Impaired Bone Mineralization Research Articles

Growth and disease burden in children with hypophosphatasia.

Hypophosphatasia, an inborn error of metabolism characterized by impaired bone mineralization, can affect growth. This study evaluated relationships between anthropometric parameters (height, weight, and body mass index) and clinical manifestations of hypophosphatasia in children. Data from children (aged <18 years) with hypophosphatasia were analyzed from the observational Global Hypophosphatasia Registry. Anthropometric parameters were evaluated by age group (<2 years and ≥2 years) at assessment. The frequency of hypophosphatasia manifestations was compared between children with short stature (< percentile) and those with normal stature. This analysis included 215 children (54.4% girls). Short stature presented in 16.1% of children aged <2 years and 20.4% of those aged ≥2 years at assessment. Among those with available data (n = 62), height was below the target height (mean: -0.66 standard deviations). Substantial worsening of growth (mean delta height z score: -1.45; delta weight z score: -0.68) occurred before 2 years of age, while in those aged ≥2 years, anthropometric trajectories were maintained (delta height z score: 0.08; delta weight z score: 0.13). Broad-ranging hypophosphatasia manifestations (beyond dental) were observed in most children. Short stature was not a consistent characteristic of children with hypophosphatasia, but growth impairment was observed in those aged <2 years, indicating that hypophosphatasia might affect growth plate activity during infancy. In addition, a broad range of clinical manifestations occurred in those above and below the third percentile for height, suggesting that height alone may not accurately reflect hypophosphatasia disease burden and that weight is less affected than longitudinal growth.

No association between methotrexate and impaired bone mineral density in a cohort of patients with polymyalgia rheumatica, giant cell arteritis, granulomatosis with polyangiitis and other vasculitides—a cross-sectional analysis with dose–response analyses

ObjectiveTo investigate whether methotrexate (MTX) use is associated with bone mineral density (BMD) in patients with polymyalgia rheumatica (PMR) and various forms of vasculitis.MethodsRh-GIOP is a cohort study designed to evaluate bone health in patients with inflammatory rheumatic diseases. This cross-sectional analysis assessed the baseline visits of all patients with PMR or any kind of vasculitis. Following univariable analysis, multivariable linear regression analysis was performed. The lowest T-score of either the lumbar spine or the femur was chosen as the dependent variable to examine the relationship between MTX use and BMD. These analyses were adjusted for a variety of potential confounders, including age, sex, and glucocorticoid (GC) intake.ResultsOf 198 patients with PMR or vasculitis, 10 patients were excluded for very high GC dose (n = 6) or short disease duration (n = 4). The remaining 188 patients had the following diseases: PMR 37.2%, giant cell arteritis 25.0%, granulomatosis with polyangiitis 16.5%, followed by rarer diseases. The mean age was 68.0 ± 11.1 years, mean disease duration was 5.58 ± 6.39 years, and 19.7% had osteoporosis by dual x-ray absorptiometry (T-score ≤ −2.5). 23.4% were taking MTX at baseline with a mean dose of 13.2 mg/week (median: 15 mg/week). 38.6% of those used a subcutaneous preparation. MTX users had similar BMD compared to non-users (minimum T-scores −1.70 (± 0.86) versus −1.75 (± 0.91), respectively; p = 0.75). There was no statistically significant dose–response relationship: neither current nor cumulative dose were associated with BMD in unadjusted or adjusted models (current dose: slope −0.02; −0.14 to 0.09; p = 0.69; cumulative dose: slope −0.12; −0.28 to 0.05; p = 0.15).ConclusionIn the Rh-GIOP cohort, MTX is used in about a quarter of patients with PMR or vasculitis. It is not associated with BMD levels.

Disulfide Bonds Are Not Necessary for Intrinsic TNSALP Activity.

Recent developments in single-molecule enzymology (SME) have allowed for the observation of subpopulations present in enzyme ensembles. Tissue-nonspecific alkaline phosphatase (TNSALP), a homodimeric monophosphate esterase central to bone metabolism, has become a model enzyme for SME studies. TNSALP contains two internal disulfide bonds that are critical for its effective dimerization; mutations in its disulfide bonding framework have been reported in patients with hypophosphatasia, a rare disease characterized by impaired bone and tooth mineralization. In this paper, we present the kinetics of these mutants and show that these disulfide bonds are not crucial for TNSALP enzymatic function. This surprising result reveals that the enzyme's active conformation does not rely on its disulfide bonds. We posit that the signs and symptoms seen in hypophosphatasia are likely not primarily due to impaired enzyme function, but rather decreased enzyme expression and trafficking.

Peculiarities of the Ukrainian model of Fracture Risk Assessment (FRAX®) among patients with liver cirrhosis accompanied by impaired bone mineral density: its diagnostic and prognostic value

Introduction. The problem of osteoporotic fractures and the evaluation thresholds for intervention in patients with liver cirrhosis (LC) remains obscure so far. Ukrainian model of fracture risk assessment (FRAX®) has never been implemented among patients with LC in Ukraine. The aim of the study. To find out the peculiarities of the Ukrainian model of Fracture Risk Assessment, its diagnostic and prognostic value for implementation among patients with liver cirrhosis accompanied by impaired bone mineral density. Materials and methods. 90 patients with LC (27 women and 63 men aged 18 to 66 years) were randomly assigned into the study. Stratification into groups was based on information about bone condition. 72 patients were included into an experimental group (EG, patients with impaired bone mineral density (IBMD), which was divided into two subgroups – EG A (patients with osteopenia, 46) and EG B (patients with osteoporosis, 26). Control group (CG) included 18 patients without IBMD. The peculiarities of the fracture risk factors and evaluation thresholds according to the Ukrainian FRAX® model (2019) amoung patients with LC with bone disorders were established (significant differences between frequency of features in groups and substantial stochastic associations of features with IBMD or its manifestations were investigated). The diagnostic characteristcs (diagnostic value, predictive value, likelihood ratio) of the detected features for IBMD in general, osteopenia and osteoporosis in particular, were revealed, and after that the post-test probability of certain bone disorders was determined among all patients with LC in the case of applying the identified features. The results. It was found that although most of the risk factors occurred more often in patients with bone disorders, significant differences were detected only between the frequency of previous fractures in EG and CG, including EG B and CG, and EG A and EG B; between the frequency of cases of normal body weight, as well as overweight in EG and CG, including EG B and CG. The evaluation thresholds according to the Ukrainian FRAX® model also differed significantly: the values above the upper evaluation threshold – in EG B and CG and in EG A and EG B; the intermediate values of fracture risk – in EG A and CG; the values below the lower evaluation threshold – in EG and CG, as well as in EG A and CG and in EG B and CG, including. Bone disorders had a substantial direct stochastic association in the following cases: IBMD in general – with the previous fractures, normal body weight and values above the upper evaluation threshold; osteopenia – with the previous fractures, normal body weight and intermediate values of fracture risk; osteoporosis – with the previous fractures, normal body weight and values above the upper evaluation threshold. All manifestations of bone disorders had substantial negative stochastic association with overweight and values below the lower evaluation threshold, as well as osteoporosis with short height (indicates that features are inherent for normal bone mineral density). It was found out that fracture risk factors and evaluation thresholds according to the Ukrainian FRAX® model are mainly single-vector markers, since they can confirm the disease being detected, or deny it in the case they are absent. The previous fractures are highly specific for IBMD, especially for osteoporosis, and can be useful for confirming these disorders being present in patient with LC. The normal body weight is medium-specific for IBMD and for osteoporosis, but can be more useful for indicating IBMD if it is present, and excluding osteoporosis being absent. The values above the upper evaluation threshold according to the Ukrainian FRAX® model are highly specific for osteoporosis and can confirm osteoporisis being present. The intermediate values of fracture risk according to the Ukrainian FRAX® model are medium-specific for osteopenia, but can be more useful for excluding osteopenia if they are absent. The overweight, especially the values below the lower evaluation threshold, will most likely indicate normal bone mineral density. Conclusions. The use of the Ukrainian model of Fracture Risk Assessment (FRAX®) has certain peculiarities and can be valuable tool for detecting or excluding impaired bone mineral density in patients with liver cirrhosis.

ОСТЕОСИНТЕЗ ПЕРЕЛОМОВ МАЛОБЕРЦОВОЙ КОСТИ: ОТ НАКОСТНОГО К ИНТРАМЕДУЛЛЯРНОМУ

Fibula plays important role in the stability of the ankle joint. Precise restora-tion of its length, axis and rotation is critically important in intraarticular malleo-lar and distal tibia fractures. Open reduction and internal fixation with plate is widely accepted method of treatment of the fractures of lateral malleolus and fib-ular shaft. Nevertheless, substantial number of complications accomplishes this treatment modality. Danger of wound complications is associated with borderline blood supply in the zone of surgery and with wide surgical exposure performed on swollen soft-tissues. Risk of secondary displacements is associated with ad-vanced osteoporosis. Both factors lead to significant increase of number of com-plications in the elderly patients with impaired bone mineral density and altered nutrition of the soft-tissues. These dangers has led to the development of less in-vasive methods of intramedullary fixation in the lateral malleolus and fibular shaft. This article provides data on evolution of the methods of surgical fixation of these fractures.

Adverse effects of the cancer therapy on osteoclast-mediated bone loss in patients with cancers: a challenge

It is well-known that cancer therapies, including chemotherapy drugs, aromatase inhibitors and gonadotropin-releasing homone analogues, commonly contribute to remarkably reduce the bone mineral density, subsequently increase the rate of bone loss. For instance, in the patients with prostate cancer treated with androgene deprivation therapy (ADT), or chemotherapy drugs such as doxorubicin and cisplatin the calcicum levels were significantly decreased in the body, thereby leading to bone loss. Besides, the aromatase inhibitors widely used to treat breast cancer, and antiresorptive agents targeting the receptor activator of nuclear factor кB ligand can also trigger bone loss. Osteoclasts (OCs), derived from monocyte/macrophage lineage, are deifferentiated into mature, multinucleated OCs (a process also known as osteoclastogenesis) via a series of osteoclastogenic signaling pathways, are responsible for resorbing bone. This review article characterizes and summarizes the adverse effects of chemotherapy drugs on accelerating OC-induced bone defects such as the increased bone resorption and the impaired bone mineral density (BMD) in the patients with cancers.

Liver fibrosis is associated with impaired bone mineralization and microstructure in obese individuals with non-alcoholic fatty liver disease.

Chronic liver diseases are associated with increased bone fracture risk, mostly in end-stage disease and cirrhosis; besides, data in non-alcoholic fatty liver disease (NAFLD) are limited. Aim of this study was to investigate bone mineralization and microstructure in obese individuals with NAFLD in relation to the estimated liver fibrosis. For this cross-sectional investigation, we analyzed data from 1872 obese individuals (44.6 ± 14.1years, M/F: 389/1483; BMI: 38.3 ± 5.3kg/m2) referring to the Endocrinology outpatient clinics of Sapienza University, Rome, Italy. Participants underwent clinical work-up, Dual-Energy X-ray Absorptiometry for assessing bone mineral density (BMD) and microarchitecture (trabecular bone score, TBS). Liver fibrosis was estimated by Fibrosis Score 4 (FIB-4). Serum parathyroid hormone (PTH), 25(OH) vitamin D, osteocalcin and IGF-1 levels were measured. Obese individuals with osteopenia/osteoporosis had greater FIB-4 than those with normal BMD (p < 0.001). FIB-4 progressively increased in presence of degraded bone microarchitecture (p < 0.001) and negatively correlated with the serum osteocalcin (p < 0.001) and IGF-1 (p < 0.001), which were both reduced in presence of osteopenia/osteoporosis. FIB-4 predicted IGF-1 reduction in multivariable regression models adjusted for confounders (β: -0.18, p < 0.001). Higher FIB-4 predicted bone fragility with OR 3.8 (95%C.I:1.5-9.3); this association persisted significant after adjustment for sex, age, BMI, diabetes, smoking status and PTH at the multivariable logistic regression analysis (OR 1.91 (95%C.I:1.15-3.17), p < 0.01), with AUROC = 0.842 (95%C.I:0.795-0.890; p < 0.001). Our data indicate the presence of a tight relation between NAFLD-related liver fibrosis, lower bone mineral density and degraded microarchitecture in obese individuals, suggesting potential common pathways underlying liver and bone involvement in obesity and insulin resistance-associated disorders.

PSAT228 Hereditary Hypophosphatemic Rickets: Management in Adults

Abstract Introduction Hereditary Hypophosphatemic Rickets (HHR) is a group of rare inherited disorders consisting of X-linked hypophosphatemic rickets (XLHR, prevalence 1 in 20,000 births), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR). XLHR is caused by loss of function mutation of the PHEX gene, ARHR is caused by loss of function mutation of the DMP1/ENPP1 gene and ADHR is caused by activating point mutations in FGF23. These mutations result in renal phosphate wasting, hypophosphatemia, and impaired bone mineralization. It presents in childhood as skeletal deformities, abnormal gait, skeletal pain, dental abnormalities, and stunted growth. Adults have osteomalacia-related pain, fractures, and arthritis. The diagnosis is made by findings consistent with rickets and normal serum calcium, normal 25-hydroxy vitamin D, low-normal 1,25-dihydroxy vitamin D, elevated alkaline phosphatase activity, and low phosphate levels. Urine studies show low urine calcium and decreased tubular maximum reabsorption of phosphate, confirming renal wasting of phosphate. The goal of treatment in adults is to reduce pain, prevent fractures, enhance mobility, and decrease osteomalacia. Phosphate and vitamin D supplementations are used with close monitoring as it is associated with severe adverse events. It can cause hypercalcemia leading to nephrocalcinosis, nephrolithiasis, chronic kidney disease, and hyperparathyroidism. There is no evidence that the treatment affects long-term skeletal complications. Burosumab, a monoclonal antibody that inhibits FGF23, is approved for the treatment of XLHR. No studies are available about the use of Burosumab in ADHR or ARHR. Case Presentation A 18-year-old male with past medical history of hypophosphatemic rickets with multiple fractures, on oral phosphate tablets and calcitriol, presented to the Endocrinology clinic to establish care. He had been following Pediatric Endocrinology in the past. His blood work showed normal calcium, low phosphate of 1.6 mg/dl (normal: 2.5-4.5 mg/dl), vitamin D 25 hydroxy level of 26 ng/ml (normal: 20-100 ng/ml), vitamin D 1,25-dihydroxy level of 25 pg/ml (normal: 30-80 pg/ml), intact parathyroid hormone level of 549 pg/ml (normal: 15-65 pg/ml), and alkaline phosphatase of 438 U/l (normal: 40-150 U/l). Urine calcium was low and urine phosphorus was elevated with phosphate/creatinine ratio more than 2000 (normal: 60-962), consistent with renal phosphate wasting. Genetic testing in the past was negative for PHEX gene mutation, so he was not a candidate for Burosumab. Conclusion There is limited knowledge about Hereditary Hypophosphatemic Rickets, especially ADHR and ARHR due to limited cases (less than 100 cases reported so far). The current standard of treatment of HHR is sub-optimal and associated with adverse effects. Burosumab has not been tested in ADHR or ARHR, so it is unclear if it will be beneficial in this subgroup. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Risk factors of vestibular disorders in patients with metabolic disorders in the bone

Actuality: Vestibular disorders of central and peripheral origin are often observed in patients with impaired bone mineral metabolism. Despite the benign nature, they cause significant disturbances in social life. Aim: study clinical and laboratory parameters and vestibular disorders in patients with different forms of benign paroxysmal positional vertigo (BPPV), related to degenerative-dystrophic changes of the musculoskeletal system and identify ways to further correct them. Materials and methods: We have studied 60 patients with BPPV. All patients underwent bone densitometry, examined the loss of bone strength of the spine and hip joint, vestibulometric study. Determined the value of mineral metabolism: the content of calcium and vitamin D in serum. To verify BPPV and its type, patients underwent posit ional tests. Results and discussions: 60 patients who complained of dizziness, on the basis of additional examination was diagnosed with BPPVs. Otitolithithiasis of the posterior semicircular canal was diagnosed in 44 patients, horizontal canal – in 8 patients, cupulo-lithiasis – in 10 patients. Depending on the condition of the vestibular systeme, patients were divided into 2 groups. Group 1 included 24 patients with peripheral vestibular disorders, group 2 included 36 patients with mixed vestibular dysfunction. According to the results of absorption densitometry in patients, mineral metabolism disorders were detected: osteopenia in 41 patients, the average T-test was (-1.9±0.3) SD, osteoporosis – In 19 patients, T-test was (-2.8 ± 0.2) SD. Serum calcium and vitamin D deficiency have been noted in patients with BPPV, indicating impaired mineral metabolism. In order to correct mineral metabolism and antirelapse therapy, patients with BPPV were prescribed vestibuloplegics, calcium, vitamin D for 12 months. Conclusions: studies have found a correlation between BPPV and bone mineral metabolic disorders. It indicated the presence of osteopenia and osteoporosis in patients with DPPD, as well as changes in the levels of mineral metabolism of bone (in addition to calcium and vitamin D in serrum). Such changes in mineral metabolism may be a biomarker of otolithic degeneration, maintain a causal relationship between lower serum vitamin D and calcium levels and the development of BPPV, and cause frequent attacks.

The Dietary and Non-Dietary Management of Osteoporosis in Adult-Onset Celiac Disease: Current Status and Practical Guidance.

Impaired bone mineral density (BMD) is a frequent complication of adult-onset celiac disease (CeD). This is usually due to malabsorption of nutrients, changes in bone metabolism in association with inflammation, and to a lesser extent, decreased overall physical health and mobility. This review aims to highlight the current status concerning surveillance, prevention, and treatment strategies for bone disease in CeD. A practical guidance on these matters is suggested. The available published research on the prevention and treatment of decreased BMD in relation to CeD is scarce. In general, publications were based on expert opinions or extrapolation from studies on postmenopausal women or inflammatory bowel disease. Optimal dietary treatment and an adequate supply of calcium and vitamin D are the cornerstones for the reduction in fracture risk in patients with CeD. In adults with low BMD or fragility fractures, CeD needs to be considered and specifically approached. When osteoporosis is documented, start treatment with an antiresorptive agent; these agents are proven to result in a long-term reduction in fracture risk in high-risk individuals. However, there are some important differences between the management of male and female patients, particularly premenopausal women, that need to be addressed. In patients with persisting diarrhea and malabsorption, parenteral medications may be preferable. Future research specifically focusing on celiac disease and the associated disorders in bone mineralization is mandatory to provide evidence-based recommendations in this field.

Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population.

(1) Hypophosphatasia (HPP) is a rare inherited disease caused by mutations (pathogenic variants) in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by impaired bone mineral metabolism due to the low enzymatic activity of TNSALP. Knowledge about the structure of the gene and the features and functions of various ALPL gene variants, taking into account population specificity, gives an understanding of the hereditary nature of the disease, and contributes to the diagnosis, prevention, and treatment of the disease. The purpose of the study was to describe the spectrum and analyze the functional features of the ALPL gene variants, considering various HPP subtypes and clinical symptoms in Russian children. (2) From 2014-2021, the study included the blood samples obtained from 1612 patients with reduced alkaline phosphatase activity. The patients underwent an examination with an assessment of their clinical symptoms and biochemical levels of TNSALP. DNA was isolated from dried blood spots (DBSs) or blood from the patients to search for mutations in the exons of the ALPL gene using Sanger sequencing. The PCR products were sequenced using a reagent BigDye Terminator 3.1 kit (Applied Biosystems). Statistical analysis was performed using the GraphPad Prism 8.01 software. (3) The most common clinical symptoms in Russian patients with HPP and two of its variants (n = 22) were bone disorders (75%), hypomyotonia (50%), and respiratory failure (50%). The heterozygous carriage of the causal variants of the ALPL gene was detected in 225 patients. A total of 2 variants were found in 27 patients. In this group (n = 27), we identified 28 unique variants of the ALPL gene, of which 75.0% were missense, 17.9% were frameshift, 3.6% were splicing variants, and 3.6% were duplications. A total of 39.3% (11/28) of the variants were pathogenic, with two variants being probably pathogenic, and 15 variants had unknown clinical significance (VUS). Among the VUS group, 28.6% of the variants (7/28) were discovered by us for the first time. The most common variants were c.571G &gt; A (p.Glu191Lys) and c.1171del (Arg391Valfs*12), with frequencies of 48.2% (13/28) and 11% (3/28), respectively. It was found that the frequency of nonsense variants of the ALPL gene was higher (p &lt; 0.0001) in patients with the perinatal form compared to the infantile and childhood forms of HPP. Additionally, the number of homozygotes in patients with the perinatal form exceeded (p &lt; 0.01) the frequencies of these genotypes in children with infantile and childhood forms of HPP. On the contrary, the frequencies of the compound-heterozygous and heterozygous genotypes were higher (p &lt; 0.01) in patients with infantile childhood HPP than in perinatal HPP. In the perinatal form, residual TNSALP activity was lower (p &lt; 0.0005) in comparison to the infantile and childhood (p &lt; 0.05) forms of HPP. At the same time, patients with the heterozygous and compound-heterozygous genotypes (mainly missense variants) of the ALPL gene had greater residual activity (of the TNSALP protein) regarding those homozygous patients who were carriers of the nonsense variants (deletions and duplications) of the ALPL gene. Residual TNSALP activity was lower (p &lt; 0.0001) in patients with pathogenic variants encoding the amino acids from the active site and the calcium and crown domains in comparison with the nonspecific region of the protein.

Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice.

Patients with the renal phosphate-wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic hormone FGF23. The mineralization defect in patients with XLH and Hyp mice is caused by a combination of hypophosphatemia and local accumulation of mineralization-inhibiting molecules in bone. However, the mechanism by which PHEX deficiency regulates bone cell metabolism remains elusive. Here, we used spatial metabolomics by employing matrix-assisted laser desorption/ionization (MALDI) Fourier-transform ion cyclotron resonance mass spectrometry imaging (MSI) of undecalcified bone cryosections to characterize in situ metabolic changes in bones of Hyp mice in a holistic, unbiased manner. We found complex changes in Hyp bone metabolism, including perturbations in pentose phosphate, purine, pyrimidine, and phospholipid metabolism. Importantly, our study identified an upregulation of several biochemical pathways involved in intra- and extracellular production of the mineralization inhibitor pyrophosphate in the bone matrix of Hyp mice. Our data emphasize the utility of MSI-based spatial metabolomics in bone research and provide holistic in situ insights as to how Phex deficiency-induced changes in biochemical pathways in bone cells are linked to impaired bone mineralization.

Prevalence of anticonvulsant-induced vitamin D deficiency

Background. Epilepsy is a common disease in children and adults, requiring long-term or lifelong use of antiepileptic drugs (AEDs) in 60% of cases. Enzyme-inducing and enzyme-inhibiting AEDs may have a negative effect on vitamin D metabolism. However, at present, standard treatment protocols for patients with epilepsy include no nutrients and vitamin-mineral vitamin D containing complexes.Objective: to analyze studies on the prevalence of vitamin D deficiency induced by AEDs intake in patients with epilepsy.Material and methods. The search for full-text publications in Russian and English was carried out in еLibrary, PubMed/ MEDLINE, ClinicalKey, Google Scholar databases, covering the last five years. The analysis included 9 domestic and 54 foreign epidemiological studies assessing prevalence of AED-induced vitamin D deficiency and, consequently, altered bone mineralization and osteomalacia/osteoporosis.Results. Both in children and adults, the prevalence of AED-induced vitamin D deficiency reaches 40% and even higher. The region of residence of patients with epilepsy does not significantly affect this indicator. Impaired bone mineralization is associated with AED-induced vitamin D deficiency and requires the inclusion of vitamin D in the protocols of disease-modifying epilepsy therapy in children and adults.Conclusion. The results of the review showed high relevance of the discussed interdisciplinary problem and need to introduce laboratory screening of vitamin D deficiency among pediatric and adult patients with epilepsy.

ENPP1 deficiency: A clinical update on the relevance of individual variants using a locus-specific patient database.

Loss-of-function variants in the ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) cause ENPP1 Deficiency, a rare disorder characterized by pathological calcification, neointimal proliferation, and impaired bone mineralization. The consequence of ENPP1 Deficiency is a broad range of age dependent symptoms and morbidities including cardiovascular complications and 50% mortality in infants, autosomal recessive hypophosphatemic rickets type 2 (ARHR2) in children, and joint pain, osteomalacia and enthesopathies in adults. Recent research continues to add to the growing clinical presentation profile as well as expanding the role of ENPP1 itself. Here we review the current knowledge on the spectrum of clinical and genetic findings of ENPP1 Deficiency reported in patients diagnosed with GACI or ARHR2 phenotypes using a comprehensive database of known ENPP1 variants with associated clinical data. A total of 108 genotypes were identified from 154 patients. Of the 109 ENPP1 variants reviewed, 72.5% were demonstrably disease-causing, a threefold increase in pathogenic/likely pathogenic variants over other databases. There is substantial heterogeneity in disease severity, even among patients with the same variant. The approach to creating a continuously curated database of ENPP1 variants accessible to clinicians is necessary to increase the diagnostic yield of clinical genetic testing and accelerate diagnosis of ENPP1 Deficiency.

Vitamin K-Dependent Carboxylation of Osteocalcin in Bone-Ally or Adversary of Bone Mineral Status in Rats with Experimental Chronic Kidney Disease?

Chronic kidney disease (CKD) commonly occurs with vitamin K (VK) deficiency and impaired bone mineralization. However, there are no data explaining the metabolism of endogenous VK and its role in bone mineralization in CKD. In this study, we measured serum levels of phylloquinone (VK1), menaquinone 4 and 7 (MK4, MK7), and VK-dependent proteins: osteocalcin, undercarboxylated osteocalcin (Glu-OC), and undercarboxylated matrix Gla protein (ucMGP). The carboxylated osteocalcin (Gla-OC), Glu-OC, and the expression of genes involved in VK cycle were determined in bone. The obtained results were juxtaposed with the bone mineral status of rats with CKD. The obtained results suggest that the reduced VK1 level observed in CKD rats may be caused by the accelerated conversion of VK1 to the form of menaquinones. The bone tissue possesses all enzymes, enabling the conversion of VK1 to menaquinones and VK recycling. However, in the course of CKD with hyperparathyroidism, the intensified osteoblastogenesis causes the generation of immature osteoblasts with impaired mineralization. The particular clinical significance seems to have a finding that serum osteocalcin and Glu-OC, commonly used biomarkers of VK deficiency, could be inappropriate in CKD conditions, whereas Gla-OC synthesized in bone appears to have an adverse impact on bone mineral status in this model.

Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).

Autosomal recessive hypophosphatemic rickets (ARHR) are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) leading to impaired bone mineralization (rickets and osteomalacia). Inactivating mutations of Dentin matrix protein 1 (DMP1) give rise to ARHR type 1 (ARHR1). Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population. Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects. The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1. Monthly administration of burosumab to 2 brothers afflicted with the disorder resulted in normalization of serum phosphate, healing of pseudofracture, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that characterizes this disorder. No adverse effects were reported following burosumab administration. The present report highlights the beneficial biochemical and clinical outcomes associated with the use of burosumab in patients with ARHR1.

Infigratinib Reduces Fibroblast Growth Factor 23 (FGF23) and Increases Blood Phosphate in Tumor‐Induced Osteomalacia

ABSTRACTTumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25‐dihydroxy‐vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1‐fibroblast growth factor receptor 1 (FN1‐FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1‐FGFR1 proteins, the effectiveness of infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, was studied in an open‐label, single‐center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)‐DOTATATE and 18Fluoride (18F)‐Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment‐related, dose‐limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher‐than‐expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment‐related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life‐limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Impact of hydrocortisone replacement on bone mineral density and bone turnover markers in patients with primary adrenal insufficiency.

A cross-sectional study was conducted in 37 PAI patients treated with HC. BMD and selected bone turnover markers (β-crosslaps and osteocalcin) were measured. A stepwise binary logistic regression model was applied to determine the independent variables associated with low BMD. Osteoporosis was noted in 14.3% and osteopenia in 34.3% of cases. These patients were older (p=0.01) and received higher daily HC dose compared to patients with normal BMD (p=0.01). BMD values in the lumbar spine and the femoral neck were negatively correlated with daily HC dose (r=-0.36, p=0.03 and r=-0.34, p=0.05, respectively). Plasma osteocalcin was negatively correlated with disease duration (r=-0.38, p=0.02) and cumulative HC dose (r=-0.43, p<0.01). In multivariate analysis, a daily HC dose ≥12 mg/m2/day was independently associated with a higher risk of osteopenia/osteoporosis [OR (95% CI), 9.0 (1.1-74.6); p=0.04]. Impaired bone mineralization in patients with PAI is correlated with HC dose. A daily HC dose ≥12 mg/m2/day was associated with an increased risk of osteopenia and osteoporosis in these patients.

Jiawei Yanghe Decoction Regulates Bone-Lipid Balance through the BMP-SMAD Signaling Pathway to Promote Osteogenic Differentiation of Bone Mesenchymal Stem Cells.

Background The Jiawei Yanghe decoction (JWYHD) is a traditional Chinese medicine formula for the treatment of osteoporosis, but its therapeutic mechanism has not been fully elucidated, and the therapeutic target of the intervention disease needs to be further verified. The dysfunction of bone mesenchymal stem cells (BMSCs) is considered to be an important pathogenesis of postmenopausal osteoporosis (PMOP). The purpose of this study was to explore how JWYHD regulates BMSC differentiation through the BMP-SMAD signal pathway. Methods In the in vivo study, we used an ovariectomized PMOP rat (n = 36, 2-month-old, 200 ± 20 g) model and femur micro-CT analysis to study the effect of JWYHD on bone loss in rats. By immunofluorescence, the translocation expression of BMP2, a key protein in the pathway, was detected. Serum bone metabolism was detected by an enzyme-linked immunosorbent assay (ELISA). Alkaline phosphatase (ALP) activity was detected by alkaline phosphatase staining (ALPS), osteogenesis and matrix mineralization were detected by alizarin red staining (ARS), the adipogenic ability of BMSCs was detected by oil red staining (ORS), and CFU is used to detect the ability of cells to form colonies. The expression of related proteins was detected by western blotting. Results In vivo and in vitro, the OP phenotypes of SD rats induced by ovariectomy (OVX) included impaired bone mineral density and microstructure, abnormal bone metabolism, and impaired MSC differentiation potential. JWYHD treatment reversed this trend and restored the differentiation potential of MSCs. JWYHD medicated serum and direct intervention of drugs activated the BMP-SMAD signaling pathway, promoted the osteogenic differentiation of BMSCs, and inhibited their adipogenic differentiation. Conclusions Our data identified that JWYHD is an effective alternative drug for the treatment of PMOP that functions to stimulate the differentiation of BMSCs into osteoblasts in the BMP-SMAD signaling-dependent mechanism.

The Bone Sialoprotein RGD Domain Modulates and Maintains Periodontal Development

Bone sialoprotein (gene: Ibsp; protein: BSP) is a multifunctional extracellular matrix protein present in bone, cementum, and dentin. Accumulating evidence supports BSP as a key regulator of mineralized tissue formation via evolutionarily conserved functional domains, including a C-terminal integrin-binding Arg-Gly-Asp (RGD) domain implicated in extracellular matrix–cell signaling. Ablation of Ibsp in mice (Ibsp−/−) results in impaired bone growth and mineralization and defective osteoclastogenesis, with effects in the craniofacial region including reduced acellular cementum formation, detachment of the periodontal ligament (PDL), alveolar bone hypomineralization, and severe periodontal breakdown. We hypothesized that BSP-RGD plays an important role in cementum and alveolar bone formation and mineralization, as well as periodontal function. This hypothesis was tested by replacing the RGD motif with a nonfunctional Lys-Ala-Glu (KAE) sequence in (IbspKAE/KAE) mice and OCCM.30 murine (IbspKAE) cementoblasts. The RGD domain was not critical for acellular or cellular cementum formation in IbspKAE/KAE mice. However, PDL volume and thickness were increased, and significantly more tartrate-resistant acid phosphatase–positive osteoclasts were found on alveolar bone surfaces of IbspKAE/KAE mice versus wild type mice. PDL organization was disrupted as indicated by picrosirius red stain, second harmonic generation imaging, dynamic mechanical analysis, and decreased asporin proteoglycan localization. In vitro studies implicated RGD functions in cell migration, adhesion, and mineralization, and this was confirmed by an ossicle implant model where cells lacking BSP-RGD showed substantial defects as compared with controls. In total, the BSP-RGD domain is implicated in periodontal development, though the scale and scope of changes indicated by in vitro studies indicate that other factors may partially compensate for and reduce the phenotypic severity of mice lacking BSP-RGD in vivo.