended as one of the choice treatments in this disease. Some evidence exists as to the positive effect of potassium (K) citrate therapy on bone mass. The aim of this work was the longitudinal evaluation of bone mineral density (BMD) changes in a group of Ca oxalate stone formers treated with K citrate for two years. Enrolled patients were 120; 109 subjects completed the study (51 males and 58 females). A metabolic study and distal radius BMD measurements were conducted both at baseline (BAS) and at the end of the study (END). BMD (0.451 +/- 0.081 vs 0.490 +/- 0.080 g/cm2), T-score (-1.43 +/- 1.02 vs -0.90 +/- 1.04), net gastrointestinal alkali absorption (40.37 +/- 50.57 vs 61.26 +/- 42.26 mEq/day), urinary citrate (2.53 +/- 1.15 vs 3.10 +/- 1.44 mmol/day) and K (58.93 +/- 22.28 vs 65.45 +/- 23.97 mmol/day) excretion significantly increased from BAS to END. Urinary Ca excretion remained unchanged from BAS to END (5.16 +/- 2.74 vs 5.57 +/- 2.85 mmol/ day). Our results indicate that long-term treatment with K citrate increases forearm BMD in idiopathic Ca stone formers. It seems probable that the alkali load provided by this drug reduces bone resorption by a buffering of the endogenous acid production. K citrate appears to be a further therapeutic opportunity for the management of osteoporosis in Ca stone formers.

Does bone mineral density predict fractures comparably in women and men?

Osteoporosis (OP) is a very common disease associated with increased morbidity, mortality and costs. For a 50-yr-old woman the lifetime risk of an osteoporotic fracture is 40%, while for a man of the same age the risk is 13%. Good evidence exists as to the correlation between bone mineral density (BMD) and fracture risk in post-menopausal women. The diagnosis of OP can be made when BMD is more >2.5 SD below the mean of normal young women (T-score < or = -2.5). In men it has not been possible, until now, to identify a definite T-score under which the diagnosis of OP can be made. Several studies produced conflicting results when they tried to answer the question as to whether males and females fracture at the same absolute BMD value. Men have a greater bone size than women even when this parameter is corrected for weight and body mass. As densitometric devices measure areal density, men appear to have a higher BMD than women. Some studies have shown that, for a given BMD, males and females have the same fracture risk, while other papers have demonstrated that fractured men have a higher BMD than fractured women. Another problem concerns the diagnosis of osteoporosis. In fact, when the T-score is calculated in men on the basis of a young female reference range the prevalence of osteoporosis can be underestimated. The official position of International Society for Clinical Densitometry (ISCD) may represent an "interim" answer in order to identify men at risk of fracture.

Alendronate reduces bone resorption in HIV-associated osteopenia/osteoporosis.

PURPOSE: To evaluate the effects of alendronate, vitamin D, and calcium supplementation on bone metabolism and bone mineral density (BMD) in both HIV-infected men and women treated with highly active antiretroviral therapy (HAART). METHOD: We performed a 52-week prospective, multicenter, randomized, open-label clinical trial. Eligible participants were on stable HAART and had BMD values at the femoral neck or lumbar spine that corresponded to a t score less than -1. Patients were randomized to receive alendronate 70 mg weekly or no alendronate; calcium 1000 mg daily and vitamin D 500 IU daily were provided to all study recipients. Primary endpoint of the study was the change in bone metabolism evaluated by N-telopeptide of type 1 collagen and bone-specific alkaline phosphatase; the secondary endpoint was BMD variation. RESULTS: 18 patients were randomized to the alendronate and 23 to the no-alendronate group (controls). The alendronate-treatment group compared to controls had a significant decrease in serum N-telopeptides, 1914 +/- 1433.4 vs. 3967 +/- 1650.5 pM/L (p = .005) after 1 year. Lumbar spine BMD increased by 4% in the alendronate group (p = .004) vs. 3.7% (p = .062) in controls, compared to baseline values. Femoral neck BMD decreased by 0.5% in the alendronate group (p = .05) and by 3.5% in the control group (p = .04). No between-groups differences for BMD were found (Delta lumbar-BMD 0.0351 +/- 0.0406 in cases and 0.0356 +/- 0.073 in controls [p = .977], Delta femoral-BMD -0.085 +/- 0.160 in cases and -0.100 +/- 0.165 in controls [p = .795]). CONCLUSION: Alendronate plus vitamin D and calcium was effective in reducing bone resorption. Alendronate improved lumbar BMD and minimized femoral BMD decrease after 52 weeks compared to treatment with vitamin D and calcium alone in patients on HAART with osteopenia/osteoporosis.

Osteoporosis and urolithiasis.

Several studies have indicated that up to 60% of idiopathic calcium stone formers present hypercalciuria. Many authors have described reduced bone mineral density (BMD) in stoneformers with hypercalciuria, but osteopenia has also been found in normocalciuric patients. Moreover, Jaeger's group found that bone mass was reduced in all patients with calcium stone disease, independently of hypercalciuria. Many factors may contribute to the pathogenesis of osteopenia in stone formers. A predominant role has been given to the low-calcium diet that is still prescribed in nephrolithiasis. Also slight metabolic acidosis, which is frequently present in stone formers eating a diet rich in animal protein, can contribute to bone loss. Finally, some authors described a pathogenetic role for cytokines, prostaglandins and vitamin D receptor gene polymorphisms.

Health-related quality of life in patients with thyroid disorders.

Limited reports are available on quality of life (HRQL) in thyroid diseases, and no data are available in euthyroid disorders, such as goiter and Hashimoto thyroiditis. Also, asymptomatic patients may suffer a reduction in perceived health status due to distress related to physical appearance and awareness of disease. We measured HRQL by means of Medical Outcome Study Short Form-36 (SF-36) and Nottingham Health Profile (NHP) questionnaires in 368 patients (hypothyroid, 81; hyperthyroid, 45 (for both states including overt and subclinical states); Hashimoto thyroiditis, 51; euthyroid goiter, 191). The final scores of the domains were compared with age- and sex-adjusted Italian normative values, by computing the effect size. All domains of SF-36, except bodily pain, were reduced in thyroid disease; this was mainly the case of role limitation (both physical and emotional), general health and social functioning. The domains of NHP were less severely affected. HRQL was impaired also in the absence of altered hormone levels. Mood/behavior disturbances were present in a large proportion of patients and were significantly associated with poor HRQL. HRQL was significantly reduced in patients with thyroid diseases referred to a secondary level endocrinology unit. Perceived health status may be considered as an additional outcome of management and therapy of thyroid disorders.

HIV-1, HAART and bone metabolism.

Much attention has been paid to the emerging complications of HIV infection in patients receiving HAART. Recently, there emerged a potentially increased risk of bone problems like osteopenia, osteoporosis and osteonecrosis as patients live longer. It could be a drug side effect, a consequence of prolonged exposure to HIV and/or activated immune cells characteristic of HIV infection, or a consequence of immune system changes that accompany suppression of virus by the drugs. Future research should focus on the etiologic mechanisms, define the incidence and prevalence prospectively, determine the relationship with HAART (especially the rule of protease inhibitors), and help to guide management. Only when the mechanism for HIV-related versus HAART-related changes can be defined, will we be much closer to designing specific interventions.