Incident Vertebral Fractures During Romosozumab Treatment in a Patient With a Pathogenic Variant.

A defect in the canonical Wnt-β-catenin pathway may lead to reduced bone strength and increased fracture risk. Sclerostin is a key inhibitor of this pathway by binding to low-density lipoprotein (LDL) receptor-related protein , thereby reducing bone formation. The effectiveness of romosozumab, a human monoclonal antibody that binds sclerostin and prevents this inhibitory effect, has been questioned in patients with inactivating genetic variants in or .

Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.

X-linked osteoporosis, caused by PLS3 genetic variants, is a rare bone disease, clinically affecting mainly men. Limited data are available on bone microarchitecture and genotype-phenotype correlations in this disease. Our aims were to assess bone microarchitecture and strength in adults with PLS3 variants using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to explore differences in the phenotype from HR-pQCT between PLS3 variants.

Evaluating the relationship between glycemic control and bone fragility within the UK Biobank: observational and one-sample Mendelian randomization analyses.

We aimed to: (1) examine the relationship between glycemic control, BMD estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 (T1D) and type 2 diabetes (T2D) and (2) perform a one-sample Mendelian randomization (MR) study to explore potential causal associations between glycemic control, eBMD, and fractures. This study comprised 452 131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA) and eBMD levels. At baseline, 4078 participants were diagnosed with T1D and 23 682 with T2D.

Oral Health-Related Quality of Life in Dutch Adults With Osteogenesis Imperfecta.

Objective: To explore the oral health-related quality of life and its possible risk factors among adults with Osteogenesis Imperfecta using the Oral Health Impact Profile (OHIP)-49 questionnaire. Secondary objectives were to investigate the impact of self-reported Osteogenesis Imperfecta, Dentinogenesis Imperfecta, and age on various dental parameters.

Materials And Methods: A cross-sectional questionnaire was distributed online to 417 Dutch adults with Osteogenesis Imperfecta at three national referral centers.

Serum phosphate in the general population: a need for sex-specific reference intervals.

Background: Phosphate is important for several metabolic functions and essential for bone mineralization. Sex-differences exist in the relation between serum phosphate and certain diseases. The reference interval for phosphate is age-adjusted in infants, but most institutions use the same intervals for adult men and women despite increasing evidence for age and sex-differences.

Functional Insights in PLS3-Mediated Osteogenic Regulation.

Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive.

Organic phosphate but not inorganic phosphate regulates expression through MAPK and TGF-ꞵ signaling.

One of the main regulators of phosphate homeostasis is fibroblast growth factor 23 (FGF23), secreted by osteocytes. The effects of organic versus inorganic dietary phosphate on this homeostasis are unclear. This study used MC3T3-E1 FGF23-producing cells to examine the transcriptomic responses to these phosphates.

A role for sirtuin 1 in FGF23 activation following β-glycerophosphate treatment.

Phosphate homeostasis is vital for many biological processes and disruptions in circulating levels can be detrimental. While the mechanisms behind FGF23 regulation have been regularly studied, the role of extracellular phosphate sensing and its impact on fibroblast growth factor 23 (FGF23) expression remains unclear. This study aimed to investigate the involvement of reactive oxygen species (ROS), silent information regulator 1 (SIRT1), and Hairy and Enhancer of Split-1 (HES1) in regulating FGF23 in FGF23 expressing MC3T3-E1 cells.

Osteopetrosis and related osteoclast disorders in adults: A review and knowledge gaps On behalf of the European calcified tissue society and ERN BOND.

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood.

Diuretic Use and Serum Phosphate: Rotterdam Study and UK Biobank.

Purpose: Hypophosphatemia (serum phosphate < 0.80 mmol/L) leads to musculoskeletal complaints. The most common drugs linked to hypophosphatemia are thiazide and loop diuretics, but studies in the general population are lacking.

Endocrine and non-endocrine causes of fatigue in adults with Neurofibromatosis type 1.

Context: Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which they are frequently referred to Internal Medicine/Endocrinology. Seeking medical help often leads to (invasive) diagnostic procedures.

The AGE-RAGE axis associates with chronic pulmonary diseases and smoking in the Rotterdam study.

Background: Chronic obstructive pulmonary disease (COPD) and asthma associate with high morbidity and mortality. High levels of advanced glycation end products (AGEs) were found in tissue and plasma of COPD patients but their role in COPD and asthma is unclear.

Methods: In the Rotterdam Study (n = 2577), AGEs (by skin autofluorescence (SAF)), FEV and lung diffusing capacity (Dc and Dc /alveolar volume [V]) were measured.

Impressive clinical improvement and disappearance of neuropathic pain in an adult patient with hypophosphatasia treated with asfotase alfa.

Hypophosphatasia (HPP) is a rare disorder, resulting from loss-of-function variants of the ALPL gene encoding non-tissue specific alkaline phosphatase (TNSALP). Presentation varies largely, with increased severity usually occurring with earlier disease onset. Here we describe the clinical improvement of a 57-year-old woman with childhood onset HPP, after initiating treatment with asfotase alfa (Strensiq®).

ERN BOND: The key European network leveraging diagnosis, research, and treatment for rare bone conditions.

There is no universally accepted definition for rare diseases: in Europe a disease is considered to be rare when affecting fewer than 1 in 2000 people. European Reference Networks (ERNs) have been the concrete response to address the unmet needs of rare disease patients and many pan-European issues in the field, reducing inequities, and significantly increasing accessibility to high-quality healthcare across Europe. ERNs are virtual networks, involving centres and patient representatives with the general scope to facilitate discussion on complex cases requiring highly specialised competences and trained expertise.

Skin autofluorescence, reflecting accumulation of advanced glycation end products, and the risk of dementia in a population-based cohort.

Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which are harmful compounds that have been implicated in dementia. Within the Rotterdam Study, we measured skin AGEs as skin autofluorescence, reflecting long-term accumulation of AGEs, and determined their association with the risk of dementia and with brain magnetic resonance imaging (MRI) measures. Skin autofluorescence was measured between 2013 and 2016 in 2922 participants without dementia.

Advanced glycation end products measured by skin autofluorescence and subclinical cardiovascular disease: the Rotterdam Study.

Background: Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD.

Methods: In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF).

Thermal Ablation for Treating Tumor-induced Osteomalacia in a Patient With IV Phosphate Dependency.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with tumors secreting fibroblast growth factor 23 that can be cured with complete surgical resection of the tumor. However, when these tumors are at difficult locations, less invasive modalities such as thermal ablation (TA) might be a good alternative. A 40-year-old woman was seen for a second opinion because of severe hypophosphatemia with complaints of fatigue, myalgia, and muscle weakness for which she needed IV phosphate for 15 to 18 hours per day in addition to oral alfacalcidol and phosphate.

Serum alkaline phosphatase can be elevated in patients with hypophosphatasia due to liver disease.

Background: Hypophosphatasia (HPP) is a rare inherited disorder caused by pathogenic loss-of-function variants in the ALPL gene, encoding the tissue-nonspecific isoenzym of alkaline phosphatase (ALP; TNSALP). Low serum ALP is the biochemical hallmark of HPP, but it is unknown whether ALP levels can increase due to concurring liver disease, which may lead to a missed diagnose of HPP. We present a patient with genetically confirmed HPP, who showed a transient increase of serum ALP levels due to alcohol-induced hepatitis.

Case Report: Unexplained Mild Hypophosphatemia and Very High Serum FGF23 Concentrations.

Fibroblast growth factor (FGF)23 is one of the major regulators of phosphate homeostasis. Hypophosphatemia can lead to muscle weakness, fatigue, and osteomalacia. In the setting of hypophosphatemia, serum FGF23 can be measured to differentiate between FGF23-mediated and non-FGF23-mediated renal phosphate wasting.

In vitro regulation of fibroblast growth factor 23 by 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D synthesized by osteocyte-like MC3T3-E1 cells.

Fibroblast growth factor 23 (FGF23) is produced and secreted by osteocytes and is essential for maintaining phosphate homeostasis. One of the main regulators of FGF23, 1,25-dihydroxyvitamin D (1,25(OH)2D3), is primarily synthesized in the kidney from 25-hydroxyvitamin D (25(OH)D) by 1α-hydroxylase (encoded by CYP27B1). Hitherto, it is unclear whether osteocytes can convert 25(OH)D and thereby allow for 1,25(OH)2D3 to induce FGF23 production and secretion locally.