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1.
Medicine (Baltimore) ; 100(31): e26715, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397808

RESUMO

BACKGROUND: Various bisphosphonate agents have been proven to be effective in preventing bone loss and fracture in osteopenic postmenopausal women. This study was designed to compare the effectiveness of various BPs on preventing the loss of bone mineral density (BMD) for postmenopausal women with osteopenia. METHODS: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were screened up to identify randomized controlled trails comparing effectiveness of BPs or placebo on the BMD of postmenopausal women with osteopenia. Network meta-analysis and standard pair-wise meta-analyses were performed. The main outcomes include the percentage changes of 6-, 12-, 24-, and 36-month BMD at lumbar, total hip and femoral neck, and frequencies of new fractures and severe adverse events. RESULTS: Fourteen randomized controlled trials were eligible, involving 11,540 participants. No significant difference was presented among the available interventions for the 6-month BMD at 3 different sites, but the magnitudes of differences among the treatment regimens became gradually increased along with the extending of follow-up periods. Daily aledronate of more than 5 mg provided the maximal percentage increase on BMD of femoral neck and lumbar spine, while zoledronate provided maximal change on BMD of total hip, at different follow-up periods. This network meta-analysis also demonstrated similar frequencies of new clinical fractures and severe adverse events among different interventions. CONCLUSIONS: A ranking spectrum depicting the effectiveness on BMD percentage change following interventions with different bisphosphonate regimens was provided. Generally, regimens with zoledronate and aledronate were found to be the most effective interventions in the 3 sites at different end points.


Assuntos
Densidade Óssea/efeitos dos fármacos , Difosfonatos/normas , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/normas , Difosfonatos/farmacologia , Humanos , Menopausa/efeitos dos fármacos , Menopausa/fisiologia , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos
2.
FASEB J ; 35(9): e21786, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34411349

RESUMO

Biological functions, including glycemic control and bone metabolism, are highly influenced by the body's internal clock. Circadian rhythms are biological rhythms that run with a period close to 24 hours and receive input from environmental stimuli, such as the light/dark cycle. We investigated the effects of circadian rhythm disruption (CRD), through alteration of the light/dark schedule, on glycemic control and bone quality of mice. Ten-week-old male mice (C57/BL6, n = 48) were given a low-fat diet (LFD) or a high-fat diet (HFD) and kept on a dayshift or altered schedule (RSS3) for 22 weeks. Mice were divided into four experimental groups (n = 12/group): Dayshift/LFD, Dayshift/HFD, RSS3/LFD, and RSS3/HFD. CRD in growing mice fed a HFD resulted in a diabetic state, with a 36.2% increase in fasting glucose levels compared to the Dayshift/LFD group. Micro-CT scans of femora revealed a reduction in inner and outer surface expansion for mice on a HFD and altered light schedule. Cancellous bone demonstrated deterioration of bone quality as trabecular number and thickness decreased while trabecular separation increased. While HFD increased cortical bone mineral density, its combination with CRD reduced this phenomenon. The growth of mineral crystals, determined by small angle X-ray scattering, showed HFD led to smaller crystals. Considering modifications of the organic matrix, regardless of diet, CRD exacerbated the accumulation of fluorescent advanced glycation end-products (fAGEs) in collagen. Strength testing of tibiae showed that CRD mitigated the higher strength in the HFD group and increased brittleness indicated by lower post-yield deflection and work-to-fracture. Consistent with accumulation of fAGEs, various measures of toughness were lowered with CRD, but combination of CRD with HFD protected against this decrease. Differences between strength and toughness results represent different contributions of structural and material properties of bone to energy dissipation. Collectively, these results demonstrate that combination of CRD with HFD impairs glycemic control and have complex effects on bone quality.


Assuntos
Glicemia/metabolismo , Osso e Ossos/fisiologia , Ritmo Circadiano , Dieta Hiperlipídica/efeitos adversos , Animais , Glicemia/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/fisiologia , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Masculino , Camundongos
3.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371870

RESUMO

Kidney transplant recipients are at high risk of progressive bone loss and low-energy fractures in the years following transplantation. Marine n-3 polyunsaturated fatty acids (n-3 PUFA) supplementation may have beneficial effects on bone strength. The Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial was an investigator initiated, randomized, placebo-controlled trial investigating the effects of marine n-3 PUFA supplementation after kidney transplantation. Effects of supplementation on bone mineral density (BMD) and calcium metabolism were pre-defined secondary endpoints. Adult kidney transplant recipients (n = 132) were randomized to 2.6 g marine n-3 PUFA supplement or olive oil (control) from 8 to 52 weeks post-transplant. Dual energy X-ray absorptiometry was performed to assess changes in bone mineral density of hip, spine, and forearm, as well as trabecular bone score (TBS) of the lumbar spine. Student's t test was used to assess between-group differences. There were no differences in ΔBMD between the two groups (intervention vs. control) at lumbar spine (-0.020 ± 0.08 vs. -0.007 ± 0.07 g/cm², p = 0.34), total hip (0.001 ± 0.03 vs. -0.005 ± 0.04, p = 0.38), or other skeletal sites in the intention-to-treat analyses. There was no difference in the change in TBS score (0.001 ± 0.096 vs. 0.009 ± 0.102, p = 0.62). Finally, no effect on biochemical parameters of mineral metabolism was seen. Results were similar when analyzed per protocol. In conclusion, we found no significant effect of 44 weeks of supplementation with 2.6 g of marine n-3 PUFA on BMD in kidney transplant recipients.


Assuntos
Densidade Óssea/efeitos dos fármacos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Transplante de Rim , Osteoporose/prevenção & controle , Fraturas por Osteoporose/prevenção & controle , Absorciometria de Fóton , Adulto , Idoso , Biomarcadores/sangue , Cálcio/sangue , Dinamarca , Suplementos Nutricionais/efeitos adversos , Ácidos Docosa-Hexaenoicos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Ácido Eicosapentaenoico/efeitos adversos , Feminino , Humanos , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/fisiopatologia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
4.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371877

RESUMO

Pathological mechanisms underlining diabetic bone defects include oxidative damage and insulin/IGF-1 imbalance. Morin is a bioflavonoid with antioxidant and anti-diabetic effects. This study evaluates morin's protective effects against altered bone histomorphometry in diabetic rats through assessing insulin/IGF-1 pathway as a potential mechanism. Diabetic animals were administered two morin doses (15 and 30 mg/kg) for 5 weeks. Different serum hepatic and renal functions tests were assessed. Bone density and histomorphometry in cortical and trabecular tissues were evaluated histologically. The expressions of insulin, c-peptide and IGF-1 were estimated. In addition, the enzymatic activities of the major antioxidant enzymes were determined. Diabetic-associated alterations in serum glucose, aminotransferases, urea and creatinine were attenuated by morin. Diabetic bone cortical and trabecular histomorphometry were impaired with increased fibrosis, osteoclastic functions, osteoid formation and reduced mineralization, which was reversed by morin; particularly the 30 mg/kg dose. Insulin/IGF-1 levels were diminished in diabetic animals, while morin treatment enhanced their levels significantly. Diabetes also triggered systemic oxidative stress noticeably. The higher dose (30 mg/kg) of morin corrected the endogenous antioxidant enzymatic activities in diabetic rats. Findings indicate the potential value of morin supplementation against hyperglycemia-induced skeletal impairments. Activation of insulin/IGF-1 signaling could be the underlining mechanism behind these effects.


Assuntos
Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fêmur/efeitos dos fármacos , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/sangue , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/patologia , Fêmur/metabolismo , Fêmur/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais , Estreptozocina
5.
Cochrane Database Syst Rev ; 7: CD012756, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34224134

RESUMO

BACKGROUND: Cerebral palsy (CP) is a heterogeneous group of non-progressive disorders of posture or movement, caused by a lesion of the developing brain. Osteoporosis is common in children with cerebral palsy, particularly in children with reduced gross motor function, and leads to an increased risk of fractures. Gross motor function in children with CP can be categorised using a tool called the Gross Motor Function Classification System (GMFCS). Bisphosphonate increases bone mineral density (BMD) and reduces fracture rates. Bisphosphonate is used widely in the treatment of adult osteoporosis. However, the use of bisphosphonate in children with CP remains controversial, due to a paucity of evidence and a lack of recent trials examining the efficacy and safety of bisphosphonate use in this population. OBJECTIVES: To examine the efficacy and safety of bisphosphonate therapy in the treatment of low BMD or secondary osteoporosis (or both) in children with cerebral palsy (GMFCS Levels III to V) who are under 18 years of age. SEARCH METHODS: In September 2020, we searched CENTRAL, MEDLINE, Embase, six other databases, and two trial registers for relevant studies. We also searched the reference lists of relevant systematic reviews, trials, and case studies identified by the search, and contacted the authors of relevant studies in an attempt to identify unpublished literature. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs), and quasi-RCTs, comparing at least one bisphosphonate (given at any dose, orally or intravenously) with placebo or no drug, for the treatment of low BMD or osteoporosis in children up to 18 years old, with cerebral palsy (GMFCS Levels III to V). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We were unable to conduct any meta-analyses due to insufficient data, and therefore provide a narrative assessment of the results. MAIN RESULTS: We found two relevant RCTs (34 participants). Both studies included participants with non-ambulatory CP or CP and osteoporosis. Participants in both studies were similar in severity of CP, age distribution, and sex distribution. The two trials used different bisphosphonate medications and different intervention durations, but further comparison of the interventions was not possible due to a lack of published data from one trial. One trial received funding and support from research, academic, and hospital foundations, with pharmaceutical companies providing components of the calcium and vitamin supplement; the other trial did not report sources of funding. We judged one study at an overall high risk of bias; the other as overall unclear risk of bias. PRIMARY OUTCOME: Compared to placebo or no treatment, both studies provided very low certainty evidence of improved BMD at least four months post-intervention in children treated with bisphosphonate. Only one study (12 participants) provided sufficient detail to assess a measure of the effect, and reported an improvement at six months post-intervention in lumbar spine z-score (mean difference (MD) 18%, 95% confidence interval (CI) 6.57 to 29.43; very low certainty evidence). SECONDARY OUTCOMES: Very low certainty evidence from one study found that bisphosphonate reduced serum N-telopeptides (NTX) more than placebo; the other study reported that both bisphosphonate plus alfacalcidol and alfacalcidol alone reduced NTX, but did not compare groups. One study reported inconclusive results between groups for serum bone-specific alkaline phosphatase (BAP). The other study reported that both bisphosphonate plus alfacalcidol and alfacalcidol alone reduced BAP, but did not compare groups. Neither study reported data for the effect of bisphosphonate treatment on changes in volumetric BMD in the distal radius or tibia, changes in fracture frequency, bone pain, or quality of life. One study reported that two participants had febrile events noted during their first dosing schedule, but no further adverse events were reported in either relevant study. AUTHORS' CONCLUSIONS: Based on the available evidence, there is very low certainty evidence that bisphosphonate treatment may improve bone health in children with cerebral palsy. We could only include one study with 14 participants in the assessment of the effect size; therefore, the precision of the effect estimate is low. We could only evaluate one planned primary outcome, as there was insufficient detail reported in the relevant studies. Further research from RCTs on the effect and safety of bisphosphonate to improve bone health in children with cerebral palsy is required. These studies should clarify the optimal standard treatment regarding weight-bearing exercises, vitamin D and calcium supplementation, and should include fracture frequency as a primary outcome.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Paralisia Cerebral/complicações , Difosfonatos/uso terapêutico , Osteoporose/tratamento farmacológico , Adolescente , Fosfatase Alcalina/sangue , Viés , Criança , Pré-Escolar , Colágeno Tipo I/sangue , Feminino , Fraturas Espontâneas/prevenção & controle , Humanos , Hidroxicolecalciferóis/uso terapêutico , Lactente , Masculino , Osteoporose/sangue , Peptídeos/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Cochrane Database Syst Rev ; 7: CD013424, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34231877

RESUMO

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism. OBJECTIVES: To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence). AUTHORS' CONCLUSIONS: Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/terapia , Insuficiência Renal Crônica/complicações , Conduta Expectante , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Viés , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/efeitos adversos , Denosumab/uso terapêutico , Feminino , Colo do Fêmur/efeitos dos fármacos , Fraturas Espontâneas/epidemiologia , Fraturas Espontâneas/prevenção & controle , Quadril , Humanos , Indóis/efeitos adversos , Indóis/uso terapêutico , Vértebras Lombares/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/mortalidade , Proteína Relacionada ao Hormônio Paratireóideo/efeitos adversos , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Cloridrato de Raloxifeno/efeitos adversos , Cloridrato de Raloxifeno/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Diálise Renal , Insuficiência Renal Crônica/terapia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/prevenção & controle , Teriparatida/efeitos adversos , Teriparatida/uso terapêutico , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico
7.
Eur J Endocrinol ; 185(4): 515-524, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34324430

RESUMO

Objective: In primary hyperparathyroidism (PHPT) with osteoporosis, bone mineral density (BMD) improves after parathyroidectomy. It is unclear whether combining surgery with postoperative bisphosphonate treatment can further improve bone health. Design: This randomized, placebo-controlled study compared the effects of surgery alone and surgery combined with zoledronic acid on bone metabolism in PHPT with osteoporosis. Methods: Fifty-six patients (f/m 47/9, mean age 68.4 years) with PHPT and osteoporosis were randomized 1-3 months after parathyroidectomy to receive a 2-year treatment of zoledronic acid or placebo. Dual-energy X-ray absorptiometry (DXA) and bone turnover markers (N-terminal propeptide of type 1 procollagen, C-terminal telopeptide of type 1 collagen, and alkaline phosphatase) were measured annually during the 2-year follow-up. Results: Two years after parathyroidectomy, BMD was significantly higher in the zoledronic acid (ZOL) group compared with the placebo (PBO) group at the femoral neck (P = 0.045 for Z-score) and lumbar spine (P = 0.039 and 0.017 for T- and Z-scores, respectively). Bone turnover markers were significantly lower in the ZOL group (P < 0.001 for all markers). Of the 18 patients who had received bisphosphonates for >1 year before surgery, BMD improved significantly in the ZOL group both in the femoral neck and lumbar spine (n = 10; all P < 0.001-0.01), but in the PBO group, only in the lumbar spine (n = 8, P = 0.03), (P = 0.08-0.95 for between-group changes). Conclusion: BMD increases after parathyroidectomy both with and without zoledronic acid but the increase is significantly higher with postoperative zoledronic acid.


Assuntos
Hiperparatireoidismo Primário , Osteoporose , Ácido Zoledrônico/administração & dosagem , Idoso , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Terapia Combinada , Método Duplo-Cego , Esquema de Medicação , Feminino , Finlândia , Humanos , Hiperparatireoidismo Primário/complicações , Hiperparatireoidismo Primário/tratamento farmacológico , Hiperparatireoidismo Primário/cirurgia , Masculino , Pessoa de Meia-Idade , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Osteoporose/cirurgia , Paratireoidectomia , Período Pós-Operatório , Resultado do Tratamento
8.
Nutrients ; 13(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210051

RESUMO

While in vitro and animal studies of osteoblastic and osteoclastic activity as well as bone resistance for copper are numerous, and the results encouraging in terms of regulation, human studies are scarce. The aim of this narrative review was to investigate the correlation of blood copper, daily copper intake, and copper supplementation with bone mineral density. This review included 10 eligible studies: five studies concerned copper blood levels, one study concerned daily copper intake, and four studies concerned copper supplementation. Blood copper levels did not show statistically significant differences in four of the studies analyzed, while only one study showed differences between osteoporotic and healthy women, although only with women between 45 and 59 years of age and not between 60 and 80 years of age. The dietary copper intake among women with or without osteoporosis did not show any differences. Only one study with a small sample of subjects carried out these assessments; therefore, it is a topic that the literature must deepen with further studies. The two studies that analyzed the integration of copper (2.5-3 mg/day) only showed good results in terms of slowing down bone mineral loss and reducing resorption markers, confirming the effectiveness of copper supplementation on bone metabolism.


Assuntos
Densidade Óssea/efeitos dos fármacos , Cobre/administração & dosagem , Cobre/sangue , Suplementos Nutricionais , Ingestão de Alimentos/fisiologia , Idoso , Idoso de 80 Anos ou mais , Reabsorção Óssea/sangue , Osso e Ossos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenômenos Fisiológicos da Nutrição , Osteoporose/sangue
9.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281215

RESUMO

Bone structure abnormalities are increasingly observed in patients chronically treated with antiepileptic drugs (AEDs). The majority of the available data concern older conventional AEDs, while the amount of information regarding newer AEDs, including stiripentol, is limited. The aim of the study was to assess the effect of stiripentol on bones. For 24 weeks, male Wistar rats, received 0.9% sodium chloride (control group) or stiripentol (200 mg/kg/day) (STP group). In the 16th week of the study, we detected lower serum PINP levels in the STP group compared to the control group. In the 24th week, a statistically significant lower 1,25-dihydroxyvitamin D3 level, higher inorganic phosphate level and higher neutrophil gelatinase-associated lipocalin (NGAL) levels in serum were found in the STP group compared to the control. Micro X-ray computed tomography of the tibias demonstrated lower bone volume fraction, lower trabecular thickness, higher trabecular pattern factor and a higher structure model index in the stiripentol group. Considering the results of this experiment on rats which suggests that long-term administration of stiripentol may impair the cancellous bone microarchitecture, further prospective human studies seem to be justified. However, monitoring plasma vitamin D, calcium, inorganic phosphate and kidney function in patients on long-term stiripentol therapy may be suggested.


Assuntos
Anticonvulsivantes/efeitos adversos , Osso e Ossos/efeitos dos fármacos , Dioxolanos/efeitos adversos , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Masculino , Distribuição Aleatória , Ratos Wistar , Microtomografia por Raio-X
10.
Nat Commun ; 12(1): 3247, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059688

RESUMO

The Wnt signaling pathway is intricately connected with bone mass regulation in humans and rodent models. We designed an antibody-based platform that generates potent and selective Wnt mimetics. Using this platform, we engineer bi-specific Wnt mimetics that target Frizzled and low-density lipoprotein receptor-related proteins and evaluate their effects on bone accrual in murine models. These synthetic Wnt agonists induce rapid and robust bone building effects, and correct bone mass deficiency and bone defects in various disease models, including osteoporosis, aging, and long bone fracture. Furthermore, when these Wnt agonists are combined with antiresorptive bisphosphonates or anti-sclerostin antibody therapies, additional bone accrual/maintenance effects are observed compared to monotherapy, which could benefit individuals with severe and/or acute bone-building deficiencies. Our data support the continued development of Wnt mimetics for the treatment of diseases of low bone mineral density, including osteoporosis.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/tratamento farmacológico , Fraturas do Fêmur/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Proteínas Wnt/agonistas , Idoso , Envelhecimento/fisiologia , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/uso terapêutico , Reabsorção Óssea/fisiopatologia , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Feminino , Fraturas do Fêmur/patologia , Fêmur/efeitos dos fármacos , Fêmur/lesões , Fêmur/patologia , Humanos , Camundongos , Osteoporose Pós-Menopausa/fisiopatologia , Via de Sinalização Wnt/efeitos dos fármacos , Adulto Jovem
11.
Lancet Child Adolesc Health ; 5(8): 569-581, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34139202

RESUMO

BACKGROUND: Faltered linear growth and pubertal delay, which are both common in children with HIV in sub-Saharan Africa, might affect adolescent bone accrual and future fragility fracture risk. We investigated the association of HIV with bone density adjusted for skeletal size in peripubertal children in Zimbabwe. METHODS: We did a cross-sectional study of baseline data from the IMVASK cohort, which enrolled children aged 8-16 years with HIV who had been taking antiretroviral therapy (ART) for at least 2 years, and children of the same age without HIV. Children with HIV were recruited from public sector HIV clinics at Parirenyatwa General Hospital and Harare Central Hospital (Harare, Zimbabwe), and children without HIV were recruited from six schools in the same suburbs that the hospitals serve. Sociodemographic, clinical, and anthropometric data were collected. Dual-energy X-ray absorptiometry (DXA) was used to measure the bone outcomes of total-body less-head bone mineral content for lean mass adjusted for height (TBLH-BMCLBM), and lumbar spine bone mineral apparent density (LS-BMAD), and we assessed the prevalence of low TBLH-BMCLBM and low LS-BMAD (defined by Z-scores of less than -2·0). Size adjustment techniques were used to overcome the size dependence of DXA measurement. We used linear regression models, with multiple imputation for missing data, to assess relationships between risk factors and TBLH-BMCLBM and LS-BMAD Z-scores in children with and without HIV. FINDINGS: We recruited 303 children with HIV (mean age 12·4 years [SD 2·5]; 151 [50%] girls) and 306 children without HIV (mean age 12·5 years [SD 2·5]; 155 [51%] girls). In children with HIV, median age of HIV diagnosis was 3·0 years (IQR 1·2-5·8), and median ART duration was 8·1 years (6·2-9·5); for 102 (34%) children, ART included tenofovir disoproxil fumarate (TDF). Children with HIV had a higher prevalence of low TBLH-BMCLBM Z-score than children without HIV (29 [10%] of 279 children with available data vs 18 [6%] of 292 with available data; p=0·066) and a higher prevalence of low LS-BMAD Z-score (40 [14%] of 279 vs 17 [6%] of 293 with available data; p=0·0007). HIV and male sex were associated with earlier pubertal (Tanner) stage. The negative associations between HIV and Z-scores for TBLH-BMCLBM and LS-BMAD were more pronounced with pubertal maturation, particularly in girls. Among children with HIV, TDF exposure and orphanhood were associated with lower TBLH-BMCLBM Z-score in confounder-adjusted analysis. Current TDF use (vs non-TDF-based ART) was associated with a reduction in TBLH-BMCLBM Z-score of 0·41 (95% CI 0·08-0·74; p=0·015) and in LS-BMAD Z-score of 0·31 (0·08-0·69; p=0·12). INTERPRETATION: Despite ART, HIV is associated with substantial skeletal deficits towards the end of puberty. The extent of bone deficits associated with TDF and its widespread use in children in sub-Saharan Africa are a concern for future adult fracture risk. FUNDING: Wellcome Trust.


Assuntos
Antirretrovirais/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Infecções por HIV , Puberdade/efeitos dos fármacos , Tenofovir/uso terapêutico , Absorciometria de Fóton , Adolescente , Criança , Estudos Transversais , Feminino , Fraturas Ósseas/etiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Zimbábue
12.
Nutrients ; 13(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072655

RESUMO

Vitamin D modulates bisphosphonate (BP) efficacy, but its contribution to bone mineral density (BMD) after BP discontinuation is not known. To address this topic, we performed a retrospective analysis of postmenopausal women exposed to alendronate (ALN) to treat osteoporosis who regularly continued the supplementation of cholecalciferol or calcifediol at recommended doses. In the ninety-six recruited women (age 61.1 ± 6.9 years), ALN was administered for 31.2 ± 20.6 months and then discontinued for 33.3 ± 18.9 months. The modification of 25(OH)D serum levels over time was associated with a change of alkaline phosphatase (r = -0.22, p = 0.018) and C-terminal collagen type 1 telopeptide (r = -0.3, p = 0.06). Women in the tertile of the highest increase in 25(OH)D level showed a 5.7% BMD gain at lumbar spine, that was twice as great in comparison with participants with a lower 25(OH)D variation. At a multiple regression analysis, BMD change was associated with time since menopause (ß = 2.28, SE 0.44, p < 0.0001), FRAX score for major fracture (ß = -0.65, SE 0.29, p = 0.03), drug holiday duration (ß = -2.17, SE 0.27, p < 0.0001) and change of 25(OH)D levels (ß = 0.15, SE 0.03, p = 0.0007). After ALN discontinuation, improving the vitamin D status boosts the ALN tail effect on BMD.


Assuntos
Alendronato , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Vitamina D , Idoso , Alendronato/administração & dosagem , Alendronato/farmacologia , Alendronato/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitamina D/administração & dosagem , Vitamina D/sangue , Vitamina D/farmacologia , Vitamina D/uso terapêutico
13.
Ann Agric Environ Med ; 28(2): 326-330, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34184518

RESUMO

INTRODUCTION: Estrogen deficiency found in postmenopausal women may lead to disturbances in the balance of bone metabolism. Study of the influence of estradiol on markers of bone turnover may help to understand the mechanisms of bone metabolism and to monitor osteoporosis therapy in postmenopausal women at high risk of fractures. The aim of the study was evaluation of the effect of estradiol on the basic markers of bone turnover in postmenopausal women. MATERIAL AND METHODS: The study was conducted in a group of 92 postmenopausal women, divided into two groups: Gr-1 with low estradiol levels ≤ 10 pg/ml and Gr-2 with reference estradiol levels ≥ 25 pg/ml). Basic markers of bone turnover were examined: Ctx (C-terminal cross-linked telopeptide of type I collagen alpha chain) and OC (osteocalcin); pro-resorptive cytokines: IL-6 and TNF-α; vitamin 25(OH)D3 and lipid profile. Women was also analyzed according to demographic and clinical data. RESULTS: A positive relationship was found between estradiol and the main bone formation marker - OC (p = 0.041, r = 0.213) and IL-6, TNF-α (p = 0.007, r = 0.281 and p = 0.018, r = 0.246, respectivly, but only in the group with a reference hormone level. Moreover, the main markers of bone turnover: Ctx and OC showed a mutual positive correlation (p = 0.013; r = 0.257) in women with reference estradiol levels. Relationships between markers of bone remodeling, pro-resorptive cytokines and vitamin D3 depending on the level of estradiol showed no statistically significant correlation. CONCLUSIONS: The study showed that only in women with the reference estradiol level (≥ 25 pg/ml) were the bone formation and resorption processes balanced.


Assuntos
Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Feminino , Humanos , Interleucina-6/metabolismo , Pessoa de Meia-Idade , Osteocalcina/metabolismo , Osteoporose Pós-Menopausa/metabolismo , Osteoporose Pós-Menopausa/fisiopatologia , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/metabolismo , Vitamina D/metabolismo
14.
Jt Dis Relat Surg ; 32(2): 313-322, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34145806

RESUMO

OBJECTIVES: We aimed to investigate the radiological, biomechanical, histopathological, histomorphometric, and immunohistochemical effects of different doses of vardenafil on fracture healing. MATERIALS AND METHODS: Fifty-one rats were divided into three groups. Group V5 was given 5 mg/kg/day of vardenafil; Group V10 was given 10 mg/kg/day of vardenafil; and the control group was given the same volume of saline. Six rats from each group were sacrificed on Day 14 (early period) and the remaining rats were sacrificed on Day 42 (late period). Callus/femoral volume and bone mineral density were measured using micro-computed tomography. Five femurs from each group in the late period were examined by biomechanical tests. In addition to the histopathological and histomorphometric evaluations, immunohistochemical analyses were performed to examine the levels of inducible nitric oxide synthase (iNOS), transforming growth factor-3 (TGF-ß3), and nuclear factor kappa B (NF-κB) proteins. RESULTS: Both doses of vardenafil increased primary bone volume and maximal bone fracture strength in late period, compared to the control group (p<0.05). Histological healing scores of vardenafil groups were significantly higher in early period (p<0.001). While cartilaginous callus/total callus ratio in early period was higher, callus diameter/femoral diameter ratio in late period was lower in vardenafil groups (p<0.01). The NF-κB immunopositivity in V10 group decreased in early period, compared to control group (p<0.001). The TGF-ß3 and iNOS immunopositivity increased in both V5 and V10 groups, compared to the control group in early period, but returned to normal in late period. CONCLUSION: During the first period of fracture healing process in which vasodilation is mostly required with increasing inflammation, vardenafil has ameliorating effects on the bone union and supports fracture healing.


Assuntos
Fraturas do Fêmur/tratamento farmacológico , Consolidação da Fratura/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/administração & dosagem , Dicloridrato de Vardenafila/administração & dosagem , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Calo Ósseo/diagnóstico por imagem , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/patologia , Modelos Animais de Doenças , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/patologia , Fêmur/diagnóstico por imagem , Fêmur/patologia , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Fator de Crescimento Transformador beta3/metabolismo , Microtomografia por Raio-X
15.
Nutrients ; 13(6)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071733

RESUMO

Although there have been reported associations between zinc and bone mineral density (BMD), no reports exist on the effect of zinc treatment in osteoporotic patients. Therefore, we investigated the efficacy and safety of zinc pharmacotherapy in Japanese elderly patients. The present investigation included 122 osteoporotic patients with zinc deficiency, aged ≥65 years, who completed 12 months of follow-up. In addition to standard therapy for osteoporosis in a clinical setting, the subjects received oral administration of 25 mg zinc (NOBELZIN®, an only approved drug for zinc deficiency in Japan) twice a day. BMD and laboratory data including bone turnover markers were collected at 0 (baseline), 6, and 12 months of zinc treatment. Neither serious adverse effects nor incident fractures were seen during the observation period. Serum zinc levels were successfully elevated by zinc administration. BMD increased significantly from baseline at 6 and 12 months of zinc treatment. Percentage changes of serum zinc showed significantly positive associations with those of BMD. Bone formation markers rose markedly from the baseline values, whereas bone resorption markers displayed moderate or no characteristic changes. Additive zinc supplementation may contribute to BMD augmentation ensuing the prevention of fracture occurrence in elderly osteoporotic patients with zinc deficiency.


Assuntos
Deficiências Nutricionais/tratamento farmacológico , Osteoporose/tratamento farmacológico , Zinco , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/efeitos dos fármacos , Feminino , Humanos , Japão , Masculino , Zinco/sangue , Zinco/deficiência , Zinco/farmacologia , Zinco/uso terapêutico
16.
Life Sci ; 277: 119593, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33979569

RESUMO

AIMS: Recent studies have reported a relationship between periodontal disease and hypertension, and previous evidence suggests that the sympathetic nervous system plays an important role in the control of bone metabolism. This study sought to evaluate the effect of the beta-2 adrenergic receptor (ß2-AR) blocker butoxamine on experimental periodontitis in a rat model. MATERIALS AND METHODS: Wistar-Kyoto and spontaneously hypertensive rats (n = 6 per group) were orally administered butoxamine 1 mg/kg/day and experimental periodontitis was induced by applying an orthodontic ligature wire. The rats were sacrificed after 4 weeks and the residual alveolar bone was measured using micro-computed tomography (micro-CT) imaging analysis software for histological analysis. KEY FINDINGS: Micro-CT imaging analysis showed a higher ratio of residual alveolar bone, BV/TV, and Tb.N in both Wistar-Kyoto and spontaneously hypertensive rats treated with butoxamine compared with the corresponding control rats. In histological analysis, compared with the Wistar-Kyoto and spontaneously hypertensive rat control groups, the corresponding butoxamine-treated groups showed a lower ratio of attachment level, lower values of osteoclast number and surface. SIGNIFICANCE: ß2-AR blockers maintained the alveolar bone mass and attachment level by suppressing osteoclast activity. Thus, ß2-AR blockers may be effective in preventing periodontitis.


Assuntos
Butoxamina/farmacologia , Periodontite/tratamento farmacológico , Receptores Adrenérgicos beta 2/metabolismo , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Perda do Osso Alveolar/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Butoxamina/metabolismo , Feminino , Hipertensão/metabolismo , Masculino , Osteoclastos/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Adrenérgicos/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Microtomografia por Raio-X/métodos
17.
Acta Orthop ; 92(4): 455-460, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33870825

RESUMO

Background and purpose - Displaced fractures of the talar neck are associated with a high risk of structural collapse. In this observational analysis we hypothesized that pharmacological inhibition of osteoclast function might reduce the risk of structural collapse through a reduction in bone resorption during revascularization of the injured bone.Patients and methods - Between 2002 and 2014 we treated 19 patients with displaced fractures of the talar neck with open reduction and internal fixation. Of these, 16 patients were available for final follow-up between January and November 2017 (median 12 years, IQR 7-13). Among these, 6 patients with Hawkins type 3 fractures and 2 patients with Hawkins type 2b fractures received postoperative antiresorptive treatment (7 alendronate, 1 denosumab) for 6 to 12 months. The remaining 8 patients received no antiresorptive treatment. The self-reported foot and ankle score (SEFAS) was available in all patients and 15 patients had undergone computed tomography (CT) at final follow-up, which allowed evaluation of structural collapse of the talar dome and signs of post-traumatic osteoarthritis.Results - The risk for partial collapse of the talar dome was equal in the 2 groups (3 in each group) and post-traumatic arthritis was observed in all patients. The SEFAS in patients with antiresorptive treatment was lower, at 21 points (95% CI 15-26), compared with those without treatment, 29 points (CI 22-35).Interpretation - Following a displaced fracture of the talar neck, we found no effect of antiresorptive therapy on the rate of talar collapse, post-traumatic osteoarthritis, and patient-reported outcomes.


Assuntos
Alendronato/administração & dosagem , Denosumab/administração & dosagem , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Tálus/cirurgia , Adolescente , Adulto , Idoso , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Inquéritos e Questionários , Tálus/lesões , Adulto Jovem
18.
BMC Cancer ; 21(1): 422, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33863312

RESUMO

BACKGROUND: Androgen deprivation therapy (ADT) is the effective treating prostate cancer but is often accompanied by cancer treatment-induced bone loss (CTIBL), which impairs the patient's quality of life. In patients with nonmetastatic castration-sensitive prostate cancer (M0CSPC) who already have osteoporosis before starting ADT, appropriate bone-modifying agent intervention must be performed in parallel, as the patient has a high risk of future fracture. However, little is known about therapeutic interventions aimed at preventing the progression of CTIBL and new fractures. The present study explored the effect of once-yearly zoledronic acid 5 mg (ZOL 5 mg) on bone mineral density (BMD) and new vertebral fractures (VFs) in M0CSPC patients with coexisting osteoporosis before starting ADT. METHODS: We conducted a retrospective, multi-institutional, cohort study involving 42 M0CSPC patients with osteoporosis who had undergone ADT with/without a single intravenous infusion of ZOL 5 mg at the start of ADT (ZOL 5 mg group, n = 26; control group, n = 16). The association of the ZOL 5 mg with changes in the BMD from baseline to 12 months and the incidence of VFs were evaluated. RESULTS: Prevalent VFs were found in 47.6% of all patients at baseline. ZOL 5 mg significantly increased the lumbar spine BMD (LS-BMD) (mean rate of change: + 4.02%, p < 0.0001) and significantly decreased the TRACP-5b (mean rate of change: - 52.1%, p < 0.0001) at 12 months after starting ADT. Incident VFs were identified in 19.0% of all patients at 12 months after starting ADT. After adjusting for the age, BMI, and changes in the LS-BMD, ZOL 5 mg was not significantly associated with incident VFs (odds ratio 0.66, 95% confidence interval 0.04-11.3, p = 0.7774). CONCLUSION: ZOL 5 mg significantly increased the LS-BMD 12 months after starting ADT, and our short-term results showed that ZOL 5 mg was not significantly correlated with the suppression of incident vertebral fractures.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Neoplasias da Próstata/epidemiologia , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/prevenção & controle , Ácido Zoledrônico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Esquema de Medicação , Humanos , Japão/epidemiologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Osteoporose/epidemiologia , Osteoporose/etiologia , Neoplasias da Próstata/patologia , Vigilância em Saúde Pública , Estudos Retrospectivos , Fatores de Risco , Fraturas da Coluna Vertebral/etiologia
19.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809778

RESUMO

OBJECTIVE: To explore the effect of physical exercise (EXE), strontium ranelate (SR), or their combination on bone status in ovariectomized (OVX) rats. DESIGN: Sixty female Wistar rats were randomized to one of five groups: sham (Sh), OVX (O), OVX+EXE (OE), OVX+SR (OSR), and OVX+EXE+SR (OESR). Animals in EXE groups were subjected to 10 drops per day (45 cm in height); rats in SR groups received 625 mg/kg/day of SR, 5 days/week for 8 weeks. Bone mineral density (BMD) and bone mineral content (BMC, dual-energy X-ray absorptiometry (DXA)), mechanical strength of the left femur (three-point bending test), and femur microarchitecture of (micro-computed tomography imaging, microCT) analyses were performed to characterize biomechanical and trabecular/cortical structure. Bone remodeling, osteocyte apoptosis, and lipid content were evaluated by ELISA and immunofluorescence tests. RESULTS: In OVX rats, whole-body BMD, trabecular parameters, and osteocalcin (OCN) levels decreased, while weight, lean/fat mass, osteocyte apoptosis, and lipid content all increased. EXE after ovariectomy improved BMD and BMC, trabecular parameters, cross-sectional area (CSA), moment of inertia, and OCN levels while decreasing osteocyte apoptosis and lipid content. SR treatment increased BMD and BMC, trabecular parameters, CSA, stiffness, OCN, and alkaline phosphatase (ALP) levels. Furthermore, fat mass, N-telopeptide (NTX) level, osteocyte apoptosis, and lipid content significantly decreased. The combination of both EXE and SR improved bone parameters compared with EXE or SR alone. CONCLUSION: EXE and SR had positive and synergistic effects on bone formation and resorption.


Assuntos
Densidade Óssea/efeitos dos fármacos , Ovariectomia , Condicionamento Físico Animal , Tiofenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Fenômenos Biomecânicos/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Osso Esponjoso/efeitos dos fármacos , Osso Cortical/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Lipídeos/química , Osteócitos/efeitos dos fármacos , Ratos Wistar
20.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919940

RESUMO

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.


Assuntos
Reabsorção Óssea/genética , Fator de Crescimento Insulin-Like I/genética , Osteogênese/efeitos dos fármacos , Proteína Plasmática A Associada à Gravidez/genética , Animais , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Proteínas de Transporte/genética , Colágeno Tipo I/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fator de Crescimento Insulin-Like I/farmacologia , Camundongos , Camundongos Knockout , Osteocalcina/genética , Osteopontina/genética , Caracteres Sexuais
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