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The cause of Paget’s disease of bone (PDB) is unknown. It emerged as a distinct entity in Britain in the late nineteenth century when it was prevalent, and florid presentation not uncommon. Epidemiological surveys in the 1970s showed that Britain had a substantially higher prevalence of PDB than any other country. Studies in the late twentieth and early twenty-first centuries have documented an unexplained change in presentation, with a greatly reduced prevalence and less severe disease than formerly. The emergence of PDB in Britain coincided with rapid industrialization which, in turn, was driven by the use of coal for energy. In the home, bituminous coal was customarily burnt on an open hearth for heating. Using data on coal production, population size, and estimates of domestic use, the estimated exposure to domestic coal burning rose threefold in Britain during the nineteenth century and began to fall after 1900. This pattern fits well with the decline in PDB documented from death certification and prevalence surveys. Colonists moving from Britain to North America, Australia and New Zealand established coal mines and also used coal for domestic heating. PDB was found in these settler populations, but was largely absent from people indigenous to these lands. In all parts of the world PDB prevalence has fallen as the burning of coal in open hearths for domestic heating has reduced. The nature of the putative factor in coal that could initiate PDB is unknown, but possible candidates include both organic and inorganic constituents of bituminous coal.

Adults with hypophosphatasia (HPP) may suffer femoral fractures resembling the atypical femoral fractures that can occur with long‐term bisphosphonate treatment, and there is an emerging consensus that bisphosphonates should not be used in adults with HPP and low bone mass. However, the spectrum of HPP in adults is wide: ranging from the severely affected—who commonly have osteomalacia—through to the minimally affected. The former typically have biallelic and the latter, heterozygous ALPL mutations. We have reviewed reports of fractures in adults with genetically proven HPP which suggest that the risk of fracture is at least 200‐fold greater in those with biallelic mutations. We also discuss two cases of postmenopausal women with heterozygous ALPL mutations. One had fractures and severe osteoporosis, but histology revealed no evidence of osteomalacia. The second had taken alendronate for 8 years, but despite profound suppression of bone turnover, histology again revealed no evidence of osteomalacia. The management of adults with HPP who have coexisting osteoporosis is challenging. More data are clearly needed, but we suggest that the risks of bisphosphonate therapy may be relatively low in patients who have heterozygous mutations and no histological evidence of osteomalacia. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Stuart Ralston and colleagues report results of a genome-wide association study for Paget's disease of bone. Their work identifies common variants at three loci associated with risk of this disease. Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1 . To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene ( P = 5.38 × 10 −24 ). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene ( P = 6.09 × 10 −13 ) and with rs3018362 on 18q21 near the TNFRSF11A gene ( P = 5.27 × 10 −13 ). These studies provide new insights into the pathogenesis of PDB and identify OPTN , CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

“Osteogenesis imperfecta” is a term used to describe a group of genetic disorders of variable phenotype usually defined by recurrent fractures, low bone mass, and skeletal fragility. Most cases are associated with mutations in one of the type I collagen genes, but in recent years several other forms have been identified with recessive inheritance. In most instances the latter result from mutations in genes encoding proteins involved in type I collagen’s complex posttranslational modification or in genes regulating bone matrix homeostasis. This article reviews the recent discoveries and an approach to classification and diagnosis. Bisphosphonates are widely used in patients with osteogenesis imperfecta, but some important questions about their optimal usage, their utility in children and adults with milder phenotypes, and their potential adverse effects are not yet resolved.

Summary box Clinical context-Mild gestational diabetes is associated with perinatal morbidity Diagnostic change-International recommendation to move from dual step testing to reliance on a single abnormal glucose value in an oral glucose tolerance test with reduced thresholds Rationale for change-An observational study showed that any degree of impaired glucose regulation in pregnancy is associated with adverse outcomes Leap of faith-Reducing mildly raised blood glucose concentrations will improve outcomes for mother and baby Effect on prevalence-Nearly 1 in 5 pregnancies will be identified as being affected by gestational diabetes: a 2-3-fold increase over existing levels of 2-6% Evidence of overdiagnosis-Despite increased diagnosis there is no evidence from randomised controlled clinical trials that outcomes are improved Harms from overdiagnosis-Many more women will experience medicalisation of their pregnancy with increased intervention Limitations-Maternal obesity and excess weight gain in pregnancy are associated with gestational diabetes; both affect birth weight and other more serious pregnancy outcomes. 6 Date Observations Recommended test Diagnostic criteria for oral glucose challenge test (mmol/L) Prevalence (%) Fasting blood glucose 1 hour 2 hour 3 hour 1930-40s Women who later developed (type 2) diabetes had high incidence of large babies and fetal loss Not yet developed - - - - NA 1950s The term \"gestational diabetes\" introduced for women with poor obstetric histories who during a subsequent pregnancy had high glucose levels on an OGTT OGTT 100 g in high risk patients - - > 9.4 - NA 1960s Women with high risk pregnancies followed postpartum with annual OGTT-a high proportion subsequently developed type 2 diabetes OGTT 100 g in high risk patients (need 2 abnormal values) >= 5.0 >= 9.2 >= 8.1 >= 6.9 2 Whole blood glucose levels 1979-80 Missed cases lead American Diabetes Association to recommend universal screening using criteria suggested by National Diabetes Data Group 50 g glucose challenge followed by OGTT 100 g (need 2 abnormal values) >= 5.8 >= 10.6 >= 9.2 >= 8.1 5 1990s Modification for using plasma not whole blood OGTT 100 g (need 2 abnormal values) >= 5.3 >= 10.0 >= 8.6 >= 7.8 6 2005-9 Randomised controlled trials in women with mild gestational diabetes identified by two step testing show modest benefit of treatment, predominantly on birth weight - - - - - - 2008-10 HAPO study shows continuous relation between untreated maternal blood glucose and some primary endpoints but no threshold for markedly increased risk OGTT 75 g, no screening and 1 abnormal value* >= 5.1 >= 10.0 >= 8.5 - 18 2013 Individual countries struggle to come up with guidelines for diagnosis. Diabetes diagnosed in early pregnancy at the first prenatal visit based on a fasting plasma glucose >=7.0 mmol/L or glycated haemoglobin (HbA1c) level >=6.5% (48 mmol/mol) would be identified as overt diabetes Glucose levels associated with an arbitrary 1.75-fold increase risk above the mean (from HAPO results) for birth weight, cord C peptide concentration, and percentage body fat being above the 90th centile would constitute a diagnosis of gestational diabetes Only one abnormal value would be needed for diagnosis since fasting, one hour, and two hour glucose values were all associated with the defined adverse outcomes Two step testing could be abandoned in favour of a single oral glucose tolerance test. [...]all of these unwelcome outcomes have other risk factors, most notably maternal obesity and gestational weight gain. 19 20 21 Separating out the role of gestational diabetes is difficult-the randomised controlled trials that showed benefit from treating gestational diabetes also ameliorated weight gain in the mothers; 13 14 the risks of obesity and glucose intolerance in the offspring associated with gestational diabetes are lost when maternal body mass index is factored into the analysis. 22 Overall, 78% of large for gestational age babies in HAPO were born to women with normal glucose tolerance. 23 We need to understand better how these factors interact to increase risks and to manage them, and not assume that lowering minimally raised blood sugar values is of paramount importance.

INTRODUCTION: Macroalbuminuria in people with type 2 diabetes is common among Pasifika peoples and is associated with end-stage kidney disease and major cardiovascular disease.AIM: In a primary care practice catering for Pasifika people, to determine the time after first recognition of macroalbuminuria to the occurrence of major cardiovascular and renal events, and to examine the relationship with retinopathy status.METHODS: In a retrospective observational cohort study, we documented the occurrence of major cardiovascular events and amputations, end-stage kidney disease and death in 115 people with type 2 diabetes reviewed by a specialist diabetes physician at the Langimalie Tongan Health practice between 2005 and 2018. The follow up was 1–19 (median 9.5) years from the first recognition of macroalbuminuria (albumin:creatinine ratio of >30 g/mol). Survival was described by using Kaplan–Meier analysis.RESULTS: Macroalbuminuria was detected a mean of 9 years after the diagnosis of diabetes, at a mean age of 52 (standard deviation 12) years. Within 6 years of macroalbuminuria detection, 4% of people had died, 15% had reached end-stage kidney disease, 15% had cardiovascular events or amputations and 30% had the composite outcome of any of these. Within 12 years, the respective proportions were: 24%, 29%, 20% and 48%. The composite outcome was less frequent (P < 0.002) in patients without retinopathy at the time macroalbuminuria was recognised. Compared to patients with retinopathy, this group were younger (P = 0.025), more obese (P < 0.0001), had better baseline renal function (P = 0.018) and a shorter interval between the diagnosis of diabetes and recognition of macroalbuminuria (P < 0.0001).DISCUSSION: In this Pasifika population, macroalbuminuria was a marker for serious adverse cardiovascular and renal disease, and mortality, but in the 29% of patients without retinopathy at the time of recognition of macroalbuminuria, the natural history was more benign. The management of such comorbid patients is a substantial challenge for primary health-care services.

We describe two women with a misdiagnosed fracturing bone disease who were treated erroneously with i.v. zoledronate. Over the next year, they suffered marked clinical and radiographic deterioration in skeletal disease. Both were eventually diagnosed with hypophosphatemic osteomalacia secondary to acquired Fanconi syndrome (caused by light‐chain myeloma in one case and tenofovir treatment in the other). Appropriate treatment with phosphate supplementation was instituted with clinical improvement. These cases illustrate the importance of not missing osteomalacia in adults presenting with fractures, and the potentially damaging effects of treatment with long‐acting inhibitors of bone resorption in these circumstances. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Osteoblast Wnt/β‐catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low‐density lipoprotein receptor‐related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β‐propeller of LRP5 or LRP6, thereby disassociating these cognate co‐receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle‐aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm2) of the lumbar spine and total hip featured accelerated increases reaching Z‐scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background Hajdu-Cheney syndrome (HCS) (#OMIM 102500) is a rare, autosomal dominant condition that presents in early childhood. It is caused by mutations in the terminal exon of NOTCH2 , which encodes the transmembrane NOTCH2 receptor. This pathway is involved in the coupled processes of bone formation and resorption. The skeletal features of HCS include acro-osteolysis of the digits and osteoporosis commonly affecting vertebrae and long bones. Fractures are a prominent feature and are associated with significant morbidity. There is no specific treatment, but with both acro-osteolysis and generalized osteoporosis, it is possible that anti-resorptive treatment might be of benefit. However, to date only a few case reports have evaluated the effectiveness of bisphosphonate treatment. Methods We describe the clinical features, treatment regimens and response to bisphosphonate treatment in 7 newly described patients aged 6–39 with HCS, and pooled the data with that from 8 previously published cases (a total of 17 courses of treatment in 15 individuals). Results The mean lumbar spine bone mineral density (BMD) z-score before treatment was − 2.9 (SD 1.2). In 14 courses of treatment (82%), there was an increase in BMD with bisphosphonate treatment, but the impact (in terms of change in spinal BMD z-score) appeared to be less with advancing age ( p  = 0.01). There was no evidence that acro-osteolysis was prevented. Conclusions Although individual response is variable and age-related, the data support a role for bisphosphonates in preventing or treating spinal osteoporosis in HCS, but bone loss from the lumbar spine may be rapid after cessation.