Integrated Management of an Adult Patient with Mucopolysaccharidosis type IVA: A Case Report with a Six-Year Follow-up.

Mucopolysaccharidosis type IVA (MPS-IVA) is a rare lysosomal storage disease caused by N-acetylglucosamine-6-sulfate-sulfatase enzyme deficiency. MPS-IVA patients show severe extra-skeletal and skeletal manifestations, featured by bone pain and deformities, frailty fractures and early onset osteoporosis. The enzyme replacement therapy (ERT) with elosulfase-α stabilizes the MPS-IVA extra-skeletal manifestations but does not significantly improve MPS-IVA skeletal manifestations. We administered an integrated therapy to an MPS-IVA 41-year-old male patient, composed of zoledronic acid, cholecalciferol and a normocalcemic (calcium intake ≥1 g/day), hyposodic (sodium intake ≤5 g/day), and normocaloric diet (bone-diet), other than ERT. During the six-year follow-up, the patient did not develop any adverse events, obtaining an improvement of bone mineral density and quality of life. Given our results, we propose this integrated treatment (i.e. ERT, zoledronic acid, cholecalciferol, and bone diet) in the management of MPS-IVA adult patients. LEARNING POINTS: Mucopolysaccharidosis type IVA (MPS-IVA) is a genetic, rare, and degenerative spondylo-epiphyso-metaphyseal dysplasia characterized by extra-skeletal and skeletal manifestations. The latter impacts on MPS-IVA patient daily activities, and enzyme replacement therapy has a poor efficacy in improving skeletal involvement.The proposed integrated management with enzyme replacement therapy, zoledronic acid, cholecalciferol and bone diet improve both bone mineral density and the prognosis quoad valetudinem of our MPS-IVA patient.

Clinical Characteristics of Malignant Phosphaturic Mesenchymal Tumor Causing Tumor-Induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually caused by oversecretion of fibroblast growth factor 23 (FGF23) from a phosphaturic mesenchymal tumor (PMT). PMTs are usually benign neoplasms but some of them show malignant characteristics. OBJECTIVE: The aim of this study was to compare the clinical characteristics of benign and malignant PMTs inducing TIO. METHODS: On March 31, 2023, we performed a systematic review of individual patient data analysis in Medline, Google Scholar, Google book, and Cochrane Library using the terms "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia," with no language restrictions and according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. RESULTS: Overall, we collected data from 837 patients with TIO in which the diagnosis of benign and malignant PMT was specified. Of them, 89 were affected by malignant PMT and 748 by benign PMT. Patients with malignant PMTs were younger and presented bone pain, functional impairment, and bone deformities more frequently. Malignant PMTs showed higher values of intact FGF23 and a higher mortality rate. CONCLUSION: The study results identify the clinical characteristics of patients with malignant TIO, permitting the early identification of patients with PMT at increased risk of malignancy. This may significantly improve the diagnostic approach to disease. Further experimental studies are mandatory to clarify the role of FGF23 in the pathogenesis of malignancy in PMTs.

Drug treatment strategies for paget's disease: relieving pain and preventing progression.

INTRODUCTION: Paget's disease of bone (PDB) is a focal bone disorder caused by a marked dysregulation of osteoblasts and osteoclasts in basic multicellular units, leading to abnormal and disorganized deposition of collagen fibers (the so-called 'woven bone'). Therefore, pagetic bones are increased in size, and at increased risk for bone pain, deformities, fractures, osteoarthritis, and, more rarely, neoplastic degeneration. AREAS COVERED: In this review, we revise the available information concerning the pharmacological treatment of PDB. EXPERT OPINION: PDB progresses slowly within the affected skeletal sites and, if untreated, often leads to bone overgrowth, with bone pain, deformity, and a likely increased risk of complications. Thus, the primary goal of treatment is the restoration of a normal bone turnover, in order to relieve bone pain or other symptoms and possibly prevent the complications. PDB long remained a poorly treatable disorder until the discovery of antiresorptive agents such as calcitonin first and bisphosphonates (BPs) later. With the recent development of potent intravenous BPs like zoledronate, allowing a better control of disease activity over the long term with a single infusion, has contributed to a marked improvement of the clinical management of this invalidating disorder.

Update on the pathogenesis and genetics of Paget's disease of bone.

Studies over the past two decades have led to major advances in the pathogenesis of Paget's disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome "Inclusion Body Myopathy, PDB, Fronto-temporal Dementia," characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades.

Tumor-induced Osteomalacia: A Systematic Review and Individual Patient's Data Analysis.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, usually caused by small, benign, and slow-growing phosphaturic mesenchymal tumors. Clinically, TIO is characterized by renal phosphate leak, causing hypophosphatemia and osteomalacia. This review was performed to assess the clinical characteristics of TIO patients described worldwide so far. EVIDENCE ACQUISITION: On June 26, 2021, a systematic search was performed in Medline, Google Scholar, Google book, and Cochrane Library using the terms: "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia." There were no language restrictions. This review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. EVIDENCE RESULTS: Overall, 1725 TIO cases were collected. TIO was more frequent in adult men, who showed a higher incidence of fractures compared with TIO women. The TIO-causing neoplasms were identified in 1493 patients. The somatostatin receptor-based imaging modalities have the highest sensitivity for the identification of TIO-causing neoplasms. TIO-causing neoplasms were equally located in bone and soft tissues; the latter showed a higher prevalence of fractures and deformities. The surgery is the preferred TIO definitive treatment (successful in > 90% of patients). Promising nonsurgical therapies are treatments with burosumab in TIO patients with elevated fibroblast growth factor-23 levels, and with radiolabeled somatostatin analogs in patients with TIO-causing neoplasm identified by somatostatin receptor-based imaging techniques. CONCLUSION: TIO occurs preferentially in adult men. The TIO clinical expressiveness is more severe in men as well as in patients with TIO-causing neoplasms located in soft tissues. Treatments with burosumab and with radiolabeled somatostatin analogs are the most promising nonsurgical therapies.

Effectiveness of basal LH in monitoring central precocious puberty treatment in girls.

OBJECTIVES: Treatment of central precocious puberty (CPP) is based on administration of GnRH agonists in order to suppress hypothalamic-pituitary-gonadal axis and thus induce the stabilization or regression of pubertal development. Our aim was to determine whether the single basal serum LH and/or FSH concentration could be an effective tool to assess the efficacy of treatment to suppress activation of hypothalamic-pituitary axis. PATIENTS AND METHODS: Serum LH and FSH were measured before and after the GnRH injection, as well as E2 basal levels in 60 girls with documented idiopathic CPP at diagnosis and 18 and 30 months after the beginning of therapy. RESULTS: At diagnosis, peaks of >5 IU/L of LH and of FSH were observed in 100 and 91.6% of girls, respectively, with basal LH values of <1 IU/L in 70% and basal FSH levels of <1 IU/L in 10%. E2 were <20 pg/mL in 36.6%. After 18 months, a suppressed peak (i.e. <3 IU/L) was recorded in 85% of girls (p<0.01) for LH and in 98.3% for FSH (p<0.01). Basal LH <1 IU/L was detected in 85% (p<0.01) and basal FSH ≤1 IU/L in 40% (p<0.01). Serum E2 ≤20 pg/mL was recorded in 61.6% (p<0.01). After 30 months, all patients showed LH suppressed peak (p<0.01) and 98.3% suppressed FSH peak (p<0.01). 100% showed basal LH concentrations <1 IU/L (p<0.01) and 38.3% FSH basal values <1 UI/mL (p<0.01). E2 ≤20 pg/mL was observed in 32.72% (p=NS). CONCLUSIONS: Basal LH values are a reliable indicator of the efficacy of GnRHa therapy after 30 months of GnRHa therapy.

Paget's Disease of Bone.

Paget's disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.

Interleukin-6 trans-signaling and pathological low back pain in patients with Paget disease of bone.

The interleukin (IL)-6 biological system plays a key role in the pathogenesis of Paget disease (PD) of bone and pathological bone pain. Bone pain, particularly in the lower back region, is the most frequent symptom in patients with PD. This case-control study aimed to evaluate the relationship between the IL-6 system and low back pain (LBP) in patients with PD. We evaluated 85 patients with PD, with the disease localized in the lumbar spine, pelvis, and/or sacrum, and classified them based on the presence or absence of LBP, before and after aminobisphosphonate treatment. We also examined 32 healthy controls without LBP. Before treatment, IL-6 levels in patients with PD were higher than those in the controls, without difference between patients with or without LBP. Patients with PD with LBP (35/85) showed higher IL-6-soluble receptor (sIL-6R) and lower soluble glycoprotein (sgp) 130 levels compared with both patients with PD without LBP and controls (sIL-6R: 46.9 ± 7.4 vs 35.4 ± 8.6 vs 29.9 ± 4.2 ng/mL; sgp130: 307.2 ± 35.4 vs 341.4 ± 41.4 vs 417.1 ± 58.5 ng/mL, respectively). Paget disease remission, 6 months after treatment, is associated with LBP improvement. This phenomenon is associated with reduced sIL-6R levels and increased sgp130 levels in patients with PD with LBP at the baseline. Considering the biological properties of IL-6, sIL-6R, and sgp130, the results of the study suggest that the perception of LBP in patients with PD could be linked to an enhanced transmission of IL-6 signal in the specialized neural system activated by nociceptors.

Risk factors for silent myocardial ischemia in patients with well-controlled essential hypertension.

Silent myocardial ischemia (SMI) is frequently observed in patients with essential hypertension (EH). The major risk factor for SMI is uncontrolled blood pressure (BP), but SMI is also observed in patients with well-controlled BP. To evaluate the prevalence of SMI and the factors associated with SMI in EH patients with well-controlled BP. The medical records of 859 EH patients who underwent simultaneous 24-h ambulatory blood pressure monitoring (ABPM) and 24-h ambulatory electrocardiogram recording (AECG) were retrospectively evaluated. Each SMI episode was characterized by: (a) ST segment depression ≥0.5 mm; (b) duration of ST segment depression >60 s; and (c) reversibility of the ST segment depression. Overall 126 EH patients (14.7 %) had at least one episode of SMI. The SMI events were more frequent among patients with poorly controlled compared to those with well-controlled BP [86/479 (17.95 %) vs. 40/380 (10.52 %), p < 0.01]. Among EH patients with well-controlled BP, current and past smoking as well as the presence of an additional metabolic syndrome (MetS) constitutive element (obesity, impaired fasting glucose level or dyslipidemia) were significantly associated with the occurrence of SMI. In all EH patients with well-controlled BP and AECG evidence of SMI, there were one or more coronary artery stenotic lesions greater than 50 % found at coronary angiography. In EH patients who are current smokers, or have one or more additional components of a MetS there is markedly reduced benefit associated with good BP control with regard to the occurrence of myocardial ischemia: in this patient category, an AECG may help detect this condition.

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

Dietary treatment of urinary risk factors for renal stone formation. A review of CLU Working Group.

OBJECTIVE: Diet interventions may reduce the risk of urinary stone formation and its recurrence, but there is no conclusive consensus in the literature regarding the effectiveness of dietary interventions and recommendations about specific diets for patients with urinary calculi. The aim of this study was to review the studies reporting the effects of different dietary interventions for the modification of urinary risk factors in patients with urinary stone disease. MATERIALS AND METHODS: A systematic search of the Pubmed database literature up to July 1, 2014 for studies on dietary treatment of urinary risk factors for urinary stone formation was conducted according to a methodology developed a priori. Studies were screened by titles and abstracts for eligibility. Data were extracted using a standardized form and the quality of evidence was assessed. RESULTS: Evidence from the selected studies were used to form evidence-based guideline statements. In the absence of sufficient evidence, additional statements were developed as expert opinions. CONCLUSIONS: General measures: Each patient with nephrolithiasis should undertake appropriate evaluation according to the knowledge of the calculus composition. Regardless of the underlying cause of the stone disease, a mainstay of conservative management is the forced increase in fluid intake to achieve a daily urine output of 2 liters. HYPERCALCIURIA: Dietary calcium restriction is not recommended for stone formers with nephrolithiasis. Diets with a calcium content ≥ 1 g/day (and low protein-low sodium) could be protective against the risk of stone formation in hypercalciuric stone forming adults. Moderate dietary salt restriction is useful in limiting urinary calcium excretion and thus may be helpful for primary and secondary prevention of nephrolithiasis. A low-normal protein intake decrease calciuria and could be useful in stone prevention and preservation of bone mass. Omega-3 fatty acids and bran of different origin decreases calciuria, but their impact on the urinary stone risk profile is uncertain. Sports beverage do not affect the urinary stone risk profile. HYPEROXALURIA: A diet low in oxalate and/or a calcium intake normal to high (800-1200 mg/day for adults) reduce the urinary excretion of oxalate, conversely a diet rich in oxalates and/or a diet low in calcium increase urinary oxalate. A restriction in protein intake may reduce the urinary excretion of oxalate although a vegetarian diet may lead to an increase in urinary oxalate. Adding bran to a diet low in oxalate cancels its effect of reducing urinary oxalate. Conversely, the addition of supplements of fruit and vegetables to a mixed diet does not involve an increased excretion of oxalate in the urine. The intake of pyridoxine reduces the excretion of oxalate. HYPERURICOSURIA: In patients with renal calcium stones the decrease of the urinary excretion of uric acid after restriction of dietary protein and purine is suggested although not clearly demonstrated. HYPOCITRATURIA: The administration of alkaline-citrates salts is recommended for the medical treatment of renal stone-formers with hypocitraturia, although compliance to this treatment is limited by gastrointestinal side effects and costs. Increased intake of fruit and vegetables (excluding those with high oxalate content) increases citrate excretion and involves a significant protection against the risk of stone formation. Citrus (lemons, oranges, grapefruit, and lime) and non citrus fruits (melon) are natural sources of dietary citrate, and several studies have shown the potential of these fruits and/or their juices in raising urine citrate levels. CHILDREN: There are enought basis to advice an adequate fluid intake also in children. Moderate dietary salt restriction and implementation of potassium intake are useful in limiting urinary calcium excretion whereas dietary calcium restriction is not recommended for children with nephrolithiasis. It seems reasonable to advice a balanced consumption of fruit and vegetables and a low consumption of chocolate and cola according to general nutritional guidelines, although no studies have assessed in pediatric stone formers the effect of fruit and vegetables supplementation on urinary citrate and the effects of chocolate and cola restriction on urinary oxalate in pediatric stone formers. Despite the low level of scientific evidence, a low-protein (< 20 g/day) low-salt (< 2 g/day) diet with high hydration (> 3 liters/day) is strongly advised in children with cystinuria. ELDERLY: In older patients dietary counseling for renal stone prevention has to consider some particular aspects of aging. A restriction of sodium intake in association with a higher intake of potassium, magnesium and citrate is advisable in order to reduce urinary risk factors for stone formation but also to prevent the loss of bone mass and the incidence of hypertension, although more hemodynamic sensitivity to sodium intake and decreased renal function of the elderly have to be considered. A diet rich in calcium (1200 mg/day) is useful to maintain skeletal wellness and to prevent kidney stones although an higher supplementation could involve an increase of risk for both the formation of kidney stones and cardiovascular diseases. A lower content of animal protein in association to an higher intake of plant products decrease the acid load and the excretion of uric acid has no particular contraindications in the elderly patients, although overall nutritional status has to be preserved.

Clinical characteristics and evolution of giant cell tumor occurring in Paget's disease of bone.

Patients with Paget's bone disease (PDB) have an increased risk of developing giant cell tumor (GCT). This study was performed to evaluate the clinical characteristics and evolution of GCT complicating PDB and to compare these clinical characteristics to those observed in two large PDB cohorts, the PDB Italian Registry and the United Kingdom's Multi-Centre Randomised Controlled Trial of Symptomatic Versus Intensive Bisphosphonate Therapy for Paget's Disease (PRISM) study. A systematic literature review identified 117 cases of PDB complicated by GCT (PDB-GCT), which involved the skeletal sites affected by PDB (110 patients) or the extraskeletal tissues adjacent to affected bones (7 patients). In contrast to what previously reported for GCT patients without GCT patients (83.2%) were white and one-fourth of them (24.8%) had multifocal GCTs. Compared to PDB patients without GCT, PDB-GCT patients showed a higher male/female ratio (2.1 versus 1.2) and more severe disease (age at PDB onset 52.1 ± 12.1 versus 63.3 ± 10.6 years; number of affected sites 6.1 ± 2.9 versus 2.34 ± 1.6; prevalence of polyostotic PDB 93.3% versus 60.6%). The mortality rate of PDB-GCT patients was higher than those occurring in GCT patients without PDB (about 50% versus 0% to 5% at 5 years) or in PDB patients without GCT (log rank = 29.002). Moreover, up to 98% of PDB-GCT cases had elevated total alkaline phosphatase levels at neoplasm diagnosis, suggestive of active PDB. Importantly, PDB-GCT patients from Southern Italy (45.6% of all GCT patients) showed a higher prevalence of multifocal GCT (51.7%) and of positive familial history for PDB (70.8%) and GCT (65.0%). Finally, indirect evidence suggests a decline in the incidence of GCT in PDB patients. The occurrence of GCT in PDB patients is associated with severe disease and reduced life expectancy of affected patients. The increased prevalence of familial diseases in PDB-GCT patients from Southern Italy suggests a founder effect. The observed changes over time in the incidence of GCT in PDB patients could be related to improved clinical management and/or living conditions of patients.

Giant cell tumor occurring in familial Paget's disease of bone: report of clinical characteristics and linkage analysis of a large pedigree.

Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree.

A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease.

Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for the T575C variant, yielding an odds ratio of 1.29 (p = 0.003), with the C allele as the risk allele. Moreover, an even more significant p-value (p = 0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly, patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively; p = 0.01), as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p = 0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, cotrasfection with mutated SQSTM1 and TNFRSF11A(A192) produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11A(V192), confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations.

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone.

Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age-related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 +/- 2.0 versus 2.19 +/- 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 +/- 2.5 versus 2.76 +/- 2.2, p < .05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations in influencing disease severity.

Bone turnover and the osteoprotegerin-RANKL pathway in tumor-induced osteomalacia: a longitudinal study of five cases.

To evaluate serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-kappaB (RANKL), and their relationship with FGF-23, lumbar bone mineral density (BMD), and bone turnover markers, five patients with tumor-induced osteomalacia (TIO) and 40 healthy controls were studied. TIO patients were followed for 360 days after surgical removal of underlying tumor (n = 2) or beginning of therapy with phosphate and calcitriol when surgical treatment was impossible (n = 3). At diagnosis, TIO patients had higher levels of FGF-23 and bone-specific alkaline phosphatase (bALP) and lower levels of cathepsin K (CathK), RANKL, and RANKL/OPG ratio compared to controls. During the follow-up, FGF-23 decreased significantly only in patients who underwent a surgical excision, while phosphate and BMD increased in all patients. The increases in BMD, phosphate, and renal phosphate reabsorption rate were directly related. In the first 60 days of follow-up, we observed a prolonged inhibition of RANKL, CathK, and bone resorption markers associated with a persistence of TIO symptoms and an increase in bALP. From day 60, levels of bone turnover markers returned progressively within the normal range and a clinical remission was observed. The inhibition of the RANKL/OPG pathway and the uncoupling of bone formation and resorption observed in patients with active TIO may be a compensatory mechanism, attempting to reduce worsening of osteomalacia. The BMD increase during TIO treatment is related to the improvement of phosphate rather than FGF-23 levels. A "hungry bone"-like syndrome was observed after surgical or pharmacological treatment.

Predictors of in-hospital and long-term clinical outcome in elderly patients with massive pulmonary embolism receiving thrombolytic therapy.

OBJECTIVES: To determine the clinical, historical, and instrumental findings associated with unfavorable short-term and long-term prognosis in elderly patients (>or=65) receiving thrombolytic therapy for pulmonary embolism (PE). DESIGN: Case-control retrospective study. SETTING: General medicine acute care ward. PARTICIPANTS: Sixty-seven elderly patients with PE complicated by hemodynamic instability (massive PE) admitted to the "Antonio Cardarelli" Hospital from January 1, 2002, to December 31, 2004, and evaluated during their hospital stay and 174.4+/-4.6 days after discharge. MEASUREMENTS: PE diagnosis was confirmed using spiral computed tomography angiography. Hemodynamic instability was defined as cardiogenic shock and systolic blood pressure less than 90 mmHg or a pressure drop of 40 mmHg or more for longer than 15 minutes not due to new-onset arrhythmia, hypovolemia, or sepsis. INTERVENTION: Weight-adapted unfractionated heparin and recombinant tissue plasminogen activator. RESULTS: Nine patients (13.4%) died during hospitalization. Higher troponin-I (cTn-I) serum levels at admission to the emergency department and the occurrence of thrombocytopenia after thrombolysis were significantly associated with in-hospital death. Nineteen of the 58 survivors (32.7%) died during follow-up. The risk factors for long-term death were historical findings of cancer and cardiovascular disease at hospital admission. CONCLUSION: Higher cTn-I serum levels in the acute phase and the occurrence of thrombocytopenia after thrombolysis were significantly associated with in-hospital mortality in elderly patients with massive PE. In the same setting, historical findings of cancer and cardiovascular disease are strong predictors of death in the long term.

Evidence for increased clinical severity of familial and sporadic Paget's disease of bone in Campania, southern Italy.

UNLABELLED: The analysis of 236 Italian patients with Paget's bone disease showed higher clinical severity and greater frequency of neoplastic degeneration among patients who live or descend from individuals living in the Campania region (southern Italy). A prevalent involvement of the spine and the skull, the sites preferentially involved in giant cell tumors complicating Paget's disease, was also shown in familial cases from this geographical region. INTRODUCTION: The Campania region in southern Italy has been recently indicated as a high prevalence area for Paget's disease of bone (PDB), and most pagetic families with multiple occurrence of neoplasms in affected members were from this geographical region. MATERIALS AND METHODS: We evaluated the PDB epidemiological characteristics in 125 patients from Campania in comparison with 111 patients from other Italian regions. Twenty-three patients from Campania and 26 patients from other Italian areas had at least one first-degree relative affected by PDB (familial cases). The remaining patients made up the sporadic cases. RESULTS: Among subjects from Campania, the patients in the familial group tended to come from larger families and showed at diagnosis higher serum total alkaline phosphatase, larger extension of disease, and earlier mean age with respect to patients with PDB of the sporadic group. The skull, spine, and humerus were the sites preferentially involved in the familial cases. In contrast, no such differences were observed between familial and sporadic PDB cases among patients from the other geographical areas, except for a lower age at diagnosis. An increased PDB clinical severity was finally observed in the PDB cohort from Campania in comparison with patients from other Italian regions. Neoplastic degeneration of pagetic bones (osteosarcoma and giant cell tumor) was exclusively observed in patients with polyostotic PDB from Campania. CONCLUSIONS: We showed a higher clinical severity of PDB with occurrence of neoplastic degeneration in the high prevalence area of Campania, with its maximum expression in cases with familial disease. This peculiar pattern might be traced to genetic predisposition and/or to the abnormal impact of a still undefined environmental trigger.

Fibroblast growth factor 23 is increased in calcium nephrolithiasis with hypophosphatemia and renal phosphate leak.

CONTEXT: Nephrolithiasis affects about 10% of the population in industrialized countries, with calcium salts composing more than 80% of renal stones. A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function show hypophosphatemia and reduced renal phosphate reabsorption (i.e. a renal phosphate leak). OBJECTIVES: The objective of the study was to compare serum levels of fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, in 110 recurrent stone formers with or without renal phosphate leak, six patients affected by X-linked hypophosphatemic rickets, five patients affected by oncogenic osteomalacia, and 60 unrelated healthy controls. DESIGN: This was a prospective interventional study. METHODS: Renal phosphate leak was identified based on the occurrence of idiopathic hypophosphatemia [serum phosphate concentration < 2.50 mg/dl (<0.80 mmol/liter)] and reduced renal threshold phosphate concentration [<2.2 mg/liter (<0.70 mmol/liter)]. RESULTS: In 22 stone formers with renal phosphate leak, serum FGF23 concentration was significantly higher as compared with 88 stone formers without renal phosphate leak and with controls [83.3 (65.6-101.1) vs. 32.1 (26.8-37.4) and 24.5 (19.8-29.1) reference units (RU)/ml, respectively]. Stone formers with renal phosphate leak showed lower FGF23, compared with patients with oncogenic osteomalacia and X-linked hypophosphatemic rickets [572.3 (235.9-908.7) RU/ml]. Among stone formers and controls, serum FGF23 concentration displayed a strong inverse association with serum phosphate (r = -0.784, P = 0.009) and the rate of tubular phosphate reabsorption (r = -0.791, P = 0.008). CONCLUSIONS: In our study population, renal phosphate leak affected 20% of stone formers and was strongly associated with increased serum FGF23 concentration.