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Heteroplasmic mitochondrial DNA (mtDNA) variants accumulate as humans age, particularly in the stem-cell compartments, and are an important contributor to age-related disease. Mitochondrial dysfunction has been observed in osteoporosis and somatic mtDNA pathogenic variants have been observed in animal models of osteoporosis. However, this has never been assessed in the relevant human tissue. Mesenchymal stem cells (MSCs) are the progenitors to many cells of the musculoskeletal system and are critical to skeletal tissues and bone vitality. Investigating mtDNA in MSCs could provide novel insights into the role of mitochondrial dysfunction in osteoporosis. To determine if this is possible, we investigated the landscape of somatic mtDNA variation in MSCs through a combination of fluorescence-activated cell sorting and single-cell next-generation sequencing. Our data show that somatic heteroplasmic variants are present in individual patient-derived MSCs, can reach high heteroplasmic fractions and have the potential to be pathogenic. The identification of somatic heteroplasmic variants in MSCs of patients highlights the potential for mitochondrial dysfunction to contribute to the pathogenesis of osteoporosis.
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ADN Mitocondrial , Células Madre Mesenquimatosas , Humanos , Células Madre Mesenquimatosas/metabolismo , ADN Mitocondrial/genética , Osteoporosis/genética , Osteoporosis/patología , Osteoporosis/metabolismo , Mitocondrias/metabolismo , Mitocondrias/genética , Análisis de la Célula Individual , Secuenciación de Nucleótidos de Alto Rendimiento , Femenino , Heteroplasmia/genética , Masculino , Citometría de Flujo , Variación Genética , Persona de Mediana EdadRESUMEN
BACKGROUND: Hypomagnesemia is associated with poor clinical outcomes in cancer patients. Patients with bone metastasis from solid malignancies receiving denosumab (Dmab) to prevent skeletal-related events often receive concurrent antineoplastic agents for cancer treatment. The incidence and risk factors of hypomagnesemia in patients receiving Dmab and the optimal frequency of monitoring serum magnesium (Mg) levels have not been studied in these patient populations. OBJECTIVE: The objective is to investigate the incidence and potential risk factors of hypomagnesemia and the optimal frequency of monitoring serum Mg levels. METHODS: A retrospective chart review identified patients with solid malignancies with bone metastases treated with Dmab at the Loma Linda University Cancer Center between January 2013 and February 2024. The incidence of hypomagnesemia was determined using the number of patients with hypomagnesemia and the total number of patients in the study. Univariate and multivariate logistic regression analyses identified risk factors for hypomagnesemia. RESULTS: Hypomagnesemia was observed in 19% (29/153) of patients, the majority of whom were on concurrent antineoplastic agents with ≥15% hypomagnesemia incidence (high-hypomagnesemic antineoplastics) or nonantineoplastic drugs with documented cases or incidence of hypomagnesemia (hypomagnesemic nonantineoplastics) in addition to high-hypomagnesemic antineoplastics. Multivariate analysis showed increased odds of developing hypomagnesemia with high-hypomagnesemic antineoplastics (odds ratio [OR]: 174.93, 95% confidence interval [CI]: 12.82 to 387.43, P < 0.001); hypomagnesemic nonantineoplastics plus high-hypomagnesemic antineoplastics (OR: 210.09, 95% CI: 11.80 to 3740.12, P < 0.001); and Mg level ≤ 0.85 prior to Dmab administration (OR: 16.79, 95% CI: 2.30 to 122.41, P = 0.005). CONCLUSION AND RELEVANCE: This study describes the incidence and potential risk factors for hypomagnesemia in patients with solid malignancies and metastatic bone disease treated with Dmab. This study's findings provide additional clinical insight into potential risk factors for hypomagnesemia and the need for more frequent serum Mg level monitoring of at-risk patients. Future prospective studies are needed to determine the exact frequencies most appropriate in monitoring serum Mg levels in this group of patients.
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Degenerative bone lesions are rarely described in reptiles and belong mainly to the broad spectrum of metabolic bone diseases. Here we describe a 7-y-old female central bearded dragon (Pogona vitticeps) with a complex unilateral neoplastic lesion in the hip joint. The animal was presented because of severe progressive swelling of the left hindlimb, apathy, and weight loss. The swelling was soft and surrounded the left femur. Full-body radiographs were performed in 2 orthogonal projections. The main radiologic findings were severe soft tissue swelling centered on the proximal third of the left femur and an absent left femoral head. The caretaker elected euthanasia, and a postmortem examination was performed, followed by subsequent histologic examination. The swelling consisted of variably sized myxomatous proliferations and cysts that invaded the femoral bone. Furthermore, several long bones had lesions consistent with metabolic bone and degenerative joint diseases. Synovial myxomas are rare lesions of the joints that have, to our knowledge, not been described previously in reptiles.
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Bone metastases are the most severe and prevalent consequences of prostate cancer (PC), affecting more than 80% of patients with advanced PC. PCBMs generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences. Radiographically, PCBMs are predominantly osteosclerotic, but the mechanisms of abnormal bone formation and how this pathological increase in bone density is related to fractures are unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM specimens and 12 cancer-free specimens as controls. We used micro-computed tomography to determine 3D organization and quantify bone characteristics, quantitative backscattering electron microscopy to characterize mineral content and details in bone structure, nanoindentation to determine mechanical properties, and histological and immunohistochemical analysis of bone structure and composition. We define 4 PCBM phenotypes: osteolytic, mixed lytic-sclerotic, and 2 subgroups of osteosclerotic lesions-those with residual trabeculae, and others without residual trabeculae. The osteosclerotic lesions are characterized by the presence of abnormal bone accumulated on trabeculae surfaces and within intertrabecular spaces. This abnormal bone is characterized by higher lacunae density, abnormal lacunae morphology, and irregular lacunae orientation. However, mineral content, hardness, and elastic modulus at micron-scale were indistinguishable between this irregular bone and residual trabeculae. The collagen matrix of this abnormal bone presents with irregular organization and a prominent collagen III composition. These characteristics suggest that osteosclerotic PCBMs initiate new bone deposition as woven bone; however, the lack of subsequent bone remodeling, absence of lamellar bone deposition on its surface, and presence of collagen III distinguish this pathologic matrix from conventional woven bone. Although the mineralized matrix retains normal bone hardness and stiffness properties, the lack of fibril anisotropy presents a compromised trabecular structure, which may have clinical implications.
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CONTEXT: SB16 is a proposed biosimilar to reference denosumab (DEN; brand name: Prolia). OBJECTIVE: This phase 3 randomized, double-blind, multicenter study evaluated the biosimilarity of SB16 to DEN in women with postmenopausal osteoporosis (PMO; NCT04664959). DESIGN: The study included 457 PMO patients who had a lumbar spine or total hip T-score between -2.5 and -4. Patients were randomized in a 1:1 ratio to receive either 60 mg of SB16 or DEN subcutaneously at Month 0 and Month 6. At Month 12, patients were re-randomized to continue with the assigned treatment or switch from DEN to SB16 up to Month 18. This report includes results up to Month 12. METHODS: The primary endpoint was the percent change from baseline in lumbar spine bone mineral density (BMD) at Month 12. Secondary endpoints including the percent change from baseline in BMD of the lumbar spine (except for Month 12), total hip and femoral neck; pharmacokinetic, pharmacodynamic (serum C-telopeptide of type I collagen [CTX] and procollagen type I N-terminal propeptide [P1NP]), safety, and immunogenicity profiles were measured up to Month 12. RESULTS: The least-squares mean differences in percent change from baseline in lumbar spine BMD at Month 12 were 0.33% (90% confidence interval [CI]: -0.25, 0.91) in the full analysis set and 0.39% (95% CI: -0.36, 1.13) in the per-protocol set; both within the pre-defined equivalence margin. The secondary endpoints were comparable between the two treatment groups. CONCLUSION: The reported efficacy, PK, PD, safety, and immunogenicity data support the biosimilarity of SB16 to DEN.
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The periosteum contains skeletal stem/progenitor cells that contribute to bone fracture healing. However, the in vivo identity of periosteal skeletal stem cells (P-SSCs) remains unclear, and membrane protein markers of P-SSCs that facilitate tissue engineering are needed. Here, we identified integral membrane protein 2A (Itm2a) enriched in SSCs using single-cell transcriptomics. Itm2a+ P-SSCs displayed clonal multipotency and self-renewal and sat at the apex of their differentiation hierarchy. Lineage-tracing experiments showed that Itm2a selectively labeled the periosteum and that Itm2a+ cells were preferentially located in the outer fibrous layer of the periosteum. The Itm2a+ cells rarely expressed CD34 or Osx, but expressed periosteal markers such as Ctsk, CD51, PDGFRA, Sca1, and Gli1. Itm2a+ P-SSCs contributed to osteoblasts, chondrocytes, and marrow stromal cells upon injury. Genetic lineage tracing using dual recombinases showed that Itm2a and Prrx1 lineage cells generated spatially separated subsets of chondrocytes and osteoblasts during fracture healing. Bone morphogenetic protein 2 (Bmp2) deficiency or ablation of Itm2a+ P-SSCs resulted in defects in fracture healing. ITM2A+ P-SSCs were also present in the human periosteum. Thus, our study identified a membrane protein marker that labels P-SSCs, providing an attractive target for drug and cellular therapy for skeletal disorders.
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Curación de Fractura , Proteínas de la Membrana , Periostio , Animales , Periostio/metabolismo , Periostio/citología , Ratones , Curación de Fractura/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Humanos , Células Madre/metabolismo , Células Madre/citología , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 2/genética , Fracturas Óseas/patología , Fracturas Óseas/metabolismo , Fracturas Óseas/terapia , Fracturas Óseas/genética , Osteoblastos/metabolismo , Osteoblastos/citología , Diferenciación Celular , Condrocitos/metabolismo , Condrocitos/citología , Masculino , Linaje de la CélulaRESUMEN
BACKGROUND: Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The trajectory of bone loss with age in this population remains unclear. The objective of this study was to estimate the average rate of change in bone mineral density (BMD) in adults with CF. METHODS: This retrospective study included adults with CF, aged 25-48 years, followed between January 2000 and December 2021. Subjects with at least one dual-energy X-ray absorptiometry (DXA) scan were included. Scans obtained post-transplantation, after the initiation of bisphosphonates or cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy were excluded. The primary outcome was BMD (g/cm2) at the lumbar spine (LS) and femoral neck (FN). A linear mixed-effects model with both random intercept and random slope terms was used to estimate the average annual change in BMD. RESULTS: A total of 1502 DXA scans in 500 adults (average age 28.4y) were included. There was a statistically significant annual decline in BMD of -0.008 gm/cm2/year (95% CI -0.009, -0.007) at the FN and -0.006 gm/cm2/year (95% CI -0.007, -0.004) at the LS. Relative to BMD at age 25, there was a -18.8% decline at the FN by age 48 years and a -11% decline at the LS. Pancreatic insufficient (PI) subjects had a faster rate of decline in BMD compared to pancreatic sufficient (PS) subjects. After adjusting for markers of disease severity, the annual rate of decline remained significant. CONCLUSIONS: Individuals with CF experience bone loss at an age when it is not anticipated, thereby entering early adulthood, where further bone loss is inevitable especially with the decrease in estrogen during menopause, with suboptimal BMD. As the CF population ages, it will become very important to consider interventions to maximize bone health.
Improved survival in people with cystic fibrosis (pwCF) presents new complexities of care, including CF-related bone disease, a common complication in older pwCF. The objective of this study was to estimate how bone mineral density (BMD) changes over time in adults with CF. The study included 500 adults with CF, aged 25-48 years, followed between January 2000 and December 2021 who underwent a scan to assess BMD. On average, BMD decreased over time both at the spine and the hip. People who have pancreatic insufficiency had a faster rate of decline in BMD than people with pancreatic sufficiency. Individuals with CF experience bone loss at an age when bone density is expected to be stable. As the CF population ages, interventions to maximize bone health should be emphasized to prevent fractures in the future.
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Sickle cell disease (SCD) is a group of inherited blood disorders characterized by abnormal hemoglobin production, affecting individuals worldwide with varying prevalence across different populations. Manifestations vary, ranging from severe to mild. SCD is characterized by the presence of hemoglobin S (HbS), which distorts erythrocytes upon deoxygenation, leading to sickling. This results in hemolytic anemia, painful vaso-occlusive crises (VOC), and multiple organ damage, including bones, due to microinfarcts. Sickle cell trait (SCT), or carrier status, is not considered an SCD and often runs a benign course. We report a 44-year-old man of African descent presenting with a one-month history of pain in his ankles and feet. He had a prior diagnosis of sickle cell "trait" without previous VOC. Hematological indices were normal. Hemoglobin electrophoresis showed absent HbA, elevated HbS, elevated HbF, and normal HbA2. X-rays and MRI revealed bilateral bone infarction in diaphyses of right proximal and bilateral distal tibias. Molecular analysis of [Formula: see text]-globin revealed compound heterozygous hemoglobin S and type 2 deletion of persistence of fetal hemoglobin (HPFH). Pulmonary function tests revealed restrictive lung disease. A literature review from 1946 to May 2024 via PubMed, EMBASE, and Medline was performed, revealing two cases of HbS-HPFH with avascular necrosis affecting the femoral neck were briefly reported more than 60 years ago. Although pulmonary function tests in SCD typically show a mild restrictive pattern with decreased diffusion capacity and rarely an obstructive pattern, no cases of HbS-HPFH were identified. In conclusion, multiple bone infarctions are extremely rare in HbS-HPFH. Lung and bone diseases might be unrecognized in this unique disorder.
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Purpose: Metabolic Bone Disease of Infancy (MBDI) is a multifactorial disorder of bone fragility that presents with multiple unexplained fractures (MUF) and is often misdiagnosed as child abuse. The diagnosis of MBDI is made by the finding of radiographic features of healing rickets and risk factors for MBDI. Our anecdotal experience indicates blood 1,25-dihydroxyvitamin D (1,25-DiOHVD) is sometimes elevated. The purpose of this retrospective study was to review cases of MBDI in which child abuse was alleged and the alleged perpetrator denied wrongdoing. Methods: We reviewed forensic cases of MBDI born between 2015 and 2021. The diagnosis was based on radiographic findings of healing rickets. Records were reviewed for blood 1,25-DiOHVD testing. Results: 22 of the 76 infants (29 %) had a blood 1,25-DiOHVD level performed at the time of presentation with fractures. The average age of presentation with fractures was 11 weeks.3 of the 22 infants (14 %) had a normal 1,25-DiOHVD blood level, and 19 of the 22 infants (86 %) had an elevated level. None had low levels. Conclusion: Blood 1,25-DiOHVD is often elevated in infants with MBDI. Elevated blood 1,25-DiOHVD levels cause increased bone resorption and decreased bone mineralization, and thus this finding is not unexpected since all infants had evidence of healing rickets on imaging studies. These results indicate blood 1,25-DiOHVD should be done in contested cases of child abuse in infants with MUF as an elevated level indicates bone fragility.
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Background: In clinical practice, internal fixation (IF) is a commonly utilized technique for metastatic bone disease (MBD) to the distal femur. Additionally, distal femoral reconstruction (DFR) has shown to be an effective surgical technique for primary tumors and MBD in the distal femur. The existing body of research comparing these methods has not focused on MBD or pathological fractures and thus does not guide surgical approach in the case of distal femoral MBD. Methods: A multi-institutional retrospective review of musculoskeletal oncology patients treated surgically with IF (n = 29) or DFR (n = 34) for distal femoral MBD between 2005 and 2023. Overall survival, revision risk, and functional status were assessed. Results: 5-year patient overall survival was 47.9 % (CI, 29.5-77.6 %) and 46.6 % (CI, 31.5-68.8 %), for DFR and IF, respectively (p = 0.91). After competing risk analysis, the 5-year risk of implant revision for DFR was 18 % (95 % CI: 5.1-37 %) and 11 % for IF (95 % CI: 2.4-28 %) (p = 0.3). DFR had longer operative times (p = 0.002), higher blood loss (p < 0.001), and greater postoperative (p = 0.006) complications than IF. In addition, patients undergoing DFR had more distal lesions than patients who received IF (p = 0.003). Conclusion: Despite similar overall survival and revision rates, IF may be preferable for patients due to its shorter operative time and lower rates of complication than DFR. However, specific anatomic location in the distal femur must be considered prior to deciding which procedure is optimal.
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Aim Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) is an autosomal recessive disorder. This study investigates the etiology of HFTC in offspring from consanguineous parents. Methods: Clinical assessment, imaging, and direct sequencing were utilized to elucidate the condition. Previously reported cases were also reviewed. Result: We identified a consanguineous Chinese family with HFTC caused by an interesting homozygous G to A substitution in GALNT3 (c.1626 + 1G > A). The parents were carriers. Conclusion: This study represents the first report of HFTC in a consanguineous Chinese family due to an interesting GALNT3 mutation. We reviewed known GALNT3 variants and associated clinical features of calcification disorders. The phenotypic difference between homozygous and complex heterozygous mutations is not clinically significant. Gene mutations affect the function of proteins mainly by affecting their binding to polyvalent ligands.
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The present study provides real-world evidence on the treatment of multiple myeloma (MM) bone disease with various bisphosphonates combined for different myeloma-specific treatments as no validated data regarding the best combination treatment for bone disease associated with MM are available. We examined retrospectively 345 MM patients treated with autologous stem cell transplantation in Finland during 1996-2020. The median age of the patients was 60 years with a median follow-up time of 50 months (1-339). At diagnosis, 72.1% of the patients had myeloma-associated bone disease and 45.8% had fractures. Most patients (58.8%) received proteasome inhibitor (PI)-containing treatment at first line. MM bone disease was treated in 91.6% of the patients; 49.9% received zoledronic acid (ZA) and 29.9% pamidronate. Inferior overall survival was associated with MM bone disease at diagnosis (p = 0.005) or a fracture at diagnosis (p = 0.003). A later fracture was identified in 29% of the patients, and in those patients without MM bone disease at diagnosis later fractures were less common after ZA treatment (p = 0.049). PI-based treatment plus ZA (p = 0.019) seemed to be the best combination to prevent later fractures, even though the same patient subgroup was more likely to experience relapse (p = 0.018), and also when excluding patients with previous induction therapy without novel agents (p = 0.008). To conclude, this study suggests that the best therapy to prevent later fractures in MM might be PI-based treatment combined with ZA.
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Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.
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Type 2 diabetes (T2D) is on the rise worldwide and is associated with various complications in the oral cavity. Using an adult-onset diabetes preclinical model, we demonstrated profound periodontal alterations in T2D mice, including inflamed gingiva, disintegrated periodontal ligaments (PDLs), marked alveolar bone loss, and unbalanced bone remodeling due to decreased formation and increased resorption. Notably, we observed elevated levels of the Wnt signaling inhibitor sclerostin in the alveolar bone of T2D mice. Motivated by these findings, we investigated whether a sclerostin-neutralizing antibody (Scl-Ab) could rescue the compromised periodontium in T2D mice. Administering Scl-Ab subcutaneously once a week for 4 weeks, starting 4 weeks after T2D induction, led to substantial increases in bone mass. This effect was attributed to the inhibition of osteoclasts and promotion of osteoblasts in both control and T2D mice, effectively reversing the bone loss caused by T2D. Furthermore, Scl-Ab stimulated PDL cell proliferation, partially restored the PDL fibers, and mitigated inflammation in the periodontium. Our study thus established a T2D-induced periodontitis mouse model characterized by inflammation and tissue degeneration. Scl-Ab emerged as a promising intervention to counteract the detrimental effects of T2D on the periodontium, exhibiting limited side effects on other craniofacial hard tissues.
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Proteínas Adaptadoras Transductoras de Señales , Pérdida de Hueso Alveolar , Diabetes Mellitus Tipo 2 , Animales , Ratones , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Pérdida de Hueso Alveolar/prevención & control , Pérdida de Hueso Alveolar/etiología , Pérdida de Hueso Alveolar/patología , Masculino , Enfermedades Periodontales/inmunología , Anticuerpos Neutralizantes/farmacología , Ligamento Periodontal/patología , Ligamento Periodontal/efectos de los fármacos , Modelos Animales de Enfermedad , Diabetes Mellitus Experimental/inmunología , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Ratones Endogámicos C57BL , Periodontitis/inmunología , Periodontitis/patología , Periodontitis/tratamiento farmacológico , Remodelación Ósea/efectos de los fármacosRESUMEN
Human aging is linked to bone loss, resulting in bone fragility and an increased risk of fractures. This is primarily due to an age-related decline in the function of bone-forming osteoblastic cells and accelerated cellular senescence within the bone microenvironment. Here, we provide a detailed discussion of the hypothesis that age-related defective bone formation is caused by senescence of skeletal stem cells, as they are the main source of bone forming osteoblastic cells and influence the composition of bone microenvironment. Furthermore, this review discusses potential strategies to target cellular senescence as an emerging approach to treat age-related bone loss.
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Envejecimiento , Senescencia Celular , Osteoblastos , Humanos , Senescencia Celular/fisiología , Envejecimiento/metabolismo , Envejecimiento/fisiología , Envejecimiento/patología , Osteoblastos/metabolismo , Animales , Osteoporosis/metabolismo , Osteoporosis/patología , Células Madre/metabolismo , Células Madre/patología , Osteogénesis/fisiología , Huesos/metabolismo , Huesos/patologíaRESUMEN
Chronic low back pain (LBP) can severely affect daily physical activity. Aberrant osteoclast-mediated resorption leads to porous endplates for the sensory innervation to cause LBP. Here, we report that the expression of proton-activated chloride (PAC) channel is induced during osteoclast differentiation in the porous endplates via a RANKL-NFATc1 signaling pathway. Extracellular acidosis evokes robust PAC currents in osteoclasts. An acidic environment of porous endplates and elevated PAC activation-enhanced osteoclast fusion provoke LBP. Further, we find that genetic knockout of PAC gene Pacc1 significantly reduces endplate porosity and spinal pain in a mouse LBP model, but it does not affect bone development or homeostasis of bone mass in adult mice. Moreover, both osteoclast bone resorptive compartment environment and PAC traffic from the plasma membrane to endosomes to form an intracellular organelle Cl channel have low pH around 5.0. The low pH environment activates PAC channel to increase sialyltransferase St3gal1 expression and sialylation of TLR2 in initiation of osteoclast fusion. Aberrant osteoclast-mediated resorption is also found in most skeletal disorders, including osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, heterotopic ossification, enthesopathy. Thus, elevated Pacc1 expression and PAC activity could be a potential therapeutic target for LBP and osteoclast-associated pain.
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Paget's disease of bone (PDB) is a chronic condition causing abnormal bone remodeling, leading to pain, fractures, and complications. A 57-year-old female patient, asymptomatic and devoid of pain, incidentally exhibited elevated levels of alkaline phosphatase. Following a thorough consideration of potential differential diagnoses, the eventual diagnosis established was PDB. We recommended Fosamax (70 mg alendronate tablets) at two tablets twice weekly for 3 months to manage PDB due to patient preference and side effects with intravenous zoledronic acid. Subsequent assessments of alkaline phosphatase levels during follow-up examinations post-treatment revealed a reduction in their values.
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BACKGROUND: Osteogenesis imperfecta (OI) is a connective tissue disorder in which the Type 1 collagen is defective. The eye is a structure rich in collagen Type 1 and is heavily impacted by the disease. Many vision-threatening eye diseases have been associated with OI. The onset of these diseases also tend to occur at an earlier age in individuals with OI. Despite the research on these risks, appropriate ophthalmological screening or care guidelines for individuals with OI remain unknown. As such, the purpose of this scoping review was to explore and describe existing ophthalmological screening and care guidelines to orient OI patient care. MAIN BODY: A scoping review based on the Joanna Briggs Institute (JBI) methodology was conducted. A search of databases (PubMed and Medline) was completed in consultation with a research librarian. A total of 256 studies were imported for screening. Primary sources matching the inclusion and exclusion criteria were screened, extracted, and analyzed using Covidence. CONCLUSION: A total of 12 primary articles met inclusion and exclusion criteria, containing case reports, case series and cohort studies. Despite the risk of blindness associated with the consequences of OI on the eye, the primary literature fails to provide detailed screening and care guidelines aimed at identifying disease early. We provide general recommendations based on the review findings to guide the ophthalmological care of patients with OI and call upon the experts to convene globally to create screening guidelines. Further investigations of ophthalmological screening are warranted to limit these vision-threatening risks with early detection and treatment. Standardized ophthalmological screening guidelines for OI remain an area for research.
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Osteogénesis Imperfecta , Osteogénesis Imperfecta/diagnóstico , Osteogénesis Imperfecta/complicaciones , HumanosRESUMEN
Objective: This study investigated the efficacy and safety of denosumab (DENOS) versus zoledronic acid (ZOL) in the bone disease treatment of newly diagnosed multiple myeloma. Methods: The clinical data of 80 patients with myeloma bone disease (MBD) at the Fifth Medical Center of PLA General Hospital between March 1, 2021 and June 30, 2023 were retrospectively reviewed. Eighteen patients with severe renal impairment (SRI, endogenous creatinine clearance rate<30 ml/min) were treated with DENOS, and 62 non-SRI patients were divided into DENOS (30 patients) and ZOL group (32 patients) . Results: Hypocalcemia was observed in 26 (33%) patients, and 22 patients developed hypocalcemia during the first treatment course. The incidence of hypocalcemia in the non-SRI patients of DENOS group was higher than that in the ZOL group [20% (6/30) vs 13% (4/32), P=0.028]. The incidence of hypocalcemia in SRI was 89% (16/18). Multivariate logistic regression analysis revealed that endogenous creatinine clearance rate<30 ml/min was significantly associated with hypocalcemia after DENOS administration (P<0.001). After 1 month of antiresorptive (AR) drug application, the decrease in the serum ß-C-terminal cross-linked carboxy-telopeptide of collagen type I concentrations of SRI and non-SRI patients in the DENOS group were significantly higher than that in the ZOL group (68% vs 59% vs 27%, P<0.001). The increase in serum procollagen type â N-terminal propeptide concentrations of patients with or without SRI in the DENOS group were significantly higher than that in the ZOL group (34% vs 20% vs 11%, P<0.05). The level of intact parathyroid hormone in each group increased after AR drug treatment. None of the patients developed osteonecrosis of the jaw and renal adverse events, and no statistically significant differences in the overall response rate, complete remission and stringent complete remission rates were found among the groups (P>0.05), and the median PFS and OS time were not reached (P>0.05) . Conclusions: In the treatment of MBD, DENOS minimizes nephrotoxicity and has strong AR effect. Hypocalcemia is a common adverse event but is usually mild or moderate and manageable.
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Conservadores de la Densidad Ósea , Enfermedades Óseas , Denosumab , Hipocalcemia , Mieloma Múltiple , Ácido Zoledrónico , Humanos , Ácido Zoledrónico/administración & dosificación , Denosumab/efectos adversos , Denosumab/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Enfermedades Óseas/etiología , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/efectos adversos , Hipocalcemia/inducido químicamente , Hipocalcemia/etiología , Masculino , Femenino , Resultado del Tratamiento , Persona de Mediana Edad , AncianoRESUMEN
An 11-month-old female Saanen goat, weighing 12.7 kg, was taken to the Veterinary Hospital of the Federal University of Minas Gerais because of sternal recumbency. On clinical examination, the animal was much smaller than expected and had hair similar to that of puppies and areas of hyperpigmentation on the head and dorsocervical and dorsothoracic cranial regions. Radiographic examination revealed fractures in both femurs and severe generalized osteoporosis. Given the unfavourable prognosis, the animal was euthanized. Necropsy revealed generalized pallor, muscular atrophy of the pelvic limbs and little reserve of subcutaneous adipose tissue. Both femurs had complete and closed diaphyseal fractures. The second lumbar vertebra was severely reduced in length as a result of a fracture, with dorsal displacement of the vertebral body towards the vertebral canal and compression of the spinal cord. Long bones and vertebrae had severe cortical thinning, enlargement of the medullary canal and reduced resistance. The thyroid gland was not in its normal anatomical location. A pale red nodule (1.0 × 0.4 cm) in the serosa of the middle third of the trachea, close to the thoracic entrance, was confirmed as ectopic thyroid tissue. Microscopically, the bones had evidence of growth arrest and severe osteoporosis. The ectopic thyroid nodule was hyperplastic with severe hypertrophy of follicular cells. The spinal cord was compressed by vertebral fractures and had focally extensive and severe myelomalacia. Based on the pathological features, the case was diagnosed as thyroid dysgenesis characterized by eutopic thyroid agenesis and ectopic thyroid tissue, associated with interruption of bone growth with dwarfism, osteoporosis and spontaneous secondary fractures with compression of the lumbar spinal cord.