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.

Vertebral fracture assessment (VFA) for monitoring vertebral reshaping in children and adolescents with osteogenesis imperfecta treated with intravenous neridronate.

PURPOSE: The study was aimed at monitoring vertebral bodies changes with the use of Vertebral Fracture Assessment (VFA) in children and adolescents affected by osteogenesis imperfecta (OI) during treatment with intravenous neridronate. METHODS: 60 children and adolescents (35 males and 25 females; age 1-16 years) with OI type I, III and IV were included in the study. Intravenous neridronate was administered at the dose of 2 mg/kg every 3 months in all patients. Lumbar spine (LS) bone mineral density (BMD) and VFA by dual X-ray absorptiometry (DXA) were assessed every 6 months up to 24 months during treatment. VFA with vertebral morphometry (MXA) was used to calculate the three indices of vertebral deformity: wedging, concavity and crushing. Serum calcium, phosphate, parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D], total alkaline phosphatase (ALP), bone alkaline phosphatase (BALP) and urinary C-terminal telopeptide of type 1 collagen (CTx) were measured at any time point. RESULTS: Mean LS BMD values significantly increased at 24 months compared to baseline (p < 0.0001); the corresponding Z-score values were -1.28 ± 1.23 at 24 months vs -2.46 ± 1.25 at baseline; corresponding mean Bone Mineral Apparent Density (BMAD) values were 0.335 ± 0.206 vs 0.464 ± 0.216. Mean serum levels of ALP, BALP and CTx significantly decreased from baseline to 24 months. By MXA, we observed a significant 19.1% reduction of the mean wedging index of vertebral reshaping at 12 months, and 38.4% at 24 months (p < 0.0001) and of the mean concavity index (16.3% at 12 months and 35.9% at 24 months; p < 0.0001). Vertebral reshaping was achieved for 66/88 (75%) wedge fractures and 59/70 (84%) concave fractures, but there were 4 incident mild fractures. Finally, VF rate was reduced at 24 months compared to baseline: 37/710 (5.2%) vs 158/710 (22.2%). CONCLUSION: Our study demonstrates the utility of VFA as a safe and alternative methodology in the follow-up of children and adolescents with OI.

Long-term bone mineral density changes after surgical cure of patients with tumor-induced osteomalacia.

This paper reports our personal experience filling the gap regarding changes of bone mineral density after surgical treatment in patient suffering from tumor-induced osteomalacia. INTRODUCTION: No systematic data are available regarding long-term bone mineral density (BMD) changes after surgical cure of patients with tumor-induced osteomalacia. METHODS: From October 2001 through April 2018, we studied 10 consecutive patients (mean age ± SD, 45.5 ± 13.8 years; 5 males and 5 females) with tumor-induced osteomalacia. We evaluated BMD when initially presented at our Center and after surgical removal of the tumor. RESULTS: Basal BMD and corresponding Z-score values (mean values ± SD) measured by DXA were as follows: L1-L4 = 0.692 ± 0.15 g/cm2, Z-score = - 2.80 ± 1.60; femur neck 0.447 ± 0.10 g/cm2, Z-score = - 2.66 ± 0.93; total femur = 0.450 ± 0.08 g/cm2, Z-score = -3.04 ± 0.85). Furthermore, Trabecular Bone Score (TBS) was evaluated in three patients (basal values, 0.990 ± 0.32). Seven patients were intermittently followed after surgical excision of the tumor while supplemented with cholecalciferol and calcium salts; the remaining three were lost to follow-up. There was a striking increase of BMD values that peaked at 26.7 ± 6.50 months: L1-L4 = 1.289 ± 0.247 g/cm2, p < 0.001, Z-score + 1.75 ± 1.42; femur neck = 0.890 ± 0.235 g/cm2, p = 0.028, Z-score = + 0.50 ± 1.40; total femur = 0.834 ± 0.150 g/cm2, p = 0.005, Z-score = - 0.74 ± 1.14. In patients with the greatest bone involvement at lumbar site, there was a striking increase of an average 1.5% (p < 0.01) in respect to baseline Z-score value for each additional month of observation during the first 2-3 years post-surgery. An improvement of trabecular microarchitecture was also documented (TBS, 1.255 ± 0.16). CONCLUSION: This is the first case series documenting an impressive increase of BMD at both lumbar and femoral sites, together with an improvement of trabecular microarchitecture as documented by TBS. This is the consequence of huge mineralization of the large amount of osteoid tissue after resolution of the disease.

Magnetic resonance imaging findings of infectious sacroiliitis associated with iliopsoas abscess: a case report in a young male.

Infectious sacroiliitis is an infection of the sacroiliac joint, not easy to diagnose because of its non-specific signs, symptoms and laboratory abnormalities. We describe a case of a 16 year-old male with 5 days' history of fever, abdominal pain, constipation, low-back and left hip pain extended to the left knee associated with sudden inability to walk. In the first place, magnetic resonance imaging (MRI) examination of his sacroiliac joint revealed an enlarged corpuscolated fluid collection near the left iliopsoas muscle, extended to homolateral paravertebral muscles and a little fluid at the left sacroiliac joint. Drainage by aspiration of the iliopsoas abscess was applied; Staphylococcus aureus was found in the aspirated fluid and isolated from the blood too. Therefore intravenous antibiotic therapy was begun. Follow-up MRI exams confirmed the muscle abscess and revealed also a spongy bone edema of the left sacroiliac joint, persisting despite the disappearance of symptoms and the normalization of inflammatory values. It is important to make an early diagnosis of infectious sacroiliitis in order to begin antibiotic therapy as soon as possible, because of the increasing morbidity of infection of sacroiliac joint. In our case MR findings have provided significant orientation towards the final diagnosis of infectious sacroiliitis.

Guidelines for the diagnosis, prevention and management of osteoporosis.

Osteoporosis poses a significant public health issue. National Societies have developed Guidelines for the diagnosis and treatment of this disorder with an effort of adapting specific tools for risk assessment on the peculiar characteristics of a given population. The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has recently revised the previously published Guidelines on the diagnosis, riskassessment, prevention and management of primary and secondary osteoporosis. The guidelines were first drafted by a working group and then approved by the board of SIOMMMS. Subsequently they received also the endorsement of other major Scientific Societies that deal with bone metabolic disease. These recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on leading experts' experience and opinion, and on good clinical practice. The osteoporosis prevention should be based on the elimination of specific risk factors. The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk, and this is the case only when the risk of fracture is rather high as measured with variables susceptible to pharmacological effect. DeFRA (FRAX® derived fracture risk assessment) is recognized as a useful tool for easily estimate the long-term fracture risk. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management.

Zenker diverticulum in the right side of the neck resembling a thyroid mass at ultrasound.

Zenker’s diverticulum represents the most common form of pharyngo-oesophageal diverticula usually occurring on the left side of the neck. Due to its anatomical proximity to the thyroid, it can mimic a thyroid mass. Here we describe the case of an asymptomatic 49-year-old man referred to the Thyroid Clinic of the Policlinico Umberto I Hospital-“Sapienza” University of Rome for thyroid sonography due to a family history of autoimmune thyroid disease. The patient’s thyroid blood tests did not reveal any abnormalities. The sonographic examination showed a dishomogeneus and hypoechoic thyroid gland. In addition, in the third middle of the right lobe, a mass (with a diameter greater than 26 mm), with heterogeneous internal echogenicity, hypoechoic margins and internal hyperechoic spots was recorded, with no appreciable flow at the Doppler evaluation. The TI-RADS score was 4c. Hence, the patient underwent ultrasound-guided fine-needle aspiration cytology that revealed the presence of squamous cells without cytological atypia, erythrocytes, muscular and vegetable fibres, colonies of bacteria in the absence of inflammatory infiltrate. This was consistent with the diagnostic hypothesis of oesophagus diverticulum, which was confirmed by means of a barium-swallow oesophagography. This case report underlines the possibility that a suspicious thyroid mass may result from a Zenker’s diverticulum, even if located on the right side, especially if the lesion has a heterogeneous echo-texture, a hypoechoic rim and internal hyperechoic spots.

Reliability of vertebral fractures assessment (VFA) in children with osteogenesis imperfecta.

The aim of this study is to evaluate the diagnostic accuracy of vertebral fractures assessment (VFA) in comparison with conventional radiography in identifying vertebral fractures in children and adolescents affected by OI. On 58 patients (33 males, 25 females; age range 1-18 years; 41 children and 17 adolescents) with osteogenesis imperfecta (OI type I, n = 44, OI type III, n = 4; OI type IV, n = 10), lateral spine images by radiographs and by dual-energy X-ray absorptiometry (DXA) were acquired. For vertebral fracture diagnosis, plain radiographs were used as "gold standard" and VFA and morphometric X-ray absorptiometry (MXA) were performed. The visualized vertebrae were 738 (97.9%) by radiographs and 685 (90.9%) by DXA of a total of 754 vertebrae from T4 to L4. VFA and MXA identified, respectively, 129 (74%) and 116 (66%) of the 175 vertebral fractures detected by radiographs. Radiographs identified 36 patients with vertebral fractures, VFA 35 and MXA 41 (6 false positives). On a per vertebra basis, radiographs and VFA had elevated agreement (93.9%; k score 0.81, 95% CI 0.76-0.86), that resulted slightly lower for MXA (90.6%; k score 0.72, 95% CI 0.65-0.78). VFA and MXA demonstrated high sensitivity (95.6 and 94.1 %, respectively) while specificity was 100% for VFA and 90.6% for MXA on a per patient basis; the agreement was excellent for VFA (98.3%; k score 0.96, 95% CI 0.89-1.03) and good for MXA (87.9%; k score 0.73, 95% CI 0.55-0.91). The diagnostic performance parameters resulted better for VFA (sensitivity 95.6%; specificity 100%; PPV 100%; NPV 97.2%), than for MXA (sensitivity 94.1%; specificity 85.4%; PPV 72.7%; NPV 97.2%). The results of our study demonstrate the reliability of VFA for diagnosis of vertebral fractures in children with OI suggesting its use as a more safe and practical alternative to conventional radiography.

Effect of risedronate in osteoporotic HIV males, according to gonadal status: a pilot study.

The aim of the study was to evaluate the effect of risedronate on bone mineral density (BMD) and bone turnover markers in HIV-infected osteoporotic males, according to their gonadal status. HIV patients were followed up for 24 months and divided into two groups: patients with osteoporosis or osteopenia with fractures (group A, n = 20) and those without (group B, n = 21). Group A and B were further divided according to the presence of reduced androgenizations. Both groups were treated with cholecalciferol 800 I.U. and calcium (Ca) 1,000 mg orally every day for the first 12 months. Risedronate 75 mg for two consecutive days a month orally was then added in group A, for another 12 months. Group B continued treatment with Ca and vitamin D. Every 6 months each patient underwent biochemical evaluation, and BMD measurement. A significant increase in lumbar BMD was observed in HIV males with adequate androgenization after 12 months of risedronate treatment in group A together with a reduction of bone turnover markers. BMD remained stable with a concomitant significant slight reduction of bone turnover markers in group B. Risedronate increased BMD and reduced bone turnover markers to a greater extent in patients with adequate androgenization compared to osteoporotic HIV males with symptomatic hypoandrogenization.

Effect of a single oral dose of 600,000 IU of cholecalciferol on muscle strength: a study in young women.

BACKGROUND: The effect of a single large oral dose of vitamin D on muscle function in young people with vitamin D deficiency has not been investigated so far. AIM: We evaluated the effect of a single oral dose of 600,000 IU of cholecalciferol on muscle strength. SUBJECTS AND METHODS: Eighteen young women with vitamin D deficiency received a single oral dose of 600,000 IU of cholecalciferol. We evaluated changes in maximal voluntary contraction (MVC) and speed of contraction (S) in response to cholecalciferol by using an hand held dynamometer at 3, 15, 30, 60 and 90 days, compared to baseline. RESULTS: We observed no significant change in MVC and S values, a significant increase of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and a significant decrease in serum parathyroid hormone (PTH) (p<0.001 for all). A significant correlation was found between MVC and S and serum phosphorus (P) after supplementation (p<0.02 and p<0.05, respectively). Conversely, we observed no association between the parameters of muscle strength and 25(OH)D, ionized calcium (Ca2+), PTH and 1,25(OH)2D. CONCLUSIONS: A single dose of 600,000 IU of cholecalciferol does not directly enhance handgrip strength in young women with vitamin D deficiency. More studies are needed on the indirect effect of the hormone on muscle.

Vertebral morphometry by dual-energy X-ray absorptiometry (DXA) for osteoporotic vertebral fractures assessment (VFA).

PURPOSE: This study was done to evaluate the diagnostic accuracy of dual-energy X-ray absorptiometry (DXA) compared with conventional radiography for identifying vertebral fractures. MATERIALS AND METHODS: A total of 930 postmenopausal women underwent conventional radiography and DXA imaging of the spine. The images were evaluated by two expert skeletal radiologists using the semiquantitative (SQ) method for conventional radiography and the morphometric vertebral fracture assessment (VFA) for DXA. RESULTS: The SQ method for radiography (SQ-Rx) analysed 99.1% of vertebrae, identifying 442 vertebral fractures; VFA analysed 97.5% vertebrae, detecting 420 vertebral fractures. Agreement between SQ-Rx and VFA reached 98.76%, and the κ-score was 0.96 [95% confidence interval (CI), 0.95-0.98]. Assessing the grading of vertebral fractures, agreement reached 97.5% and the κ-score was 0.841 (95% CI, 0.821-0.891). Considering SQ-Rx method as "gold standard", VFA had a sensitivity of 97.85 % and a specificity of 99.81%. The negative (NPV) and positive (PPV) predictive value for VFA were 99.83 % and 98.15%, respectively. Fractures were identified in 251 (27 %) and 242 (26 %) of patients on SQ-Rx and VFA, respectively. On a per-patient basis, the agreement between the two methods was 97% and the κ-score was 0.95 (95% CI, 0.920-0.968). The diagnostic parameters for VFA were 97.23% sensitivity, 98.86% specificity, 97.60% PPV and 98.84% NPV. CONCLUSIONS: This study demonstrated that VFA with DXA may reach a high level of accuracy for diagnosing vertebral fractures, suggesting that VFA should be introduced in the screening of individuals with a risk of osteoporosis and in the follow-up of osteoporotic patients receiving treatment.

A new predictive index for vertebral fractures: the sum of the anterior vertebral body heights.

UNLABELLED: Evaluation of osteoporotic vertebral fracture risk is currently based on measurement of bone mineral density (BMD), but bone strength depends also on bone quality parameters. Aim of this study was to evaluate the validity of a new vertebral morphometric index, the Anterior Vertebral Heights sum (AHs) in discriminating women at high risk of vertebral fracture, comparing its diagnostic accuracy with that of BMD measured at lumbar spine (LS-BMD) and femoral neck (FN-BMD). MATERIALS AND METHODS: A total of 163 Caucasian post-menopausal women (age range 46-74 years, mean age+/-SD=63.8+/-7.1 years), who did not present prevalent fractures at baseline evaluation, were observed at longitudinal follow-up. X-ray of the thoracic and lumbar spine, LS-BMD and FN-BMD measurements were obtained in all patients at baseline and repeated at the second follow-up visit 18-24 months later (mean 21+/-1.7 months). Radiographs of spine were analysed in order to identify vertebral fractures using a visual semiquantitative method (SQ) and vertebral morphometry as well as by calculating the AHs morphometric index. RESULTS: During follow-up, 21/163 patients (12.9%) sustained a new vertebral fracture; 95.2% (20/21) of fractured patients but only 4.9% (7/142) of non-fractured women had reduced AHs values. As regarding BMD, 66.6% (14/21) and 61.9% (13/21) of women with incident fracture were osteoporotic at lumbar spine and femoral neck baseline evaluation , whereas among non-fractured women, 38% (54/142) at LS-BMD and 33.1% (47/142) at FN-BMD were osteoporotic . Analyses of Receiver Operating Characteristic (ROC) curves showed that AHs discriminated vertebral fractures almost perfectly (AUC 0.97; 95% CI 0.95-0.99). On the other hand, the AUC for LS-BMD was only 0.73 (95% CI 0.64-0.81) and for FN-BMD was 0.72 (95%CI 0.63-0.80), showing that the diagnostic accuracy of AHs was significantly higher compared to that of LS-BMD (p<0.001) or FN-BMD (p<0.001). A modified Poisson regression model for binary data was used to assess the independent role of AHs in predicting vertebral fracture. The effect of AHs remained statistically significant (p<0.001) after adjusting by FN-BMD, age, weight and body height. CONCLUSIONS: Results of this study indicate the validity of this new morphometric index in evaluating the risk of osteoporotic vertebral fractures thus suggesting that AHs should be considered a valid parameter in clinical practice to assess the need for primary prevention of vertebral fractures.

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

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

Vertebral morphometry: current methods and recent advances.

Vertebral fractures are the hallmark of osteoporosis and are associated with increased morbility and mortality. Because a majority of vertebral fractures often occur in absence of specific trauma and are asymptomatic, their identification is radiographic. The two most widely used methods to determine the severity of vertebral fractures are the visual semiquantitative (SQ) assessment and the morphometric quantitative approach, involving the measurements of vertebral body heights. The measurements may be made on conventional spinal radiographs (MRX: morphometric X-ray radiography) or on images obtained from dual X-ray absorptiometry (DXA) scans (MXA: morphometric X-ray absorptiometry).The availability of a rapid, low-dose method for assessment of vertebral fractures, using advanced fan-beam DXA devices, provides a practical method for integrated assessment of BMD and vertebral fracture status. The visual or morphometric assessment of lateral DXA spine images may have a potential role for use as a prescreening tool, excluding normal subjects prior to performing conventional radiographs.

Cyclical changes of vertebral body heights and bone loss in healthy women after menopause.

Annual changes in vertebral body heights (VHs) and lumbar bone mineral density (LBMD) were evaluated in 120 healthy pre- and post-menopausal women aged 45-74 years. Subjects were divided into groups according to menstrual status and years since menopause (YSM). Vertebral heights were evaluated, using radiological morphometry as the sum of anterior vertebral body heights (AVHs) from T4 to L5 at baseline and exactly 12 months later. Results indicate that the sum of VHs is inversely correlated with advancing age, and the decrease in VHs is not a constant process over time but rather exhibits cyclical damping oscillations. When log-linear trend of VH decrease was transformed into a constant considering annual percentage changes, the presence of a cyclical component of 7 years was evident. Employing a harmonic regression model, the cyclical component was also statistically significant on baseline data. The cyclical decrease of VHs corresponds to an analogous cyclical behavior of LBMD values. These results suggest that a lack of estrogen acts as a synchronizer on bone remodeling, triggering a latent cyclical rhythm of bone loss, accompanied by cyclical bone microarchitecture deterioration and consequent vertebral body deformities, which after menopause persists throughout life. The existence of a chronobiological rhythm of bone loss and trabecular bone strength reduction at vertebral level after menopause, if confirmed, could have important clinical implications.

Abdominal CT findings may suggest coeliac disease.

BACKGROUND: Coeliac disease is the most common gastrointestinal immunological disorder in the western countries. Many adult patients present non-specific symptoms and signs of malabsorption such as chronic diarrhoea, anaemia, weight loss and abdominal distention. In non-specific and doubtful conditions, computed tomography is often the first medical examination performed. In a clinical practice, a critical review of computed tomography signs is therefore mandatory. AIMS: To evaluate the abdominal computed tomography findings, which are useful to suggest the presence of coeliac disease in adult patients. PATIENTS AND METHODS: The computed tomography studies of 28 coeliac patients were reviewed, looking for any intestinal and extraintestinal abnormality. The computed tomography findings evaluated were: abnormalities of intestinal fold pattern, bowel dilatation, fluid and air excess, duodenal abnormalities, intestinal intussusception, bowel wall thickening, lymphadenopathy, ascites, intestinal stenosis, mesenteric vascular changes. The abdominal computed tomography of a group of 30 normal subjects was also analysed. RESULTS: Intestinal fold pattern abnormalities were seen in 23/28 patients. Intestinal dilatation was seen in 21/28. Fluid excess in 18/28 and lymphadenopathy was seen in 12/28 patients; engorgement of mesenteric vessels in 7/28. Bowel wall thickening was observed in 6/28 patients and transient intussusception was observed in 6/28 patients. Increased air content within the bowel in 4/28 and ascites in 2/28 patients. Bowel dilatation together with fluid excess was observed in 18/28 patients. None of the above mentioned abnormalities abnormalities were seen in normal subjects. CONCLUSIONS: Data of the present study show that several abdominal computed tomography findings may be seen in coeliac adult patients; these findings should be taken into consideration with a high in level of suspicion by radiologists, to avoid diagnostic delay and unnecessary diagnostic and therapeutic procedures.

Type II benign osteopetrosis (Albers-Schönberg disease) caused by a novel mutation in CLCN7 presenting with unusual clinical manifestations.

A 16-year-old male patient with type II autosomal dominant benign osteopetrosis (ADO) was genotyped and found to harbor a novel mutation in exon 25 of the gene encoding for the osteoclast-specific chloride channel, CLCN7, inherited from the father, who was asymptomatic. The patient had normal biochemical findings and acid-base balance, except for increased serum levels of creatine kinase, lactic dehydrogenase, and the bone formation markers bone alkaline phosphatase isoenzyme, osteocalcin and N-terminal type I collagen telopeptide/creatinine ratio. Unusual generalized osteosclerosis was observed together with a canonical increase in vertebral and pelvis bone mass. An affected first grade cousin presented with normal biochemical findings and a milder osteosclerotic pattern of the pelvis. At the cellular level, cultured osteoclasts from the patient showed increased motility, with lamellipodia, membrane ruffling and motile pattern of podosome distribution, all of which could have contributed to functional impairment of bone resorption. The present report documents a novel mutation of the CLCN7 gene causing osteopetrosis in a radiologically uncertain form of the diseases, with apparent incomplete penetrance.

Adrenomedullin concentrations are elevated in plasma of patients with primary hyperparathyroidism.

The aim of the study was to evaluate plasma adrenomedullin (AM) concentration in primary hyperparathyroidism (PHP) and its effect on the regulation of blood pressure. Forty-one patients with PHP (25 normotensive and 16 hypertensive), and 31 healthy subjects (HS) were included in the study. As expected the total and ionized calcium and i-PTH serum levels were significantly higher in patients with PHP than in HS (P <.001). No significant difference was found in calcium-phosphorus metabolism parameters between normotensive and hypertensive PHP patients. Serum i-PTH levels correlated positively with systolic blood pressure (SBP) (r = 0.510; P <.02), diastolic blood pressure (DBP) (r = 0.586; P <.01) and heart rate (HR) (r = 0.486; P <.043) only in hypertensive PHP patients. Overall, mean plasma AM concentrations were significantly higher in PHP patients (16.1 +/- 7.9 pg/mL) than in HS (11.3 +/- 4.8 pg/mL) (P <.003) and correlated with i-PTH (r = 0.430; P <.005). However, in hypertensive PHP patients plasma AM levels (22.5 +/- 4.7 pg/mL) were higher than in normotensive PHP patients (11.6 +/- 1.8 pg/mL) (P <.001) and correlated with DBP (r = 0.902, P <.0029). In HS no correlation was found between plasma AM values and biohumoral, hormonal, or hemodynamic parameters. In conclusion, we demonstrated that in patients with PHP, plasma AM concentrations are increased and correlate with i-PTH and blood pressure values. We suggest that increased AM levels could be a compensatory factor in the defence mechanism against further blood pressure elevation.

Cyclical behavior of bone remodeling and bone loss in healthy women after menopause: results of a prospective study.

Annual changes in lumbar bone mineral density (LBMD) and bone remodeling markers were measured in 238 healthy pre- and postmenopausal women, aged 45-74 years. The subjects were divided into groups according to their menstrual status and years since menopause. The results obtained indicate that bone loss is not a constant process over time but rather exhibits cyclical damping oscillations. When the log-linear trend of LBMD decrement was transformed into a constant by considering annual percentage changes, the presence of a cyclical component of 7 years was evident. By employing a harmonic regression model, the cyclical component was also statistically significant on baseline data. The cyclical behavior of LBMD decrement corresponded to an analogous behavior of the bone remodeling markers. These results suggest that a lack of estrogen acts as a synchronizer on bone remodeling by triggering a latent cyclical rhythm of bone loss that persists throughout life after menopause. The existence of a chronobiological rhythm of bone loss starting after menopause, if confirmed, could have important clinical implications.

Plasma adrenomedullin concentrations in patients with adrenal pheochromocytoma.

BACKGROUND: The hypotensive peptide adrenomedullin was first isolated in extracts of human pheochromocytoma. There is, however, no information available on the behaviour of circulating adrenomedullin or on the correlation with catecholamines in patients with pheochromocytoma. OBJECTIVES: 1) to investigate whether plasma adrenomedullin levels were changed in 10 patients with pheochromocytoma when compared to 21 healthy subjects and 16 patients with essential hypertension; 2) to determine whether or not adrenomedullin has a counter-regulatory role in catecholamine excess in pheochromocytoma or is responsible for hemodynamic modifications before and after tumour resection; 3) to determine tissue distribution of iradrenomedullin in the pheochromocytoma. METHODS: Plasma adrenomedullin and catecholamine levels were measured in all patients with pheochromocytoma before and four weeks after tumour removal. In the four patients undergoing resection of tumours, plasma levels of adrenomedullin were measured at different time-points during surgery. RESULTS: The mean plasma adrenomedullin concentrations ( SD) in patients with pheochromocytoma (37.9 +/- 6pg/ml) were significantly higher (p<0.0001) than those in normal subjects (13.7 +/- 6.1 pg/mI) and patients with essential hypertension (22.5 +/- 9.lpg/ml). Adrenomedullin levels correlated with plasma noradrenaline (r = 0.516, p = 0.0124). In all patients with pheochromocytoma, plasma adrenomedullin concentrations decreased after removal of tumours (from 37.9 +/- 6 to 10.9 +/- 4.6 pg/ml; p < 0.0001). In the four patients studied during surgery, baseline plasma adrenomedullin and noradrenaline levels were markedly elevated, and increased significantly with tumour manipulation, decreasing 24 hours after operation. Adrenal medulla cells surrounding the pheochromocytoma site stained for ir-adrenomedullin, whereas only isolated cells of pheochromocytoma stained for the peptide. CONCLUSIONS: This study demonstrates that circulating adrenomedullin is increased in pheochromocytoma, and is also correlated with plasma noradrenaline levels. Adrenomedullin may represent an additional biochemical parameter for clinical monitoring of patients with pheochromocytoma.