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Bone forming agents, also known as anabolic therapies, are essential in managing osteoporosis, particularly for patients at very high-risk of fractures. Identifying candidates who will benefit the most from these treatments is crucial. For example, this group might include individuals with severe osteoporosis, multiple vertebral fractures, a recent fragility fracture or those unresponsive to antiresorptive treatments. Definitions of patients with a very high fracture risk vary across nations, are often based on fracture history, bone mineral density (BMD), and/or fracture risk calculated by FRAX® or other algorithms. However, for very high-risk patients, anabolic agents such as teriparatide, abaloparatide, or romosozumab are commonly recommended as first-line therapies due to their ability to stimulate new bone formation and improve bone microarchitecture, offering significant benefits in rapid fracture reduction over antiresorptive therapies. The cost-effectiveness of these agents is a critical consideration for decision-makers. Despite their higher costs, their effectiveness in significantly reducing fracture risk and improving quality of life can justify the investment, especially when long-term savings from reduced fracture rates and associated healthcare costs are considered. Additionally, after completing a course of anabolic therapy, transitioning to antiresorptive agents like bisphosphonates or denosumab is crucial to maintain the gains in bone density and minimize subsequent fracture risks. This sequential treatment approach ensures sustained protection and optimal resource utilization. In summary, the effective use of bone forming agents in osteoporosis requires a comprehensive strategy that includes accurate patient identification, consideration of cost-effectiveness, and implementation of appropriate sequential treatments, ultimately maximizing patient outcomes and healthcare efficiency.
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Conservadores da Densidade Óssea , Densidade Óssea , Osteoporose , Humanos , Osteoporose/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Fraturas por Osteoporose/prevenção & controle , Anabolizantes/uso terapêutico , Teriparatida/uso terapêutico , Análise Custo-BenefícioRESUMO
Bone markers are a group of substances released into circulation during bone formation and/or resorption. These substances can be measured in blood and urine to obtain information about metabolic bone disorders. This review provides an insight into factors influencing bone marker variability and describes different approaches to minimize variability and interpret results appropriately. Variability in bone marker concentrations results from biological and analytical variability across assays. Other influencing factors include gender, age, physical exercise, circadian rhythm, and diet. The multiplicity of influencing factors hinders the establishment of accurate reference values. Gaining a deep understanding of bone marker variability is the first step to ascertain their clinical usefulness. Bone marker variability can be minimized by controlling as many variables as it is possible and through the standardization of patient preparation and sample collection and handling.
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The evolution of pain and quality of life after a symptomatic vertebral fracture differs according to patient gender, with a worse evolution in women independently of the treatment received. PURPOSE: In a previous randomized clinical study comparing the effect of vertebroplasty (VP) vs. conservative therapy (CT) on pain evolution and quality of life (QoL) of patients with symptomatic vertebral fractures (VF), we observed the development of chronic back pain in 23% of subjects, independently of the therapy received. This study analyses the effect of gender on the evolution of pain and QoL in these subjects. METHODS: 118/125 randomized patients (27 males/91 females) with recent symptomatic VFs were evaluated. All received a standardized analgesic and antiosteoporotic format of treatment. Pain and QoL were evaluated by VAS and Qualeffo-41, respectively, at baseline, at 2 weeks and 2 and 6 months. We compared pain evolution and QoL after treatment (CT vs. VP) according to gender, and analysed factors including age, time of evolution, treatment received, baseline VAS, previous VFs (total and recent), incidental VFs, lumbar and femoral T-scores, and analgesic and antiosteoporotic treatment. RESULTS: At baseline, there were no differences in age (males 74.8 ± 11.2 vs. females:73.2 ± 8.7 years), time of evolution, number of VFs (males:3.8 ± 2.4 vs. females: 3.1 ± 2.4), treatment received (VP, males:59%, females:45%), lumbar or femoral T-score, baseline VAS (males:6.8 ± 2.1 vs. females:6.8 ± 2.2) or Qualeffo score (males:52.2 ± 24.4 vs. females:59.7 ± 20.6). Pain and QoL evolution differed according to gender, being better in males. These differences were significant after two months independently of the treatment and the development of incidental VF during follow-up. CONCLUSIONS: Pain and QoL evolution after a symptomatic VF differs according to gender, with a worse evolution in women independently of the treatment received.
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Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Vertebroplastia , Masculino , Humanos , Feminino , Qualidade de Vida , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/cirurgia , Dor nas Costas , Analgésicos/uso terapêutico , Fraturas por Osteoporose/cirurgiaRESUMO
INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.
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Difosfonatos , Osteíte Deformante , Humanos , Difosfonatos/efeitos adversos , Osteíte Deformante/complicações , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/genética , Proteína Sequestossoma-1/genética , Ácido Zoledrônico/uso terapêutico , Testes Genéticos , BiomarcadoresAssuntos
Humanos , /classificação , /farmacologia , Anabolizantes/classificação , Anabolizantes/farmacologia , EspanhaRESUMO
Increased life expectancy means that women are now in a hypoestrogenic state for approximately one-third of their lives. Overall health and specifically bone health during this period evolves in accordance with aging and successive exposure to various risk factors. In this review, we provide a summary of the approaches to the sequential management of osteoporosis within an integrative model of care to offer physicians a useful tool to facilitate therapeutic decision-making. Current evidence suggests that pharmacologic agents should be selected based on the risk of fractures, which does not always correlate with age. Due to their effect on bone turnover and on other hormone-regulated phenomena, such as hot flushes or breast cancer risk, we position hormone therapy and selective estrogen receptor modulators as an early postmenopause intervention for the management of postmenopausal osteoporosis. When the use of these agents is not possible, compelling evidence supports antiresorptive agents as first-line treatment of postmenopausal osteoporosis in many clinical scenarios, with digestive conditions, kidney function, readiness for compliance, or patient preferences playing a role in choosing between bisphosphonates or denosumab during this period. For patients at high risk of osteoporotic fracture, the "anabolic first" approach reduces that risk. The effect on bone health with these bone-forming agents or with denosumab should be consolidated with the subsequent use of antiresorptive agents. Regardless of the strategy, follow-up and treatment should be maintained indefinitely to help prevent fractures.
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Introduction and objectives: osteoclasts are terminally differentiated giant multinucleated cells derived from the fusionof mononuclear progenitors of the monocyte/macrophage hematopoietic lineage. The objective of our group was to achie-ve the best method for osteoclast differentiation, from both RAW 264.7 cells and peripheral blood monocytes.Material and methods: RAW 264.7 cells and human PBMCs were differentiated into osteoclasts. Success in differentiationwas assessed by TRAP staining. Osteoclast activity was detected by the resorption pits in Corning® Osteo Assay SurfacePlates.Results: the optimal cell density for RAW 264.7 cell differentiation was 25,000 cells/cm2 with 30 ng/mL of RANKL for6 days. Osteoclasts differentiated from PBMCs were observed after 4 weeks with 25 ng/mL M-CSF and 30 ng/mL RANKL.Individual pits or multiple pit clusters were observed on the surface plates.Conclusions: we report optimal conditions for the differentiation of osteoclasts from.(AU)
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Humanos , Osteoclastos , Células RAW 264.7 , Reabsorção Óssea , Diferenciação Celular , Osteoporose , Doenças ÓsseasRESUMO
OBJECTIVES: To estimate the incidence of clinical fragility fractures in postmenopausal women with rheumatoid arthritis (RA) and analyze risk factors for fracture. METHODS: Incidence of clinical fragility fractures in 330 postmenopausal women with RA was compared to that of a control population of 660 age-matched postmenopausal Spanish women. Clinical fractures during the previous five years were recorded. We analyzed associations with risk factors for fracture in both populations and with disease-related variables in RA patients. RESULTS: Median age of RA patients was 64 years; median RA duration was eight years. Sixty-nine percent were in remission or on low activity. Eighty-five percent had received glucocorticoids (GCs); 85 %, methotrexate; and 40 %, ≥1 biologic DMARD. Fifty-four patients and 47 controls had ≥1 major osteoporotic fracture (MOF). Incidence of MOFs was 3.55 per 100 patient-year in patients and 0.72 in controls (HR: 2.6). Risk factors for MOFs in RA patients were age, previous fracture, parental hip fracture, years since menopause, BMD, erosions, disease activity and disability, and cumulative dose of GCs. Previous fracture in RA patients was a strong risk for MOFs (HR: 10.37). CONCLUSION: Of every 100 postmenopausal Spanish women with RA, 3-4 have a MOF per year. This is more than double that of the general population. A previous fracture poses a high risk for a new fracture. Other classic risk factors for fracture, RA disease activity and disability, and the cumulative dose of GCs are associated with fracture development.
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Artrite Reumatoide , Fraturas por Osteoporose , Humanos , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Pós-Menopausa , Incidência , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , Fraturas por Osteoporose/etiologia , Fatores de Risco , Densidade ÓsseaRESUMO
Nearly 10% of subjects with severe idiopathic osteoporosis present pathogenic WNT1 mutations. Clinical characteristics include a family history of osteoporosis, early adulthood onset, and fragility fractures which may evolve to pseudoarthrosis. WNT1 should be genetically screened in these patients as the phenotype is often variable and therapeutic approaches may differ. INTRODUCTION: Recent studies have shown that homozygous WNT1 gene mutations may be related to severe osteoporosis resembling osteogenesis imperfecta (OI). Conversely, heterozygous WNT1 mutations are linked to a milder phenotype of early-onset osteoporosis. Treatment with bisphosphonates is reported to be unsatisfactory. Our aim was to analyze the presence and prevalence of WNT1 mutations and the main associated clinical characteristics in subjects with primary early-onset osteoporosis. METHODS: A cohort comprising 56 subjects (aged 19-60 years) with severe, early-onset osteoporosis was screened by massive parallel sequencing with a 23-gene panel. The gene panel included 19 genes known to cause OI (including the WNT1 gene), three genes related to osteoporosis, and the gene related to hypophosphatasia (ALPL). RESULTS: We identified five patients (3 men) with heterozygous WNT1 variants. All presented severe osteoporosis with early fracture onset and a family history of fragility fractures. None presented a characteristic phenotype of OI or skeletal deformities. One patient was previously treated with bisphosphonates, presenting inadequate response to treatment and two developed pseudoarthrosis after upper arm fractures. All subjects were diagnosed in adulthood. CONCLUSIONS: Nearly 1/10 adult subjects with severe idiopathic osteoporosis may present pathogenic WNT1 mutations. Clinical characteristics commonly include a family history of osteoporosis, onset in early adulthood, marked decrease in bone mass, and prevalent fractures, particularly vertebral. WNT1 should be genetically screened in these subjects as the phenotype is often variable and the therapeutic approach may differ. The role of WNT1 mutations in the development of pseudoarthrosis should also be elucidated.
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Osteoporose , Proteína Wnt1 , Humanos , Difosfonatos/uso terapêutico , Fraturas do Úmero , Mutação , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/diagnóstico , Osteoporose/genética , Osteoporose/tratamento farmacológico , Pseudoartrose/tratamento farmacológico , Proteína Wnt1/genéticaRESUMO
Bilirubin and bile acids have deleterious effects on osteoblasts, which may explain the low bone formation of liver diseases with cholestasis. Although there is some clinical evidence of increased bone resorption in this condition, the effects of these substances on osteoclasts are unknown. The objective was to analyze the effects of bilirubin and bile acids -lithocholic acid (LCA) and ursodeoxycholic acid (UDCA)- on osteoclast viability and apoptosis, and on the expression of osteoclast-related microRNAs (miRNAs). RAW 264.7 cells and human PBMCs were differentiated into osteoclasts. Success in differentiation was assessed by TRAP stain and osteoclast-specific gene expression; osteoclast activity was detected by the resorption pits in Corning® Osteo Assay Surface Plates. Cells were treated with camptothecin (CAM) or with bilirubin, LCA or UDCA, at several concentrations and combinations, including non-treated cells as control. Cell viability was measured using WST-1 assay and apoptosis assessing Caspase-3 by Western blot. Expression of miR-21a, miR-29b, miR-31, miR-148a, miR-155 and miR-223 were analyzed by Real Time. Viability increased gradually in osteoclasts differentiated from RAW 264.7 cells, as the concentration of bilirubin increased, being particularly high with bilirubin 100 µM (61 %) as compared to the untreated control (p < 0.007). Viability decreased significantly with CAM, LCA and UDCA (80 %, 62 % and 27 %, respectively), effects which were abolished by bilirubin. Moreover, bilirubin increased viability in osteoclasts derived from human PBMCs (p < 0.03). Caspase-3 decreased by 46 % with bilirubin 50 µM and increased 10-fold with LCA 100 µM and CAM (p < 0.01). Bilirubin increased miR-21 and miR-148a expression as compared to controls (115 % and 59 %, respectively; p < 0.007). In conclusion, bilirubin increases viability and decreases apoptosis of osteoclasts, and overexpresses the osteoclastogenic miR-21 and miR-148a. The effects of bilirubin counteract the actions of LCA and UDCA. Therefore, bilirubin may contribute to the increased bone resorption and to the development of osteoporosis in advanced liver diseases.
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Reabsorção Óssea , Hepatopatias , MicroRNAs , Osteoporose , Apoptose , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/farmacologia , Bilirrubina/metabolismo , Bilirrubina/farmacologia , Reabsorção Óssea/metabolismo , Caspase 3/metabolismo , Diferenciação Celular , Humanos , Hepatopatias/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoclastos/metabolismo , Osteoporose/genética , Ligante RANK/metabolismoRESUMO
The main well recognized action of bisphosphonates (BPs) is their antiresorptive capacity, making them first-line drugs in the treatment of osteoporosis and other metabolic bone diseases. In this review we have compiled other possible actions of BPs, particularly in the areas of immunomodulation, anti-inflammatory capacity and in the prevention of structural joint damage in inflammatory rheumatic diseases. The immunomodulatory capacity of BPs has been focused on the mechanisms involved in the acute-phase response associated with the administration of nitrogen containing BPs (N-BPs), with the stimulus of pro-inflammatory cytokines, through the mevalonate pathway, activation of T-cells and the decrease in the cytotoxic T-lymphocyte antigen-4 (CTLA-4). In relation to their anti-inflammatory capacity, special attention has been given to their effect on preventing structural damage in inflammatory joint diseases and on the differential immune response in bone lesions of the most common and representative inflammatory rheumatic diseases, i.e. rheumatoid arthritis and spondyloarthropathies. The present data indicate that more studies are needed to improve the knowledge on the effect of BPs on inflammatory-mediated diseases and particularly on the prevention and/or treatment of the structural damage in these disorders, since these agents could be a potential useful concomitant therapy.
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Artrite Reumatoide , Osteoporose , Doenças Reumáticas , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Citocinas , Difosfonatos/uso terapêutico , Humanos , Doenças Reumáticas/tratamento farmacológicoRESUMO
CONTEXT: Denosumab discontinuation is characterized by an increase in bone turnover overriding pre-treatment status, a rapid bone loss in the majority and multiple vertebral fractures (VFx) in some patients. METHODS: A working group of the European Calcified Tissue Society (ECTS) performed an updated systematic review of existing literature on changes of bone turnover, bone mineral density (BMD), and fracture risk after denosumab discontinuation and provided advice on management based on expert opinion. RESULTS: Important risk factors for multiple VFx following denosumab cessation are prevalent VFx, longer duration off therapy, greater gain in hip BMD during therapy, and greater loss of hip BMD after therapy according to a retrospective analysis of the FREEDOM Extension Study. Case series indicate that prior bisphosphonate therapy mitigates the biochemical rebound phenomenon after denosumab discontinuation, but it is uncertain whether this attenuation prevents BMD loss and fractures. Current evidence indicates partial efficacy of subsequent antiresorptive treatment with results seemingly dependent on duration of denosumab treatment. CONCLUSIONS: A careful assessment of indications to start denosumab treatment is advised, especially for younger patients. A case for long-term treatment with denosumab can be made for patients at high fracture risk already on denosumab treatment given the favorable efficacy and safety profile. In case of denosumab discontinuation, alternative antiresorptive treatment should be initiated 6 months after the final denosumab injection. Assessment of bone turnover markers may help define the optimal regimen, pending results of ongoing RCTs. Patients having sustained VFx should be offered prompt treatment to reduce high bone turnover.
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OBJECTIVE: The aim of this study was to identify the risk factors associated with fragility fracture (FF) development in glucocorticoid (GC)-treated patients. METHODS: 127 patients (aged 62±18 years, 63% women) on GC-treatment (mean dose 14.5±14.1 mg/day and duration 47.7±69 months) were included. The clinical data collected included bone metabolism study (including gonadal axis), GC-treatment, disease activity, dual-energy X-ray absorptiometry analysis (evaluating densitometric osteoporosis (OP) and trabecular bone score (TBS) degraded microarchitecture values (DMA)), X-ray (assessing vertebral fractures (VF)), FRAX risk (GC-adjusted) and previous FF. RESULTS: 17% of the patients had VF, 28% FF (VF and/or non-VF), 29% OP and 52% DMA. Patients with VF received more GC boluses (57.1% vs 29.5%, p=0.03), were older (68±13 vs 60±19 years, p=0.02), postmenopausal (100% vs 67%, p=0.02), had low testosterone levels (57% vs 11%, p=0.02), lower TBS values (1.119±0.03 vs 1.237±0.013, p<0.001) and higher FRAX risk (17.2±16 vs 9.3±7.6, p=0.003). Patients with FF showed higher accumulated GC doses (16.6±18.4 vs 11.1±12.9 g, p=0.046). On multivariate analysis, hypogonadism (OR 12.38; 95% CI 1.85 to >100, p=0.01) and having received GC boluses (OR 3.45; 95% CI 1.04 to 12.15, p=0.01) were the main factors related to VF. Hypogonadism (OR 7.03; 95% CI 1.47 to 38.37, p=0.01) and FRAX >20 (OR 7.08; 95% CI 1.28 to 53.71, p=0.02) were factors related to FF. CONCLUSION: Hypogonadism is the principal risk factor for developing fractures in GC-treated men and women, whereas receiving GC boluses is a major factor for VF. These results indicate the importance of evaluating the gonadal axis in these patients.