The prevalence and natural history of normocalcaemic hyperparathyroidism and hypoparathyroidism

Normocalcaemic hyperparathyroidism (NPHPT) is characterised by persistently normal calcium levels, elevated PTH values on at least two consecutive measurements, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease in the literature varies significantly due to various definitions used; it is reported to be between 0.1 and 8.9%. The data on the natural history of this disease are sparse and inconclusive. Normocalcaemic hypoparathyroidism (NHYPO) is characterised by persistently low levels of parathyroid hormone (PTH) with normal levels of calcium. There is little in current literature on this disease, with only two studies published on its prevalence whilst its natural history remains relatively unknown. The aims of this study were: to identify the prevalence of NPHPT in a UK referral population using the international criteria and study the natural history of this disorder and the variability of serum calcium; to compare the variability of calcium in NPHPT and PHPT; to identify the prevalence of NHYPO and to study the natural history of the disorder and the variability of serum calcium. The prevalence of NPHPT in our UK referral population was found to be low. NPHPT patients often have episodes of hypercalcemia, so they probably suffer from PHPT. The variability of NPHPT and PHPT patients is similar. The prevalence of NHYPO calculated from this UK referral population is lower when compared to results from previous studies. NHYPO patients often have episodes of hypocalcaemia with some cases having no apparent reason for calcium levels below the reference range. The next steps are to find out the cause of this biochemical abnormality and the consequences, if any

Classical and nonclassical manifestations of primary hyperparathyroidism

This narrative review summarizes data on classical and nonclassical manifestations of primary hyperparathyroidism (PHPT). It is based on a rigorous literature search, inclusive of a Medline search for systematic reviews from 1940 to December 2020, coupled with a targeted search for original publications, covering four databases, from January 2013-December 2020, and relevant articles from authors' libraries. We present the most recent information, identify knowledge gaps, and suggest a research agenda. The shift in the presentation of PHPT from a predominantly symptomatic to an asymptomatic disease, with its varied manifestations, has presented several challenges. Subclinical nephrolithiasis and vertebral fractures are common in patients with asymptomatic disease. The natural history of asymptomatic PHPT with no end organ damage at diagnosis is unclear. Some observational and cross-sectional studies continue to show associations between PHPT and cardiovascular and neuropsychological abnormalities, among the different disease phenotypes. Their causal relationship is uncertain. Limited new data are available on the natural history of skeletal, renal, cardiovascular, neuropsychological, and neuromuscular manifestations and quality of life. Normocalcemic PHPT (NPHPT) is often diagnosed without the fulfillment of rigorous criteria. Randomized clinical trials have not demonstrated a consistent long-term benefit of parathyroidectomy (PTX) versus observation on nonclassical manifestations. We propose further refining the definition of asymptomatic disease, into two phenotypes: one without and one with evidence of target organ involvement, upon the standard evaluation detailed in our recommendations. Each of these phenotypes can present with or without non-classical manifestations. We propose multiple albumin-adjusted serum calcium determinations (albumin-adjusted and ionized) and exclusion of all secondary causes of high parathyroid hormone (PTH) when establishing the diagnosis of NPHPT. Refining the definition of asymptomatic disease into the phenotypes proposed will afford insights into their natural history and response to interventions. This would also pave the way for the development of evidence-based guidance and recommendations. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Establishing race-, gender- and age-specific reference intervals for pyridoxal 5’-phosphate in the NHANES population to better identify adult hypophosphatasia

Introduction Bisphosphonate treatment in adults with hypophosphatasia (HPP) may increase fracture risk. PLP is a useful marker in biochemically differentiating HPP from osteoporosis in adults. In order to identify elevated PLP, robust reference intervals are needed which are calculated in a large, representative sample population. Methods Complete data from 9069 individuals (ages 20–80, 50.6% female) from two years of the NHANES Survey (2007–2008 and 2009–2010) were investigated. Differences in PLP in the presence of four factors; inflammation (CRP ≥5.0 mg/L), low ALP (<36 IU/L), chronic kidney disease (eGFR <60 mL/min/1.732), and daily vitamin B6 supplementation, were investigated. Race, gender and age differences in PLP were then investigated; 95% reference intervals were calculated that reflected these differences. Results Inflammation and chronic kidney disease were associated with lower PLP (p < .0001 and p = .0005 respectively), while low ALP and vitamin B6 supplementation were associated with higher PLP (both p < .0001). Individuals were excluded based on the presence of these factors; a reference interval population (n = 4463) was established. There were significant differences in PLP depending on race and gender (p < .0001) Increasing age was correlated with decreasing PLP (spearman's rho −0.204, p < .0001). Race- and gender-specific 95% reference intervals were calculated. In male patients, these were also calculated according to age groups: young and older adults (ages 20–49 years and ≥50 years respectively). Conclusions In order to identify adult hypophosphatasia based on elevated PLP, considerations must be made depending on the race, gender and age of the individual. Factors associated with significant differences in PLP must also be considered when assessing biochemical measurements

A meta-analysis of previous falls and subsequent fracture risk in cohort studies

NC Harvey acknowledges funding from the UK Medical Research Council (MC_PC_21003; MC_PC_21001). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. Funding for the MrOS USA study comes from the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. Funding for the SOF study comes from the National Institute on Aging (NIA), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), supported by grants (AG05407, AR35582, AG05394, AR35584, and AR35583). Funding for the Health ABC study was from the Intramural research program at the National Institute on Aging under the following contract numbers: NO1-AG-6–2101, NO1-AG-6–2103, and NO1-AG-6–2106.Peer reviewedPostprin

Serum Osteoprotegerin, RANKL, and Dkk-1 Levels in Adults with Langerhans Cell Histiocytosis

Context: Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology with a strong evidence of immunological dysfunction secondary to cytokine dysregulation. Objective: This study aimed to evaluate serum receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), and Dickkopf-1 (Dkk-1) levels in adult patients with LCH at various stages of the disease. Design: This was a cross-sectional study in an adult LCH cohort followed for 12.2 +/- 2.1 yr. Setting: The study was conducted in an outpatient clinic. Subjects: Twenty-five adult patients with a definitive LCH diagnosis and 50 matched controls participated in the study. Interventions: Early morning, fasting, venous sampling was conducted in all subjects. Main Outcome Measure: We compared RANKL, OPG, and Dkk-1 serum levels between patients and controls, as well as their association with disease parameters. Results: Serum OPG levels were significantly higher (3.0 +/- 0.2 vs. 1.7 +/- 0.1 pmol/liter; P &lt; 0.001), whereas RANKL/OPG ratio was significantly lower (0.201 +/- 0.041 vs. 0.471 +/- 0.072; P = 0.02) in LCH patients compared to controls. Both higher OPG (adjusted odds ratio, 3.431; 95% confidence interval, 1.329-8.924) and lower RANKL (adjusted odds ratio, 0.144; 95% confidence interval, 0.034-0.605) levels were independently associated with LCH in logistic regression analysis, after adjustment for all other parameters. Dkk-1 did not differ among patients and controls. Conclusions: Adults with LCH have high serum OPG levels and low serum RANKL levels. In contrast with other disorders involving the skeleton, serum Dkk-1 levels are similar between LCH patients and controls. (J Clin Endocrinol Metab 97: E618-E621, 2012

A meta-analysis of previous falls and subsequent fracture risk in cohort studies

Summary: the relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm.Introduction: previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD).Methods: the resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients.Results: falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men.Conclusions: a previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.</p

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

UNLABELLED: The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction