Adult Paget's disease of bone: a review.

Adult PD of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterized by increased bone cell activity, with bone-resorbing osteoclasts often larger and containing more nuclei than normal, and osteoblasts producing increased amounts of disorganized bone. This leads to expanded bone of poor quality possessing both sclerotic and lytic areas. PD of bone has a strong genetic element, with a family history being noted in 10-20% of cases. A number of genetic defects have been found to be associated with the condition. The most common disease-associated variants identified affect the SQSTM1 gene, providing insights into disease aetiology, with the clinical value of knowledge of SQSTM1 mutation status currently under active investigation. The diagnosis may be suggested by an isolated raised total ALP without other identifiable causes. This can be confirmed on plain X-rays and the extent determined by isotope bone scan. The mainstays of treatment are the bisphosphonates, especially i.v. zoledronate, which results in long-term suppression of bone turnover. ALP is the usual means of monitoring the condition, although more specific bone turnover markers can be helpful, especially in coincident liver disease. Patients should be followed up to monitor for biochemical relapse or development of complications, which may require medical or surgical intervention.

Diagnosis and treatment of Paget's disease of bone : A clinical practice guideline.

Paget's disease of bone (osteitis deformans) is a benign focal disorder of accelerated skeletal remodeling. Either a single bone (monostotic) or multiple bones (polyostotic) can be affected. In patients with suspected Paget's disease plain radiographs of the suspicious regions of the skeleton are recommended. The initial biochemical evaluation of a patient should be done using serum total ALP (alkaline phosphatase) or with the use of a more specific marker of bone formation: PINP (intact N-terminal type 1 procollagen propeptide) or CTX (cross-linked C­telopeptide). Treatment with a bisphosphonate is recommended for most patients with active Paget's disease who are at risk for further skeletal and extraskeletal complications. A single dose of 5 mg i.v. zoledronate as the treatment of choice in patients without contraindications is suggested. Oral bisphosphonates are less potent when compared to zoledronate. Treatment with an antiresorptive agent induces a more rapid decrease in resorption markers compared to formation marker. Measurement of total ALP or other baseline disease activity markers (e. g. CTX) at 6 to 12 weeks, when bone turnover will have shown a substantial decline, is an acceptable and cost-effective option. Maximum suppression of high bone turnover may require measurement at 6 months after administration. In patients with increased bone turnover, biochemical follow-up is recommended to be used as a more objective indicator of relapse rather than symptoms. The prolonged response after zoledronate treatment should be assessed every 1-2 years after normal bone turnover. With less potent drugs, every 6 to 12 months is appropriate.

Clinical efficacy of oral risedronate therapy in Japanese patients with Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic disorder characterized by localized bone regions with excessive bone turnover. Although oral risedronate (17.5 mg daily for 8 weeks) was recently approved in Japan, its efficacy is not well understood. We retrospectively examined the efficacy of oral risedronate in PDB patients in a clinical setting. Eleven patients whose serum alkaline phosphatase (ALP) level exceeded the upper limit of the normal range were treated. Patients whose ALP levels normalized and remained so for 12 months after therapy initiation were defined as responders. Treatment was repeated if bone pain recurred or if serum ALP levels increased at least 25% above the nadir. Six patients (55%) were responsive to the therapy. A higher prevalence of skull lesions, higher serum calcium levels at treatment initiation and antecedent treatments of bisphosphonates were predictors of resistance against the therapy. Fresh frozen serum samples obtained from some treatment sessions were evaluated for metabolic bone markers such as bone-specific ALP (BAP), type I procollagen N-terminal pro-peptide (PINP), N-treminal crosslinking telopeptide of type I collagen and C-treminal crosslinking telopeptide of type I collagen (CTX). A significant reduction of P1NP preceded that of serum ALP levels in the responders, which was followed by a similar occurrence for BAP and osteocalcin (BGP) levels. A temporary decrease in CTX levels was noted. No significant changes in markers (including ALP level) were observed in non-responder and repeat-treatment groups. P1NP levels may be more useful than ALP levels in assessing treatment efficacy. Repeat treatment effectiveness for the repeat-treatment group was limited.

Efficacy of zoledronic acid treatment in Paget disease of bone.

UNLABELLED: Clinical trials have shown that zoledronic acid was more effective than other bisphosphonates in the treatment of Paget disease. We retrospectively reviewed remission and relapse statuses of 12 patients with Paget disease. Remission was achieved in all patients after treatment. We recommend zoledronic acid in the first-line treatment of Paget disease. INTRODUCTION: Paget disease is a disease of bone of unknown etiology with increased bone turnover that results in defective bone microarchitecture and bone deformity. Bisphosphonates are used in symptomatic Paget disease of bone. Clinical trials have shown that zoledronic acid was more effective than other bisphosphonates in the treatment of Paget disease. METHODS: In this study, we retrospectively reviewed the remission and relapse statuses of 12 patients with Paget disease of bone who were seen as outpatients between October 2011 and October 2013.We evaluated alkaline phosphates, osteocalcin, and deoxypyridinoline levels measured before and at 6th, 12th, and 18th months of treatment. RESULTS: Pretreatment and posttreatment values for alkaline phosphates, deoxypyridinoline, and osteocalcin were as follows: 473 ± 256 U/L, 14.99 ± 7.63 mmol/L, 21.09 ± 3.18 ng/ml, and 82 ± 13 U/L, 5.14 ± 1.11 mmol/L, and 8.57 ± 4.31 ng/ml. Remission was achieved in all patients after treatment. The levels indicated that remission continued at 12th and 18th months of treatment. There was statistically significant difference between pretreatment and posttreatment values. No statistically significant difference between the levels measured at 6th, 12th, and 18th months of treatment was detected. CONCLUSION: We recommend zoledronic acid in the first-line treatment of Paget disease of bone in achieving and maintaining remission.

Asymptomatic Paget's bone disease in ethnic Thais: a series of four case reports and a review of the literature.

Paget's bone disease is quite common in some parts of Europe and countries inhabited by European emigrants, but it is rare in Asia. There have been only 13 reported cases in Southeast Asia, including one reported case from Thailand. Half of the previously reported cases had bone symptoms and the other half were asymptomatic, but were incidentally discovered when patients were being investigated for other medical problems. Here are reported cases of four asymptomatic patients who presented elevation of serum alkaline phosphatase during routine annual medical checkups. All patients were of Chinese descent and all cases were proven by biopsy. Based on this experience, we are of the opinion that a substantial number of unrecognized cases of Paget's disease exist among ethnic Thais. We feel that they would be revealed if clinicians were alerted of its presence and if they included it as a possible diagnosis together with metastasis and osteoporosis when examining bone lesions or when results for elevated serum alkaline phosphatase are detected during routine checkups. We also anticipate that a higher prevalence of this disease may occur in future Thai generations due to the addition of offspring from Asian-European intermarriages to offspring of Chinese descent in the ethnic Thai population.

Pain in Paget's disease: a retrospective study of treatment efficacy.

The authors addressed the role and the management of pain in Paget's disease by a retrospective study. The objectives were: to assess the presence of pain in Paget's disease; to look for a relationship between pain and the levels of total alkaline phosphatase (total ALP); to verify if the most commonly used drugs in Paget's disease, calcitonin and bisphosphonates, were able to reduce the pain and the levels of total ALP. The study analyzed 107 Italian patients with Paget's disease who were hospitalized at the same Institute between 1970 and 2010; all patients affected by severe arthritis were excluded. From the analysis of the clinical records it emerged that as many as 85% of patients had pain and that total ALP was also increased in most of the patients with pain in comparison with patients without pain. The clinical and metabolic effects of different therapies were then assessed: many patients had not received any specific therapy (58%), others had been treated with calcitonin (25%) and others with bisphosphonates (17%). In fact, the patients treated with bisphosphonates had significantly lower levels both of pain and total ALP. The authors hypothesize that the pain in Paget's disease has a primary origin and is correlated to the degree of bone metabolic hyperactivity. Finally, treatment with bisphosphonates appeared to be the most appropriate treatment, having been able to control both the pain and the metabolic hyperactivity.

Profound hypocalcemia following effective response to zoledronic acid treatment in a patient with juvenile Paget's disease.

Juvenile Paget's disease (JPD) is a rare, autosomal recessive osteopathy. Although it has phenotypic overlap with Paget's disease of bone (PDB), it is probably a distinct entity. Because of its rarity, optimal disease management has not yet been established by randomized controlled trials. However, clinical, biochemical, and radiographic improvement has been reported after treatment with antiresorptive agents, including calcitonin and bisphosphonates (BPs). Compared with other BPs, zoledronic acid (ZOL) has a higher affinity to bone mineral and is a stronger inhibitor of the enzyme farnesyl pyrophosphate synthase (the main target of nitrogen-containing BPs), properties that explain the prolonged effect of ZOL on bone turnover and render it a therapeutic option for JPD, similar to PDB. We describe hereby, for the first time in the literature, the case of a patient with JPD who developed severe hypocalcemia and secondary hyperparathyroidism following effective treatment with ZOL.

Dual-energy X-ray absorptiometry and quantitative ultrasound in patients with Paget's disease of bone before and after treatment with zoledronic acid: association with serum bone markers and Dickkopf-1.

The main aim of this study was to determine the effect of zoledronic acid (ZOL) on parameters of dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in unaffected bones of patients with Paget's disease of bone (PDB). The secondary aim was the association of bone markers and Dickkopf (DKK)-1 with parameters of DXA and QUS. Ten consecutive patients with polyostotic PDB (median age: 63 yr) received a single 5-mg ZOL infusion. The patients were subjected to calcaneal QUS and DXA of both lumbar spine (LS) and femoral neck (FN). Blood samples for serum bone markers and DKK-1 were serially obtained for 12 mo. There was a significant increase in LS (p=0.005) and FN bone mineral density (BMD) (p=0.021) 12 mo after ZOL infusion. QUS parameters remained unaffected throughout the study. A significant correlation between broadband ultrasound attenuation and DKK-1 (p<0.001) and between speed of sound and DKK-1 (p=0.033) at baseline was found, which remained significant after adjustment for gender, age, and body mass index. Our data suggest that a single ZOL infusion significantly increases nonpagetic BMD 12 mo after treatment but has no effect on QUS parameters or DKK-1. Significant correlations were observed between QUS parameters and DKK-1 at baseline.

Circulating and tissue-derived isoforms of bone alkaline phosphatase in Paget's disease of bone.

BACKGROUND: Alkaline phosphatase (ALP) is routinely used in the assessment of Paget's disease of bone (PDB); however, the individual bone ALP isoforms (B/I, B1, and B2) have not been investigated in this disorder. METHODS: Subjects comprised 37 patients (mean age 74 years) with symptomatic PDB confirmed by radiograph and stratified into high and low total ALP activity groups and 66 healthy individuals (mean age 64 years). Extracts of human cancellous and cortical bone tissues were also investigated. The bone ALP isoforms, measured by HPLC, were compared with two bone ALP immunoassays (Metra and Ostase), and the bone formation marker intact amino-terminal procollagen type I propeptide (iPINP). RESULTS: All bone ALP isoforms were increased in high ALP activity PDB compared with the low ALP activity and control groups (p < 0.0001). The B2 isoform had the greater relative activity representing 36%, 50%, and 71%, of the total ALP activity in the control, low and high ALP activity groups, respectively. Compared with controls, B2 was increased in the low ALP activity PDB group (p < 0.05). ROC analysis showed a validity of approximately 80% for B2 to discriminate patients with PDB. CONCLUSION: All bone ALP isoforms were increased in patients with high ALP activity PDB and the B2 isoform was even elevated in the low ALP activity PDB group. The bone ALP isoform B2 may be of use in the management of PDB but that has to be further elucidated in subsequent studies.

Preventive Role of Vitamin D Supplementation for Acute Phase Reaction after Bisphosphonate Infusion in Paget's Disease.

CONTEXT: Intravenous aminobisphosphonates (N-BPs) can induce an acute phase reaction (APR) in up to 40% to 70% of first infusions, causing discomfort and often requiring intervention with analgesics or antipyretics. OBJECTIVE: Our aim was to explore the risk factors of APR in a large sample of patients with Paget's disease of bone (PDB) and to assess the possible preventive effects of vitamin D administration. METHODS: An observational analysis was performed in 330 patients with PDB at the time of N-BP infusion. Then, an interventional study was performed in 66 patients with active, untreated PDB to evaluate if vitamin D administration (oral cholecalciferol 50 000 IU/weekly for 8 weeks before infusion) may prevent APR. RESULTS: In a retrospective study, APR occurred in 47.6% and 18.3% of naive or previously treated patients, respectively. Its prevalence progressively increased in relation to the severity of vitamin D deficiency, reaching 80.0% in patients with 25-hydroxyvitamin D (25OHD) levels below 10 ng/mL (relative risk (RR) = 3.7; 95% confidence interval (CI) 2.8-4.7, P < .0001), even in cases previously treated with N-BPs. Moreover, APR occurred more frequently in patients who experienced a previous APR (RR = 2.8; 95% CI 1.5-5.2; P < .001) or in carriers of SQSTM1 mutation (RR = 2.3; 95% CI 1.3-4.2; P = .005). In the interventional study, vitamin D supplementation prevented APR in most cases, equivalent to a RR of 0.31 (95% CI 0.14-0.67; P < .005) with respect to prevalence rates of the observational cohort. A similar trend was observed concerning the occurrence of hypocalcemia. CONCLUSIONS: The achievement of adequate 25OHD levels is recommended before N-BP infusion in order to minimize the risk of APR or hypocalcemia in PDB.

Osteoclast signaling-targeting miR-146a-3p and miR-155-5p are downregulated in Paget's disease of bone.

MicroRNA (miRs) are small, non-coding RNA that post-transcriptionally regulate DNA expression. We hypothesized that specific miR profiles may be a feature of overactive osteoclasts in Paget's disease of bone (PDB), a disorder characterized by an increased and disorganized bone remodeling that typically begins with excessive bone resorption. We compared the expression profile of 13 miRs in human osteoclasts differentiated in vitro from peripheral blood mononuclear cells (PBMCs) of patients with PDB (n = 10) or age- and sex- matched healthy subjects (n = 10). We selected 13 miRs for testing, on the basis of their previously reported roles either in human osteoclast differentiation, in bone diseases, or in osteoclast important signaling pathways. From those expression results, 3 miRNAs were further selected for in-vitro studies aiming at modulating miR expression in human cord blood monocyte derived osteoclasts: 2 miRs (miR-146a-3p and miR-155-5p) whose expression was significantly reduced in pagetic osteoclasts, as well as miRNA-133a-3p, stable in PDB relative to controls, but with known regulatory importance within osteoclasts. We demonstrated a positive (miR-133a-3p) or negative (miR-155-5p, miR-146a-3p) impact of those miRs on the formation of osteoclasts and/or their bone resorption capacity in this human model. Signaling pathways were significantly affected, including p38 MAP-kinase (miR-133a-3p), RANKL-induced TRAF6/NFκB signaling (miR-146a-3p), and MITF expression (miR-155-5p). Osteoclast miRNA profiles might have an important value to yield significant new insights into the osteoclast phenotype in PDB and in other bone diseases with hyperactive osteoclasts.

The effect of zoledronic acid on serum dickkopf-1, osteoprotegerin, and RANKL in patients with Paget's disease of bone.

Overexpression of dickkopf (DKK)-1 in pagetic osteoblast cultures resulted in stimulation of osteoclast proliferation and inhibition of osteoblast growth. The aim of this study was to evaluate for the first time in Paget's disease of bone (PDB): 1) the serum levels of DKK1; 2) the association of DKK-1 with receptor activator of nuclear factor kappa B (RANKL) and osteoprotegerin (OPG); and 3) the effect of zoledronic acid (ZOL) on serum DKK-1, RANKL, and OPG. The study was conducted as a prospective open-label cohort study. Eleven patients with PDB (median age 60 years) were recruited. Twelve age- gender- and body mass index (BMI)-matched healthy individuals were used as controls at baseline. Blood samples were obtained before treatment (baseline) and after 3, 6, 12, and 18 months following ZOL infusion in patients with PDB. Patients with PDB had significantly higher RANKL (p=0.002), OPG (p=0.001), and bone markers (total alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen) compared with controls at baseline. There was no difference between groups in DKK-1 at baseline. Bone markers were both significantly decreased after therapy. Serum OPG, RANKL, RANKL:OPG ratio, and DKK-1 remained unaffected throughout the study. No correlations were found between OPG, RANKL, RANKL:OPG ratio, and DKK-1 at baseline nor between their changes during the study. Although both OPG and RANKL were increased in patients with PDB, ZOL had no effect on their serum levels. Serum DKK-1 was neither increased in patients with PDB nor related to OPG and RANKL, and was unaffected by ZOL.

Diagnosis and Management of Paget's Disease of Bone in Adults: A Clinical Guideline.

An evidence-based clinical guideline for the diagnosis and management of Paget's disease of bone (PDB) was developed using GRADE methodology, by a Guideline Development Group (GDG) led by the Paget's Association (UK). A systematic review of diagnostic tests and pharmacological and nonpharmacological treatment options was conducted that sought to address several key questions of clinical relevance. Twelve recommendations and five conditional recommendations were made, but there was insufficient evidence to address eight of the questions posed. The following recommendations were identified as the most important: 1) Radionuclide bone scans, in addition to targeted radiographs, are recommended as a means of fully and accurately defining the extent of metabolically active disease in patients with PDB. 2) Serum total alkaline phosphatase (ALP) is recommended as a first-line biochemical screening test in combination with liver function tests in screening for the presence of metabolically active PDB. 3) Bisphosphonates are recommended for the treatment of bone pain associated with PDB. Zoledronic acid is recommended as the bisphosphonate most likely to give a favorable pain response. 4) Treatment aimed at improving symptoms is recommended over a treat-to-target strategy aimed at normalizing total ALP in PDB. 5) Total hip or knee replacements are recommended for patients with PDB who develop osteoarthritis in whom medical treatment is inadequate. There is insufficient information to recommend one type of surgical approach over another. The guideline was endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. The GDG noted that there had been a lack of research on patient-focused clinical outcomes in PDB and identified several areas where further research was needed. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

Tartrate-resistant acid phosphatase 5b, but not periostin, is useful for assessing Paget's disease of bone.

BACKGROUND: Periostin is a matricellular protein with a preferential location in cortical bone and periosteal tissue, and tartrate-resistant acid phosphatase 5b (TRAP5b) is a marker of osteoclast numbers. In Paget's disease of bone (PDB), there is increased cortical thickening and probably increased periosteal apposition, along with increased osteoclast numbers. OBJECTIVES: To analyse if circulating periostin is a biomarker for PDB, and if it is associated with disease activity and involvement of long bones that represent major cortical contribution. Also, to analyse whether TRAP5b, a scarcely explored bone resorption marker, is useful in the assessment of PDB. PATIENTS AND METHODS: We recruited 42 patients with PDB (13F/29M; 71 ±â€¯11.6 yrs). 71.4% had active disease, 66.6% had polyostotic disease and 54.8% had long bone involvement. Blood and urine samples were taken between 8:00 and 10:00 A.M. after an overnight fast. Periostin and TRAP5b were measured in serum, using commercial ELISA assays (Biomedica and IDS, respectively). Serum total ALP, PINP, CTX, bone ALP and urinary NTX were measured. Reference values for periostin and TRAP5b were obtained from 45 healthy subjects. RESULTS: Serum periostin did not differ between patients and controls (989.4 ±â€¯173.2 vs. 966.9 ±â€¯195.4 pMol/L, p = 0.572). No significant differences were observed between patients with and without active disease (964.5 ±â€¯168.8 vs.1051.6 ±â€¯175.6 pMol/L, p = 0.143), involvement or not of long bones (1022.2 ±â€¯145.8 vs 949.7 ±â€¯198.2 pMol/L, p = 0.181) and monostotic or polyostotic disease (963.8 ±â€¯198.7 vs 1002.2 ±â€¯161.4 pMol/L, p = 0.505). There were significant correlations between serum periostin and all bone turnover markers (bone ALP, PINP, uNTX, sCTX and TRAP5b) in PDB patients with active disease, but not in the inactive PDB group. Serum TRAP5b was significantly higher in PDB patients than in controls (4.43 ±â€¯1.76 vs. 3.21 ±â€¯1.02 U/L, p < 0.001), in those with active disease (4.98 ±â€¯1.76 vs. 3.07 ±â€¯0.72 U/L, p < 0.001) and in patients with polyostotic disease than in those with monostotic disease (4.81 ±â€¯1.79 vs 3.68 ±â€¯1.5 U/L, p = 0.005). TRAP5b levels were not influenced by previous bisphosphonate treatment (4.14 ±â€¯1.42 vs. 4.84 ±â€¯2.02 U/L, p = 0.206). CONCLUSIONS: Periostin is not useful for assessing PDB, whilst TRAP5b, which has been a scarcely explored bone turnover marker until now, may be useful in the analysis of this disease, providing new information on the resorption process. In addition, periostin levels correlate with all classical BTMs in active PDB, suggesting that this marker may reflect periosteal and cortical metabolism in accelerated bone turnover states.

Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease.

BACKGROUND: The advent of bisphosphonates advanced therapy for Paget's disease, but more effective and convenient agents are needed to increase adherence. Zoledronic acid, a bisphosphonate administered as a single intravenous infusion, might meet these needs. METHODS: In two identical, randomized, double-blind, actively controlled trials of 6 months' duration, we compared one 15-minute infusion of 5 mg of zoledronic acid with 60 days of oral risedronate (30 mg per day). The primary efficacy end point was the rate of therapeutic response at six months, defined as a normalization of alkaline phosphatase levels or a reduction of at least 75 percent in the total alkaline phosphatase excess. The results of the studies were pooled. RESULTS: At six months, 96.0 percent of patients receiving zoledronic acid had a therapeutic response (169 of 176), as compared with 74.3 percent of patients receiving risedronate (127 of 171, P<0.001). Alkaline phosphatase levels normalized in 88.6 percent of patients in the zoledronic acid group and 57.9 percent of patients in the risedronate group (P<0.001). Zoledronic acid was associated with a shorter median time to a first therapeutic response (64 vs. 89 days, P<0.001). Higher response rates in the zoledronic acid group were consistent across all demographic, disease-severity, and treatment-history subgroups and with changes in other bone-turnover markers. The physical-component summary score of the Medical Outcomes Study 36-item Short-Form General Health Survey, a measure of the quality of life, increased significantly from baseline at both three and six months in the zoledronic acid group and differed significantly from those in the risedronate group at three months. Pain scores improved in both groups. During post-trial follow-up (median, 190 days), 21 of 82 patients in the risedronate group had a loss of therapeutic response, as compared with 1 of 113 patients in the zoledronic acid group (P<0.001). CONCLUSIONS: A single infusion of zoledronic acid produces more rapid, more complete, and more sustained responses in Paget's disease than does daily treatment with risedronate.

Paget disease of bone: therapeutic options.

Paget disease of bone is a disorder of unknown etiology involving disturbances in bone remodeling, typically leading to bone pain and other complications such as skeletal deformities, fractures, hearing loss, and neurologic complications. Bisphosphonates (BPs), both oral and intravenous, have improved Paget treatment by reducing and normalizing bone turnover, as measured by biochemical markers and by alleviating symptoms. Six BPs are currently approved by the US Food and Drug Administration (FDA) for the treatment of Paget disease, and each has unique characteristics, such as response rates and requirements for dosage and administration, relevant to clinical outcome. This review provides an overview of these agents-including oral drugs such as alendronate and risedronate, and the intravenous agent zoledronic acid-and briefly discusses other options for managing Paget disease and monitoring treatment efficacy.

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.

Clinical utility of bone markers in various diseases.

Measurements of bone markers (BMs) in peripheral blood or urine are a pivotal part of bone research within modern clinical medicine. In recent years the use of BMs increased substantially as they can be useful either to diagnose bone (related) disease and to follow its natural history, but also to monitor the effects of interventions. However, the use of BMs is still complicated mainly due to (pre)analytical variability of these substances, limited accessibility of assays, variable cut-off values in different countries and laboratories and heterogeneous results with regard to clinical implications of measuring BMs in several studies. This review will provide the clinician with a practical guide, based on current evidence, in which circumstances to test which bone markers for optimal diagnostic purposes, in order to improve patient care in different areas of bone diseases including Paget's disease, primary osteoporosis, tumor induced osteomalacia, hypophosphatemic rickets, van Buchem disease, chronic kidney disease, rheumatoid arthritis, neoplasma/multiple myeloma, type 2 diabetes mellitus and primary hyperparathyroidism. The clinician should consider fasting state, recent fractures, aging, menopausal status, concomitant liver and kidney disease when ordering and interpreting BM measurements as these factors might result in misleading BM concentrations. We found that BMs are clearly useful in the current diagnosis of tumor induced osteomalacia, van Buchem disease, Paget's disease and hypophosphatemic rickets. In addition, BMs are useful to monitor disease activity in chronic kidney disease, Paget's disease and are useful to monitor treatment adherence in osteoporosis.

Delayed development of Paget's disease in offspring inheriting SQSTM1 mutations.

UNLABELLED: Familial Paget's disease is associated with mutations in SQSTM1. We compared the age at diagnosis and severity of Paget's disease in parents with SQSTM1 mutations to their offspring who inherited a mutation. At any given age, the offspring were less likely to be diagnosed with Paget's disease and had less severe disease than their parents. INTRODUCTION: Mutations in sequestosome 1 (SQSTM1) occur in 25-50% of cases of familial Paget's disease and are thought to be disease-causing. We sought to determine whether there are differences in age at diagnosis and severity of disease in parents and their offspring who share the same genetic predisposition to Paget's disease. MATERIALS AND METHODS: Eighty-four offspring from 10 families (29 index patients with Paget's disease) with mutations in SQSTM1 were approached, and 58 agreed to participate. The ubiquitin-binding domain region of SQSTM1 was sequenced, and the presence or absence of the known mutation was established. The presence of Paget's disease in offspring who had inherited an SQSTM1 mutation was determined by bone scintigraphy and measurement of serum alkaline phosphatase (ALP). RESULTS: Twenty-three of 58 offspring had inherited a germline mutation in SQSTM1. The mean ALP was 77 U/liter in offspring with mutations and 72 U/liter in those without mutations (p=0.84). Scintiscans from four offspring (mean age, 45 years; mean ALP, 139 U/liter; mean skeletal involvement, 6%) showed evidence of Paget's disease but were normal in the other 19 (mean age, 44 years; mean ALP, 64 U/liter). In comparison, in the 15 parents of the 23 offspring, the mean age of diagnosis was 48 years, the mean ALP was 850 U/liter, and the mean skeletal involvement was 30%. There was a 63% reduction in the risk of being diagnosed with Paget's disease at a comparable age in the offspring compared with the parents (p=0.028). CONCLUSIONS: Only 17% of offspring inheriting an SQSTM1 mutation had evidence of Paget's disease on scintigraphy, and this was diagnosed at a later age and was less extensive than in their affected parents. SQSTM1 thus shows incomplete penetrance. The data are consistent with the hypothesis that an environmental factor is important in the pathogenesis and clinical phenotype of familial Paget's disease and that exposure to this factor may be falling.