The Decline of Paget's Disease of Bone and Domestic Coal Use-A Hypothesis.

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.

Compound heterozygosity for a frameshift mutation and an upstream deletion that reduces expression of SERPINH1 in siblings with a moderate form of osteogenesis imperfecta.

SERPINH1 encodes the collagen chaperone HSP47 that binds to arginine-rich sequences in the type I procollagen trimers and provides the final steps in the folding and stabilization of the triple helical domain. Loss of both alleles in mice results in very early embryonic lethality. SERPINH1 mutations have been associated with one of the rarest forms of recessively inherited osteogenesis imperfecta (OI) with a moderate to severe phenotype. We identified a family with non-consanguineous unaffected parents who had two children with moderate short stature, low bone density, and fractures. Both children were compound heterozygotes for two mutations: a frameshift in the last exon that deleted the RER retention signal, and a 5,274 bp deletion 2.37 kb upstream from the transcription start site. The maternally-inherited frameshift allele was expressed at normal levels, but the protein was unstable. The mRNA encoded by the second allele represented about 50% of that from the frameshift-containing allele. The upstream deletion was inherited from the father, and the mRNA encoded by that allele in his cultured dermal fibroblasts was also expressed at a low level, which confirmed that this domain had a regulatory function for SERPINH1. Regulatory mutations are uncommon causes of human genetic disorders, and the ability to measure expression levels in appropriate cells is key to their identification.

Growth, body composition, and bone density following pediatric liver transplantation.

Patients transplanted for cholestatic liver disease are often significantly fat-soluble vitamin deficient and malnourished pretransplant, with significant corticosteroid exposure post-transplant, with increasing evidence of obesity and metabolic syndrome post-LT. Our study aimed to assess growth, body composition, and BMD in patients post-pediatric LT. Body composition and bone densitometry scans were performed on 21 patients. Pre- and post-transplant anthropometric data were analyzed. Bone health was assessed using serum ALP, calcium, phosphate, and procollagen-1-N-peptide levels. Median ages at transplant and at this assessment were 2.7 and 10.6 years, respectively. Physiological markers of bone health, median z-scores for total body, and lumbar spine aBMD were normal. Bone area was normal for height and BMAD at L3 was normal for age, indicating, respectively, normal cortical and trabecular bone accrual. Median z-scores for weight, height, and BMI were 0.6, -0.9, 1.8 and 0.6, 0.1, 0.8 pre- and post-transplant, respectively. Total body fat percentages measured on 21 body composition scans revealed 2 underweight, 7 normal, 6 overweight, and 6 obese. Bone mass is preserved following pediatric LT with good catch-up height. About 52% of patients were either overweight/obese post-transplant, potentially placing them at an increased risk of metabolic syndrome and its sequelae in later life. BMI alone is a poor indicator of nutritional status post-transplant.

Type 2 diabetes in young adults in Central Auckland: demography and complications.

BACKGROUND: Type 2 diabetes (T2D) in young adults is associated with a high risk of diabetes complications. AIMS: To investigated the demography and the emergence of complications of young adults with T2D in the central Auckland region where there has been substantial immigration. METHODS: In total, 310 young adults with T2D (<40 years) were registered with the Auckland Diabetes Centre in 2015. We documented demographic, anthropometric and metabolic variables and prevalence and the emergence of complications. RESULTS: Three demographic groups accounted for 243 participants (78%): 135 (44%) were migrants of Asian or Pacific Island origin, diagnosed a median 9 years after migration at a mean age of 28 ± 6 years; 88 (29%) were New Zealand-born Pasifika descent, with a high prevalence of morbid obesity and 37 (12%) had major mental illness or intellectual disability. At diagnosis, the median HbA1c was 80 mmol/mol, and in 28%, it was ≥100 mmol/mol. A median 6 years after diagnosis, 56% had some degree of retinopathy, with the prevalence related both to the duration of diabetes and glycaemic control (P = 0.001). Forty-four percent of subjects had abnormal albuminuria at diagnosis (12% with macroalbuminuria). Increased albuminuria was strongly associated with obesity (P = 0.002). The development of CKD stages 4-5 was related both to the severity of retinopathy and degree of albuminuria at diagnosis (P = 0.0001). Major cardiovascular events were related to the severity of retinopathy at diagnosis (P = 0.0001). CONCLUSIONS: New migrants, New Zealand-born Pasifika and patients with mental illness or an intellectual disability comprise the bulk of young onset T2D. The disease is aggressive, and by the age of 40, patients are already developing advanced complications.

Adherence to medication, glycaemic control and hospital attendance in young adults with type 2 diabetes.

Type 2 diabetes is becoming common among people in their 20s and 30s. Glycaemic control is suboptimal in this group and is associated with poor medication adherence. We studied medication adherence over a 24-month period in all diabetes clinic registrants (n = 266) between the ages of 18 and 39 years. We reviewed their glycaemic control using mean HbA1c over the study period and examined hospital records to determine the number of hospital attendances during this time. We found that less than half the group (47%) had good adherence (>90%) and 21% of the group had very poor adherence (<50%). Mean adherence was slightly poorer in women compared to men (73% vs 76%, P = 0.04). There was a marked inverse relationship between adherence and glycaemic control. Mean HbA1c is 70 mmol/mol among those with good adherence and mean HbA1c is 97 mmol/mol among those with very poor adherence (P < 0.05). Fifty-seven per cent of the study group had at least one hospital attendance during this time. Eighty-eight hospital attendances were due to a medical cause. Study of trend showed more medical admissions among those with very poor adherence (P = 0.03). Mean HbA1c was higher in those who required medical admissions (87 mmol/mol vs 75 mmol/mol) when compared to those with no hospital attendance. Our study shows that poor adherence is common and significantly related to glycaemic control as well as unplanned hospital attendances for medical conditions. Despite limitations, our study provides valuable information on medication adherence and its impact on glycaemic control and morbidity among young people with type 2 diabetes.

Long-Term Effects of Intravenous Ibandronate in Paget's Disease of Bone.

We have previously demonstrated that intravenous ibandronate produces high initial response rates in Paget's disease, but the durability of this effect is unknown. It might be expected to be short lived because ibandronate has a low affinity for bone. Here we report long-term follow-up (up to 14 years) of patients from that trial. Twenty-five patients with active Paget's disease [baseline serum total alkaline phosphatase (ALP) ~3 times the upper limit of normal] received either 6 or 12 mg intravenous ibandronate at baseline. There were prompt reductions in ALP following treatment, with normalization in 88%. ALP remained in the normal range in most patients for 20-30 months, but some subjects then showed gradual increases. Three years after ibandronate, before any patients had received additional treatment, ALP was normal in 61%. Six patients maintained normal ALP beyond 6 years without further intervention. Responses to 6 and 12 mg were similar. These results indicate that long-term remissions in Paget's disease can be achieved with bolus delivery of a potent bisphosphonate, even if the drug has a low affinity for bone. Therefore, bisphosphonate retention in bone might not be the only factor determining duration of remission. Intravenous bisphosphonates are likely to produce high drug concentrations within pagetic lesions which might result in cytotoxicity to the pagetic cells, leading to long durations of remission. These findings strengthen the evidence that potent bisphosphonates delivered in a single intravenous dose are a very efficient way to manage this condition.

Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen.

Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.

Evolution of Paget's disease of bone in adults inheriting SQSTM1 mutations.

CONTEXT: The cause of Paget's disease of bone (PDB) is unknown, but genetic factors, particularly SQSTM1 mutations, and environmental factors are important. OBJECTIVE: To investigate the development of PDB in asymptomatic relatives carrying SQSTM1 mutations to determine whether a secular trend towards a less severe phenotype is evident, and to estimate prospectively the rate at which PDB emerged in this genetically susceptible population. DESIGN: We recruited first-degree relatives of patients with PDB [33 adult offspring (mean age 45) and 1 sibling] with a familial SQSTM1 mutation. We determined the presence of PDB with skeletal scintiscans and confirmatory radiographs. Those negative for PDB on the initial scan were investigated again a mean 5·1 years later. RESULTS: The initial skeletal scintiscan demonstrated PDB in six subjects; 26 of the remaining 28 unaffected subjects had a second scintiscan, with two new cases of monostotic PDB diagnosed in 134 patient-years of follow-up. In the total eight adult offspring diagnosed with PDB, the age of diagnosis was greater, by at least 10 years, than that in the 21 probands with clinically identified PDB (P = 0·005). In adult offspring who were older at the time of skeletal scintigraphy than their affected parents were at the time of clinical diagnosis, the difference was even more marked (P < 0·001). In adult offspring with PDB, the disease was significantly less extensive than in their affected parent, as judged by alkaline phosphatase and disease extent (P < 0·003). CONCLUSION: These findings suggest a substantial gene-environment interaction: the emergence of PDB in offspring inheriting SQSTM1 mutations is delayed by at least a decade, has a substantially attenuated phenotype and occurs at a low rate between the (mean) ages of 45 and 50 years. The nature of the environmental factor is unknown.

Republished: Paget's disease of bone: clinical review and update.

Paget's disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. In this article, we review clinical aspects of PD with an emphasis on recent findings. The epidemiology of PD appears to be changing rapidly, with several groups in different parts of the world reporting a marked reduction in the prevalence and incidence of PD, as well as in the severity of disease seen by clinicians. These findings seem most likely to be caused by changes in exposure to unknown environmental factors that have a role in the development of PD. However, genetic factors are also important. Mutations in SQSTM1 occur in 25-50% of familial PD. Genotype-phenotype relationships are present, as PD develops at an earlier age and is more extensive and severe in those with SQSTM1 mutations, and these findings are more pronounced in those with truncating mutations. However, the prevalence of PD in adults with SQSTM1 mutations is uncertain, and it is not known how such mutations might cause PD. Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors. Lastly, clinical trials have shown that potent bisphosphonates are highly effective treatments for active PD, and reduce pain, improve quality of life, normalise bone turnover and heal lytic lesions on radiographs. They can also induce sustained remission that persists for many years.

The effect of an apparent change to a branded or generic medication on drug effectiveness and side effects.

OBJECTIVE: Generic medications are associated with reduced perceived effectiveness, increased perceived adverse effects, and increased rates of nonadherence compared with brand-name medications. This study examined the effect of an apparent medication formulation change on subjective and objective measures of medication effectiveness and medication side effects. METHODS: Sixty-two university students participated in a study purportedly testing the effectiveness of fast-acting ß-blocker medications in reducing preexamination anxiety. All tablets were placebos. In session 1, all participants received a yellow tablet ("Betaprol"). In session 2, participants were randomly allocated to receive Betaprol (no change condition) or a white tablet labeled either as "Novaprol" (branded change condition) or "Generic" (generic change condition). Blood pressure and state anxiety were measured before and after tablet ingestion. Side effects attributed to medication were assessed. RESULTS: The no change group showed significantly greater decreases in systolic blood pressure (mean [M] [standard deviation] = -7.72 mm Hg, standard error [SE] = 1.45) than the branded change (M = -2.75 mm Hg, SE = 1.44, p = .02) and generic change (M = -3.26 mm Hg, SE = 1.45, p = .03) groups. The no-change group showed significantly greater decreases in state anxiety (M = -1.53, SE = 0.33) than the branded change (M = -0.50, SE = 0.33, p = .03) and generic change (M = -0.52, SE = 0.33, p = .04) groups. Significantly more side effects were attributed to the medication in the generic change (M = 1.83, SE = 0.23) (but not the branded change) condition when compared with the no change condition (M = 0.87, SE = 0.31, p = .03). CONCLUSIONS: Medication formulation change, particularly to generic medication, seems to be associated with reduced subjective and objective measures of medication effectiveness and increased side effects.

Establishing consensus in the diagnosis of gestational diabetes following HAPO: where do we stand?

New proposals for the diagnosis of gestational diabetes (GDM), promulgated by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), will substantially increase the number of women diagnosed with GDM. This will have an enormous impact on healthcare resources, diverting attention away from genuinely high risk diabetic pregnancies. Randomized trials in 'mild' GDM indicate that the main effects of treatment are a 2 %-3 % reduction in birth weight, fewer 'big babies', and less shoulder dystocia. However, these studies used different diagnostic criteria, and women diagnosed by the broader IADPSG criteria may not derive the same modest benefit. Modeling indicates a very high cost per QALY, unless later development of type 2 diabetes can be prevented. Far from producing consensus, the IADPSG suggestion has thrown sharply into focus the need to assess critically the risks, costs and benefits of adopting criteria that may pathologize a large number of otherwise normal pregnancies.

LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low-Density Lipoprotein Receptor-Related Protein 6.

Osteoblast Wnt/ß-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 ß-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.

Recent advances in osteogenesis imperfecta.

"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.

Impact of Bariatric Surgery on Unplanned Hospital Admissions for Infection.

PURPOSE: Both obesity and type 2 diabetes are associated with an increased risk of skin and soft tissue (SSTI), urinary tract, and lower respiratory tract infections but it is not clear whether the incidence of such infections is reduced after bariatric surgery. MATERIALS AND METHODS: In people accepted onto our publicly funded bariatric program, we recorded unplanned admissions to public hospitals over a median follow-up of 4.5 years in those successfully undergoing surgery and in those who withdrew from the program. Rates of admission for the composite outcome (SSTI, urinary tract, or lower respiratory infection) were compared. RESULTS: Of 774 people accepted onto the program, 49% underwent surgery. Infections accounted for 27% of unplanned admissions in those not completing surgery and 13% of those who underwent surgery (p < 0.001). The rate of admission was 60% lower in people who underwent surgery than those who did not: 4.3 vs 12.2 per 100 patient-years (P < 0.002), a difference maintained across 8 years' follow-up. The impact of surgery was independent of enrolment age, BMI, or diabetes and smoking status. Of the three types of infection in the composite outcome, SSTI were the most prevalent and showed the greatest reduction (p < 0.0001). The median day stay for infection was 0.5 day less in those who underwent surgery (p < 0.01). CONCLUSIONS: Hospitalization for these three infectious diseases in people undergoing bariatric surgery was lower than that in people enrolled in the bariatric program but not completing surgery. The effect was greatest for SSTI, and sustained to at least 8 years.

Socio-economic deprivation and healthcare service use of young people with type 1 and type 2 diabetes.

AIM: Lower socio-economic status (SES) is linked to greater morbidity in people with young-onset type 2 (T2D) and type 1 diabetes (T1D). We assessed healthcare utilisation from this population and the impact of SES. METHODS: Retrospective analysis of 1,350 people with T2D and 731 with T1D diagnosed between 15-30 years of age referred to secondary diabetes services in Auckland, New Zealand. Primary care visits, referral to/attendance at diabetes clinics, and hospital admissions were recorded; their relationship to a validated national index of deprivation (NZDep) was assessed. RESULTS: The proportion with primary care attendance was similar in both groups with no significant variation with NZDep. For T2D, NZDep was a predictor of delayed referral (≧1-year post-diagnosis) to diabetes services, following adjustment for age and HbA1c in the year of diagnosis (OR 1.15 for every decile increase in NZDep, 95% CI 1.07-1.24, p=0.0003). The median number of appointments offered over a 2-year period was greater for T1D (2.0 (IQR 0, 7) vs (0 (IQR 0, 2), p<0.001); non-attendance increased with NZDep for T2D (p=0.016). The proportion with hospital admissions was similar in both groups and increased with NZDep (T1D p<0.001, T2D p=0.015). CONCLUSION: SES impacts several measures of healthcare utilisation. Current healthcare models are inadequately servicing people with young-onset T2D.

Deletion of the last two exons of FGF10 in a family with LADD syndrome and pulmonary acinar hypoplasia.

Pulmonary acinar hypoplasia (PAH) and lacrimo-auriculo-dento-digital (LADD) syndrome have both been associated with loss-of-function variants in, or deletions of FGF10. Here we report a multi-generational family with seven members manifesting varying features of LADD syndrome, with one individual dying in early infancy of PAH. Whole genome sequencing in one family member identified a 12,158 bp deletion on chromosome 5p12 that removes two of the three exons of FGF10. Allele-specific PCR demonstrated that all affected family members, including the individual with PAH, carried the 12 kb deletion. We conclude the deletion is pathogenic and expands the mutational spectrum of FGF10 variants in LADD syndrome. The common mechanism underlying the variable clinical features of LADD syndrome is defective terminal branching of salivary and lacrimal glands and pulmonary acini, regulated by the TBX4-FGF10-FGFR2 pathway. The variable phenotypic expressivity of FGF10 haploinsufficiency from relatively benign to lethal is likely due to variation at other genetic loci.

Familial Paget disease and SQSTM1 mutations in New Zealand.

Genetic factors play an important role in the pathogenesis of Paget disease of bone (PDB). SQSTM1 is the most important disease-associated gene identified to date. We investigated the relationship of family history, phenotype, and SQSTM1 mutation status in New Zealand (a country with a high prevalence of PDB) in patients with a family history and/or a severe phenotype. We studied 61 unrelated subjects with familial PDB. Family history was subclassified into three groups according to the closeness of the relationship. We also studied a fourth group of 19 unrelated patients defined by early onset and/or severe disease but no family history. The PDB phenotype was defined according to age, alkaline phosphatase activity, and disease extent on scintiscan at the time of diagnosis. Mutations in exon 8 of SQSTM1 were detected by screening of genomic DNA. Four different mutations were identified; the ubiquitous P392L mutation and the truncating mutation E396X accounted for 89% of cases. Overall 26% of patients with familial PBD in New Zealand had disease-associated mutations in the SQSTM1 gene. Mutations were most prevalent (60%) in those with a parent or sibling and at least one other relative affected (P < 0.002). The severity of the phenotype was significantly related to SQSTM1 mutation status but not the strength of the family history (P < 0.005). SQSTM1 mutations were found in 10.5% of patients with early onset and/or severe disease but no family history.