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BACKGROUND: In patients with X-linked hypophosphatemia (XLH), conventional therapy with oral phosphate salts and active vitamin D has been associated with nephrocalcinosis. However, the nature of the relationships among XLH, its treatment, nephrocalcinosis, and kidney function remain poorly understood. METHODS: Renal ultrasounds were performed and glomerular filtration rates were estimated (eGFR) at baseline in burosumab-naïve patients with XLH who participated in burosumab clinical trials (NCT02181764, NCT02526160, NCT02537431, NCT02163577, NCT02750618, NCT02915705) or enrolled in the XLH Disease Monitoring Program (XLH-DMP; NCT03651505). In this cross-sectional analysis, patient, disease, and treatment characteristics were described among patients with and without nephrocalcinosis. RESULTS: The analysis included 196 children (mean [SD] age 7.6 [4.0] years) and 318 adults (40.3 [13.1] years). Mean (SD) height z-score was -1.9 (1.2) for children and -2.3 (1.7) for adults. Nearly all children (97%) and adults (94%) had previously received conventional therapy. Nephrocalcinosis was detected in 22% of children and 38% of adults. In children, reduced eGFR <90 ml/min/1.73 m2 was more prevalent in those with nephrocalcinosis (25%) than in those without (11%), a finding that was not observed in adults. Children with nephrocalcinosis had lower mean values of TmP/GFR (P<.05), serum 1,25(OH)2D (P<.05), and eGFR (P<.001) and higher mean serum calcium concentrations (P<.05) than did those without nephrocalcinosis. Adults with nephrocalcinosis had lower mean serum phosphorus (P<.01) and 1,25(OH)2D (P<.05) concentrations than those without. Exploratory logistic regression analyses revealed no significant associations between the presence of nephrocalcinosis and other described patient or disease characteristics. CONCLUSIONS: Nephrocalcinosis was observed in nearly one quarter of children and more than one-third of adults with XLH. Further study is needed to better understand the predictors and long-term consequences of nephrocalcinosis, with surveillance for nephrocalcinosis remaining important in the management of XLH.
BACKGROUND: Conventionally, patients with X-linked hypophosphatemia (XLH) were treated with phosphate and vitamin D taken by mouth. However, this therapy might lead to a buildup of calcium in the kidney, called nephrocalcinosis. Here, we tried to better understand how XLH, conventional therapy, nephrocalcinosis, and kidney function are related. METHODS: Nephrocalcinosis was detected with kidney ultrasounds. Kidney function, called the estimated glomerular filtration rate (eGFR), was determined using the blood level of creatinine. Patients had been part of burosumab clinical trials or part of the XLH Disease Monitoring Program. Data were collected from patients before they received burosumab. RESULTS: The study included 196 children and 318 adults. Almost all children and adults had received conventional therapy. 22% of children had nephrocalcinosis and 38% of adults had nephrocalcinosis. In children, low eGFR was more common in those with nephrocalcinosis (25%) than in those without (11%). In adults, levels of eGFR were similar among those with and without nephrocalcinosis.Some lab values were different among patients with versus those without nephrocalcinosis. Children with nephrocalcinosis had significantly greater loss of phosphate by the kidneys, lower blood levels of the active form of vitamin D (1,25(OH)2D), lower eGFR, and higher blood levels of calcium than those without nephrocalcinosis. Adults with nephrocalcinosis had significantly lower blood levels of phosphorus and 1,25(OH)2D concentrations than those without. CONCLUSIONS: Nearly one quarter of children and more than one-third of adults with XLH, most of whom had received conventional therapy, had nephrocalcinosis. Further study is needed to better understand what factors can predict who will get nephrocalcinosis and to understand the long-term consequences of nephrocalcinosis. It remains important to monitor patients with XLH for nephrocalcinosis.
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INTRODUCTION: Pregnancy and lactation-associated osteoporosis (PLO) is a rare condition characterized by fragility fractures occurring during late pregnancy or lactation, primarily affecting the spine and causing significant morbidity and back pain. PLO can lead to mobility impairment and work incapacity, with recovery taking up to several years. Due to the lack of clinical trials, treatment strategies remain poorly defined, historically focusing on calcium supplements, vitamin D, and weaning from breastfeeding. However, recent attention has turned to teriparatide (TPD) as an option due to its anabolic properties and potential suitability for women of childbearing age. METHODS: This review evaluates TPD's use in PLO treatment, using published systematic reviews and case studies. Over 300 cases with PLO were identified through PubMed, Google Scholar, and Cochrane searches until August 2023. RESULTS: We identified 175 cases with PLO treated with TPD alone or followed by antiresorptive therapy. Most women (85.7%) were primiparas. The mean ± SD duration of TPD use was 15 ± 6 months. Among the study patients, 91.4% used TPD alone, while 8.6% (15/175) utilized sequential therapy. Approximately 93% of our cohort exhibited potential risk factors for PLO. Despite the increased risk of recurrent fractures in PLO, only 14.7% (20/175) of those treated with TPD sustained new fractures during a 9-month to 9 years' follow-up period. The mean ± SD percent increase in BMD at the LS was 21.14% ± 7.4%, and at the FN it was 12.1% ± 9.3%. The baseline Z-scores at the LS ranged from -3.3 (-3.7 to -2.7), while the baseline Z-scores at the FN ranged from -2.0 (-2.7 to -1.5). CONCLUSION: This review emphasizes PLO severity, advocating for increased awareness and timely interventions. TPD emerges as a promising therapeutic option in certain cases.
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Osteoporotic fractures, also known as fragility fractures, are reflective of compromised bone strength and are associated with significant morbidity and mortality. Such fractures may be clinically silent, and others may present clinically with pain and deformity at the time of the injury. Unfortunately, and even at the time of detection, most individuals sustaining fragility fractures are not identified as having underlying metabolic bone disease and are not evaluated or treated to reduce the incidence of future fractures. A multidisciplinary international working group with representation from international societies dedicated to advancing the care of patients with metabolic bone disease has developed best practice recommendations for the diagnosis and evaluation of individuals with fragility fractures. A comprehensive narrative review was conducted to identify key articles on fragility fractures and their impact on the incidence of further fractures, morbidity, and mortality. This document represents consensus among the supporting societies and harmonizes best practice recommendations consistent with advances in research. A fragility fracture in an adult is an important predictor of future fractures and requires further evaluation and treatment of the underlying osteoporosis. It is important to recognize that most fragility fractures occur in patients with bone mineral density T scores higher than -2.5, and these fractures confirm the presence of skeletal fragility even in the presence of a well-maintained bone mineral density. Fragility fractures require further evaluation with exclusion of contributing factors for osteoporosis and assessment of clinical risk factors for fracture followed by appropriate pharmacological intervention designed to reduce the risk of future fracture. Because most low-trauma vertebral fractures do not present with pain, dedicated vertebral imaging and review of past imaging is useful in identifying fractures in patients at high risk for vertebral fractures. Given the importance of fractures in confirming skeletal fragility and predicting future events, it is recommended that an established classification system be used for fracture identification and reporting.
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Absorciometría de Fotón , Fracturas Osteoporóticas , Humanos , Fracturas Osteoporóticas/prevención & control , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/diagnóstico , Absorciometría de Fotón/métodos , Densidad Ósea , Guías de Práctica Clínica como Asunto , Osteoporosis/diagnóstico , Osteoporosis/diagnóstico por imagen , Femenino , Factores de RiesgoRESUMEN
INTRODUCTION: Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism. METHODS: PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m2. RESULTS: At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m2 from baseline (P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m2. In participants with baseline eGFR < 60 mL/min/1.73 m2, 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m2 (P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide. CONCLUSION: In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT04701203.
Chronic hypoparathyroidism is caused by inadequate parathyroid hormone (PTH) levels. Hypoparathyroidism is managed with conventional therapy (active vitamin D and calcium), but over time the disease itself and conventional therapy can increase the risk of medical complications including kidney problems. This study looked at how a new treatment for chronic hypoparathyroidism, palopegteriparatide (approved in the European Union under the brand name YORVIPATH®), affects kidney function in adults in the PaTHway clinical trial. Participants were randomly assigned to receive palopegteriparatide or a placebo injection once daily along with conventional therapy. For both groups, clinicians used a protocol to eliminate conventional therapy while maintaining normal blood calcium levels. After 26 weeks, participants on placebo switched to palopegteriparatide. Ninety-five percent of participants were still enrolled in the PaTHway trial after 52 weeks. Of those, 86% had normal blood calcium levels and 95% did not need conventional therapy (not taking vitamin D and not taking therapeutic doses of calcium [> 600 mg/day]). After 52 weeks of treatment with palopegteriparatide, significant improvements were seen in a measure of kidney function called estimated glomerular filtration rate (eGFR). Improvements in eGFR from the beginning of the trial to week 52 were considered clinically meaningful for over 57% of participants. In participants with impaired kidney function at the beginning of the trial, eGFR improvements were even greater, and 74% of participants had a clinically meaningful improvement. These results suggest that palopegteriparatide treatment may be beneficial for kidney function in adults with chronic hypoparathyroidism, especially those with impaired kidney function.
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Tasa de Filtración Glomerular , Hipoparatiroidismo , Humanos , Hipoparatiroidismo/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Método Doble Ciego , Tasa de Filtración Glomerular/efectos de los fármacos , Adulto , Hormona Paratiroidea/sangre , Hormona Paratiroidea/uso terapéutico , Anciano , Enfermedad Crónica , Vitamina D/uso terapéutico , Resultado del Tratamiento , Calcio/uso terapéuticoRESUMEN
Hypoparathyroidism (HypoPT) is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing pharmacokinetics and pharmacodynamics of different dosing regimens of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for treating HypoPT. The present study (NCT03364738) was a phase 4, 1-yr open-label extension of PARALLAX. Patients received only 2 doses of rhPTH(1-84) in PARALLAX and were considered treatment-naive at the start of the current study. rhPTH(1-84) was initiated at 50 µg once daily, with doses adjusted based on albumin-corrected serum calcium levels. Albumin-corrected serum calcium (primary outcome measure), health-related quality of life (HRQoL), adverse events, and healthcare resource utilization (HCRU) were assessed. The mean age of the 22 patients included was 50.0 yr; 81.8% were women, and 90.9% were White. By the end of treatment (EOT), 95.5% of patients had albumin-corrected serum calcium values in the protocol-defined range of 1.88 mmol/L to the upper limit of normal. Serum phosphorus was within the healthy range, and albumin-corrected serum calcium-phosphorus product was below the upper healthy limit throughout, while mean 24-h urine calcium excretion decreased from baseline to EOT. Mean supplemental doses of calcium and active vitamin D were reduced from baseline to EOT (2402-855 mg/d and 0.8-0.2 µg/d, respectively). Mean serum bone turnover markers, bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide, and type I collagen C-telopeptide increased 2-5 fold from baseline to EOT. The HCRU, disease-related symptoms and impact on HRQoL improved numerically between baseline and EOT. Nine patients (40.9%) experienced treatment-related adverse events; no deaths were reported. Treatment with rhPTH(1-84) once daily for 1 yr improved HRQoL, maintained eucalcemia in 95% of patients, normalized serum phosphorus, and decreased urine calcium excretion. The effects observed on urine calcium and the safety profile are consistent with previous findings. Clinical trial identifier: NCT03364738.
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Context: Medical devices fall under the broad topic encompass everything from basic hardware to integrated software systems. The integration of software into hardware devices is not simple due to requirements of regional regulatory bodies. Therefore, medical businesses need to oversee not only the creation of devices but also the observance of guidelines and standards established by regulatory bodies. While plan-driven methodologies prevented software from evolving or changing, agile methodologies have inherent characteristics of insufficient planning and documentation. Objectives: The objective of our research is to propose a suitable process model for medical device development, keeping in mind the regulatory requirements. Methods: First, based on the detailed analysis of literature and McHughs proposed model, we suggested the Enhanced Agile V-Model (EAV), which combines plan-driven and agile approaches. Second, we mapped the proposed model to the MDEVSPICE framework to confirm that it adhered to the rules outlined in the standard IEC62304. Finally, the proposed model is evaluated through implication to case study of wave therapeutic medical device. Results: The support of both agile and waterfall approach in EAV model helps in accommodating new requirements in the medical devices and the proposed systems engineering approach helps in hardware and software integration. The mapping of the EAV model to the MDEVSPICE shows complete compliance. Moreover, the implication of the proposed model has been clearly shown statistically and successfully implemented in our case study. Further, device usability and efficiency metrics showed confidence of P < 0.05 and for device safety and efficiency, we conducted an experiment which shows significant improvement in selected parameters. Conclusion: The proposed model shows conformance to regulatory standards, and successfully implemented in development of wave therapeutic device. However, its applicability to more compact and straightforward medical products is unknown and can be determined by using this model to analyze the performance of other medical products.
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Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.
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Hipofosfatasia , Adulto , Niño , Humanos , Adolescente , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Fosfatasa Alcalina/genética , Europa (Continente) , Prevalencia , MutaciónRESUMEN
Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.
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Hipofosfatasia , Lactante , Adulto , Recién Nacido , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/epidemiología , Hipofosfatasia/genética , Fosfatasa Alcalina/genética , Mutación , PrevalenciaRESUMEN
BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.
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Hipofosfatasia , Adulto , Niño , Humanos , Hipofosfatasia/diagnóstico , Hipofosfatasia/genética , Mutación , Estudios Retrospectivos , Fosfatasa Alcalina/genética , Genotipo , FenotipoRESUMEN
OBJECTIVE: Romosozumab is a bone-forming agent approved for osteoporosis treatment. Here we report results of the protocol-specified, noninferiority osteoarthritis substudy of the fracture study in postmenopausal women with osteoporosis (FRAME), which evaluated the effect of romosozumab versus placebo on knee osteoarthritis in patients with a clinical history of osteoarthritis. METHODS: Women in FRAME with a history of knee osteoarthritis were eligible for enrollment in the osteoarthritis substudy; key inclusion criteria were osteoarthritis-related signal knee pain, morning stiffness lasting less than 30 minutes, knee crepitus, and knee osteoarthritis confirmed by x-ray within 12 months. The protocol-specified outcomes were change from baseline through month 12 in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, incidence of worsening knee osteoarthritis, and treatment-emergent adverse events (TEAEs) with romosozumab versus placebo. In a post hoc analysis, percentage change from baseline to month 12 in bone mineral density (BMD) was assessed. RESULTS: Of 7180 women in FRAME, 347 participated in the osteoarthritis substudy (placebo, 177; romosozumab, 170). At month 12, no significant difference in progression of knee osteoarthritis was observed with romosozumab versus placebo (least squares mean total WOMAC score: -2.2 vs. -1.3; P = 0.71). Incidence of worsening symptoms of knee osteoarthritis was comparable between romosozumab (17.1%) and placebo (20.5%) (odds ratio 0.9 [95% confidence interval: 0.5, 1.7]; P = 0.69). Incidence of TEAEs of osteoarthritis was numerically lower with romosozumab (13 [7.7%]) versus placebo (21 [12.0%]). BMD gains were higher with romosozumab. CONCLUSION: Romosozumab treatment did not impact knee pain or function in postmenopausal women with osteoporosis and knee osteoarthritis and resulted in significant BMD gains in these women.
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Serum phosphate concentration is regulated by renal phosphate reabsorption and mediated by sodium-phosphate cotransporters. Germline mutations in genes encoding these cotransporters have been associated with clinical phenotypes, variably characterized by hyperphosphaturia, hypophosphatemia, recurrent kidney stones, skeletal demineralization, and early onset osteoporosis. We reported a 33-year-old male patient presenting a history of recurrent nephrolithiasis and early onset osteopenia in the lumbar spine and femur. He was tested, through next generation sequencing (NGS), by using a customized multigenic panel containing 33 genes, whose mutations are known to be responsible for the development of congenital parathyroid diseases. Two further genes, SLC34A1 and SLC34A3, encoding two sodium-phosphate cotransporters, were additionally tested. A novel germline heterozygous mutation was identified in the SLC34A1 gene, c.1627G>T (p.Gly543Cys), currently not reported in databases of human gene mutations and scientific literature. SLC34A1 germline heterozygous mutations have been associated with the autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis type 1 (NPHLOP1). Consistently, alongside the clinical features of NPHLOP1, our patient experienced recurrent nephrolithiasis and lumbar and femoral osteopenia at a young age. Genetic screening for the p.Gly453Cys variant and the clinical characterization of his first-degree relatives associated the presence of the variant in one younger brother, presenting renal colic and microlithiasis, suggesting p.Gly453Cys is possibly associated with renal altered function in the NPHLOP1 phenotype.
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Raquitismo Hipofosfatémico Familiar , Nefrolitiasis , Osteoporosis , Humanos , Masculino , Adulto , Nefrolitiasis/complicaciones , Nefrolitiasis/genética , Raquitismo Hipofosfatémico Familiar/genética , Mutación , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato/genética , Sodio , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIaRESUMEN
CONTEXTE: Au Canada, plus de 2 millions de personnes vivent avec l'ostéoporose, une maladie qui accroît le risque de fracture, ce qui fait augmenter la morbidité et la mortalité, et entraîne une perte de qualité de vie et d'autonomie. La présente actualisation des lignes directrices vise à accompagner les professionnelles et professionnels de la santé au Canada dans la prestation de soins visant à optimiser la santé osseuse et à prévenir les fractures chez les femmes ménopausées et les hommes de 50 ans et plus. MÉTHODES: Le présent document fournit une actualisation des lignes directrices de pratique clinique de 2010 d'Ostéoporose Canada sur le diagnostic et la prise en charge de l'ostéoporose au pays. Nous avons utilisé l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) et effectué l'assurance de la qualité conformément aux normes de qualité et de présentation des rapports de la grille AGREE II (Appraisal of Guidelines for Research & Evaluation). Les médecins de premier recours et les patientes et patients partenaires ont été représentés à tous les niveaux des comités et des groupes ayant participé à l'élaboration des lignes directrices, et ont participé à toutes les étapes du processus pour garantir la pertinence des informations pour les futurs utilisateurs et utilisatrices. Le processus de gestion des intérêts concurrents a été entamé avant l'élaboration des lignes directrices et s'est poursuivi sur toute sa durée, selon les principes du Réseau international en matière de lignes directrices. Dans la formulation des recommandations, nous avons tenu compte des avantages et des risques, des valeurs et préférences de la patientèle, des ressources, de l'équité, de l'acceptabilité et de la faisabilité; la force de chacune des recommandations a été déterminée en fonction du cadre GRADE. RECOMMANDATIONS: Les 25 recommandations et les 10 énoncés de bonne pratique sont répartis en sections : activité physique, alimentation, évaluation du risque de fracture, instauration du traitement, interventions pharmacologiques, durée et séquence du traitement, et monitorage. La prise en charge de l'ostéoporose devrait se fonder sur le risque de fracture, établi au moyen d'une évaluation clinique réalisée avec un outil d'évaluation du risque de fracture validé. L'activité physique, l'alimentation et la pharmacothérapie sont des éléments essentiels à la stratégie de prévention des fractures, qui devraient être personnalisés. INTERPRÉTATION: Les présentes lignes directrices ont pour but d'outiller les professionnelles et professionnels de la santé et la patientèle afin qu'ensemble ils puissent parler de l'importance de la santé osseuse et du risque de fracture tout au long de la vie adulte avancée. La détection et la prise en charge efficace de la fragilité osseuse peuvent contribuer à réduire les fractures et à préserver la mobilité, l'autonomie et la qualité de vie.
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Fracturas Óseas , Osteoporosis , Humanos , CanadáRESUMEN
Adiposity is central to aging and several chronic diseases. Adiposity encompasses not just the excess adipose tissue but also body fat redistribution, fat infiltration, hypertrophy of adipocytes, and the shifting of mesenchymal stem cell commitment to adipogenesis. Bone marrow adipose tissue expansion, inflammatory adipokines, and adipocyte-derived extracellular vesicles are central to the development of osteopenic adiposity. Adipose tissue infiltration and local adipogenesis within the muscle are critical in developing sarcopenic adiposity and subsequent poorer functional outcomes. Ultimately, osteosarcopenic adiposity syndrome is the result of all the processes noted above: fat infiltration and adipocyte expansion and redistribution within the bone, muscle, and adipose tissues, resulting in bone loss, muscle mass/strength loss, deteriorated adipose tissue, and subsequent functional decline. Increased fat tissue, typically referred to as obesity and expressed by body mass index (the latter often used inadequately), is now occurring in younger age groups, suggesting people will live longer with the negative effects of adiposity. This review discusses the role of adiposity in the deterioration of bone and muscle, as well as adipose tissue itself. It reveals how considering and including adiposity in the definition and diagnosis of osteopenic adiposity, sarcopenic adiposity, and osteosarcopenic adiposity will help in better understanding the pathophysiology of each and accelerate possible therapies and prevention approaches for both relatively healthy individuals or those with chronic disease.
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BACKGROUND: In Canada, more than 2 million people live with osteoporosis, a disease that increases the risk for fractures, which result in excess mortality and morbidity, decreased quality of life and loss of autonomy. This guideline update is intended to assist Canadian health care professionals in the delivery of care to optimize skeletal health and prevent fractures in postmenopausal females and in males aged 50 years and older. METHODS: This guideline is an update of the 2010 Osteoporosis Canada clinical practice guideline on the diagnosis and management of osteoporosis in Canada. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework and quality assurance as per Appraisal of Guidelines for Research and Evaluation (AGREE II) quality and reporting standards. Primary care physicians and patient partners were represented at all levels of the guideline committees and groups, and participated throughout the entire process to ensure relevance to target users. The process for managing competing interests was developed before and continued throughout the guideline development, informed by the Guideline International Network principles. We considered benefits and harms, patient values and preferences, resources, equity, acceptability and feasibility when developing recommendations; the strength of each recommendation was assigned according to the GRADE framework. RECOMMENDATIONS: The 25 recommendations and 10 good practice statements are grouped under the sections of exercise, nutrition, fracture risk assessment and treatment initiation, pharmacologic interventions, duration and sequence of therapy, and monitoring. The management of osteoporosis should be guided by the patient's risk of fracture, based on clinical assessment and using a validated fracture risk assessment tool. Exercise, nutrition and pharmacotherapy are key elements of the management strategy for fracture prevention and should be individualized. INTERPRETATION: The aim of this guideline is to empower health care professionals and patients to have meaningful discussions on the importance of skeletal health and fracture risk throughout older adulthood. Identification and appropriate management of skeletal fragility can reduce fractures, and preserve mobility, autonomy and quality of life.
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Fracturas Óseas , Osteoporosis , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Canadá , Estado Nutricional , Osteoporosis/complicaciones , Osteoporosis/diagnóstico , Osteoporosis/tratamiento farmacológico , Calidad de VidaRESUMEN
Autosomal dominant hypocalcemia (ADH1) is a genetic disorder characterized by low serum calcium and low or inappropriately normal levels of parathyroid hormone. The disease is caused by a heterozygous activating mutation of the calcium-sensing receptor (CaSR) gene, encoding a G-Protein-coupled cell membrane sensor of extracellular calcium concentration mainly expressed by parathyroid glands, renal tubules, and the brain. ADH1 has been linked to 113 unique germline mutations, of which nearly 96% are missense mutations. There is often a lack of a clear genotype/phenotype correlation in the reported literature. Here, we described a case series of 6 unrelated ADH1 probands, each one bearing a gain-of-function CaSR mutation, and two children of one of these cases, matching our identified mutations to the same ones previously reported in the literature, and comparing the clinical and biochemical characteristics, as well as the complication profile. As a result of these genetic and clinical comparisons, we propose that a genotype/phenotype correlation may exist because our cases showed similar presentation, characteristics, and severity, with respect to published cases with the same or similar mutations. We also contend that the severity of the presentation is highly influenced by the specific CaSR variant. These findings, however, require further evaluation and assessment with a systematic review.
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Mutación con Ganancia de Función , Receptores Sensibles al Calcio , Receptores Sensibles al Calcio/genética , Calcio , Investigación , MutaciónRESUMEN
Recombinant human parathyroid hormone (1-84), rhPTH(1-84), is an approved adjunctive treatment to oral calcium and active vitamin D for adult patients with hypoparathyroidism; however, there is limited information on the effect of twice daily (BID) dosing of rhPTH(1-84). This was a phase I, open-label, randomized, crossover, multicenter study conducted in adult patients with chronic hypoparathyroidism. The primary objective was to assess the pharmacokinetic profile and pharmacodynamic effects of 1 day of treatment with rhPTH(1-84) administered subcutaneously at 25 µg BID, 50 µg BID, and 100 µg once daily (QD) with or without supplemental oral calcium. Safety and tolerability were evaluated as secondary objectives. In total, 33 patients with chronic hypoparathyroidism completed the study. Treatment with rhPTH(1-84), both BID and QD, over the short-term maintained serum calcium, lowered serum phosphorus, decreased urinary calcium excretion, and increased urinary phosphorus excretion. The decrease in urinary calcium excretion was numerically greater for BID than QD. Generally, baseline-adjusted pharmacokinetic parameters including area under the curve and maximum observed concentration increased with increasing rhPTH(1-84) dose, although this effect was not dose proportional. No new safety findings were observed. Our study revealed no differences thought to be clinically meaningful in pharmacokinetic or pharmacodynamic parameters with BID versus QD rhPTH(1-84) dosing. Future long-term studies are warranted to further elucidate the effects of alternative dosing strategies. © 2023 Takeda Development Center Americas, Inc and The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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INTRODUCTION: Denosumab is an effective antiresorptive molecule and reduces the risk of fracture in postmenopausal osteoporosis. Cessation of denosumab therapy however is associated with rapid declines in bone mineral density (BMD), rises in bone remodeling, and an increased risk of fracture. We evaluated the effect of low dose denosumab (30 mg every 6 months) on the prevention of bone loss following a switch from standard dose (60 mg of denosumab every 6 months) in a prospective observational study. METHODS: We recruited 114 women 50-90 years of age with postmenopausal osteoporosis at a moderate fracture risk without prior fragility fractures, who had been on denosumab 60 mg every 6 month. These women switched to low dose denosumab 30 mg every 6 months. Mean percentage change in lumbar spine (LS), femoral neck (FN), total hip (TH) and 1/3 distal radius (1/3RAD) BMD at 12 and 24 months were evaluated. Predictors for change in BMD were explored. Subgroup analysis for patients on denosumab 60 mg every 6 months for <3 years and for ≥3 years before switching to low dose denosumab 30 mg was evaluated. RESULTS: At 12 months following a switch from 60 mg to 30 mg of denosumab every 6 months we observed an increase in LS BMD mean percentage change (+2.03%, 95% CI 1.18-2.88, p < 0.001). BMD was stable at the hip and radial sites. Age was found to be a predictor of the mean percentage change in LS BMD for the overall sample. At 24 months, there was a further increase in LS BMD mean percentage change (+3.44%, 95% CI 1.74-5.12, p < 0.001), with stable BMD at other skeletal sites. The 12 month mean BMD percentage change at the LS (p = 0.015), FN (p < 0.001), TH (p < 0.001), and 1/3 RAD (p < 0.001) were found to be predictors of the 24 month mean BMD percentage change. No clinical fractures were reported during 24 months of follow up. CONCLUSION: We observed stable BMD following a switch from denosumab 60 mg every 6 months to 30 mg every 6 months in this prospective observational study conducted in postmenopausal women at a moderate fracture risk.
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Conservadores de la Densidad Ósea , Fracturas Óseas , Osteoporosis Posmenopáusica , Osteoporosis , Humanos , Femenino , Densidad Ósea , Denosumab/farmacología , Denosumab/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Posmenopausia , Osteoporosis/tratamiento farmacológico , Fracturas Óseas/prevención & controlRESUMEN
INTRODUCTION: Osteoporosis is a major disease state associated with significant morbidity, mortality, and health care costs. Less than half of the individuals sustaining a low energy hip fracture are diagnosed and treated for the underlying osteoporosis. OBJECTIVE: A multidisciplinary Canadian hip fracture working group has developed practical recommendations to meet Canadian quality indicators in post hip fracture care. METHODS: A comprehensive narrative review was conducted to identify and synthesize key articles on post hip fracture orthogeriatric care for each of the individual sections and develop recommendations. These recommendations are based on the best evidence available today. CONCLUSION: Recommendations are anticipated to reduce recurrent fractures, improve mobility and healthcare outcomes post hip fracture, and reduce healthcare costs. Key messages to enhance postoperative care are also provided.
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Fracturas de Cadera , Osteoporosis , Humanos , Canadá/epidemiología , Fracturas de Cadera/cirugía , Fracturas de Cadera/complicaciones , Osteoporosis/complicaciones , Osteoporosis/terapia , Indicadores de Calidad de la Atención de Salud , Resultado del TratamientoRESUMEN
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.