Sildenafil delays bone remodeling of fractured femora in aged mice by reducing the number and activity of osteoclasts within the callus tissue.

The elderly exhibit a reduced healing capacity after fracture, which is often associated with delayed or failed bone healing. This is due to a plethora of factors, such as an impaired bone vascular system and delayed angiogenesis. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil exerts pro-angiogenic and pro-osteogenic effects. Hence, we herein investigated in aged mice whether sildenafil can improve fracture healing. For this purpose, 40 aged CD-1 mice (16-18 months) were daily treated with 5 mg/kg body weight sildenafil (n = 20) or vehicle (control, n = 20) by oral gavage. The callus tissue of their femora was analyzed at 2 and 5 weeks after fracture by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry as well as Western blotting. These analyses revealed a significantly increased bone volume and higher ratio of callus to femoral bone diameter in sildenafil-treated mice at 5 weeks after fracture when compared to controls. This was associated with a reduced number and activity of osteoclasts at 2 weeks after fracture, most likely caused by an increased expression of osteoprotegerin (OPG). Taken together, these findings indicate that sildenafil does not improve fracture healing in the elderly but delays the process of bone remodeling most likely by reducing the number and activity of osteoclasts within the callus tissue.

Towards understanding how bisphosphonate-dependent alterations to nutrient canal integrity can contribute to risk for atypical femoral fractures: Biomechanical considerations and potential relationship to a real-world analogy.

Bisphosphonates are a class of drugs which have shown good efficacy in the treatment of post-menopausal osteoporosis, as well as a good safety profile. However, side-effects such as risk for atypical femoral fractures (AFF) have appeared, leading to a decline in use of the drugs by many patients who would benefit from the treatment. While patient characteristics have contributed to improved understanding of risk factors, the mechanisms involved that explain AFF risk have not appeared. Recently, the possibility that the mechanism(s) involved drug-induced modification of cells of the nutrient canals of the femur and subsequent compromise in the bone matrix has been published. The present Hypothesis article builds on the concept presented earlier and expands into biomechanical considerations. An analogy of the mechanisms involved to a real-life scenario is also presented. While this analogy has limitations, consideration of the biomechanical implications of progressive alterations to defects presented by compromised nutrient canal-bone matrix also presents potential relationships with AFF risk.

The effects of hydroxychloroquine-induced oxidative stress on fracture healing in an experimental rat model.

OBJECTIVES: The purpose of this study was to investigate whether hydroxychloroquine (HCQ) sulfate causes oxidative stress (OS) and its effect on fracture healing in an experimental rat model. MATERIALS AND METHODS: In this experimental study, open diaphyseal femur fractures were induced in 24 eight-week-old male rats (mean weight: 225±25 g; range, 200 to 250 g) and then fixed with K-wire. The rats were divided into four groups: HCQ-2, control-2 (C-2), HCQ-4, and control-4 (C-4). During the study period, rats in the HCQ groups received an HCQ solution (160 mg/kg/day), whereas rats in the control groups received saline. The HCQ-2 and C-2 groups were sacrificed on the 14th day, and the HCQ-4 and C-4 groups were sacrificed on the 28th day. After sacrifice, malondialdehyde levels induced by OS were calculated for each rat, and fracture healing was evaluated radiographically, histomorphometrically, histopathologically, and immunohistochemically. RESULTS: Malondialdehyde levels were higher in the HCQ groups than in the control groups (p<0.05). Hydroxychloroquine caused OS in rats. The ratio of total callus diameter to femur bone diameter was lower in HCQ groups compared to control groups (p<0.05). No differences were observed when comparing radiological and histological healing results between the control and HCQ groups. Alkaline phosphatase levels were lower in the HCQ-4 group than the C-4 group at week four (p<0.05), although osteocalcin and osteopontin levels did not differ between groups (p>0.05). Oxidative stress had no adverse effects on histologic healing outcomes and osteoblast functions. Cathepsin K and tartrate-resistant acid phosphatase-5b levels were higher in the HCQ-4 group than in the C-4 group (p<0.05). While the number and function of osteoclasts increased due to OS in callus tissue, a decrease in the number of chondrocytes was observed. CONCLUSION: Hydroxychloroquine-induced OS increases the number and function of osteoclasts and decreases the number of hypertrophic chondrocytes and endochondral ossification but has no significant effect on mid-late osteoblast products and histological fracture healing scores.

Factors Affecting the Second Complete Atypical Femoral Fracture after the First Atypical Fracture.

OBJECTIVES: Atypical femoral fracture (AFF) is an atypical low-energy subtrochanteric and diaphyseal femoral fracture. Even if bone fusion is achieved in patients with AFF, the risk of AFF in the contralateral femur must be considered. This study aimed to investigate the factors affecting complete AFF in the contralateral femur and conservatively treated incomplete AFF. SUBJECT AND METHODS: Radiographs of 111 femurs in 104 AFF cases were examined, and the femurs were classified as follows: 85 contralateral femurs with complete AFF; 18 contralateral femurs with incomplete AFF; 8 femurs with incomplete AFF without surgical treatment. Various patients' clinical data were collected, and we investigated the factors affecting the second complete AFF. RESULTS: Complete fractures occurred in 10 (9.7%) of 103 femurs without incomplete AFF at the first visit and in 3 (37.5%) of 8 femurs with incomplete AFF. The Kaplan-Meier curve revealed that lateral cortical bone thickening and thigh pain were associated with significantly poorer prognoses (p = 0.026 and p = 0.013, respectively). Multivariate analyses revealed that eldecalcitol usage after AFF onset (p = 0.0094) and previous use of bisphosphonate or denosumab (p = 0.0126) were protective factors for second complete AFF and that the presence of thigh pain (p = 0.0134) was a risk factor for second complete AFF. CONCLUSIONS: Eldecalcitol administration after bone union of first AFF may prevent AFF recurrence. In addition, painful incomplete AFF has a high risk of developing a complete fracture.

The effects of cephalexin on fracture healing in a rat femur fracture model.

OBJECTIVES: The aim of this study was to examine the effects of cephalexin on the fracture union histomorphometrically, radiologically, biomechanically, immunohistochemically, and histopathologically in a rat femur fracture model and to evaluate the effects of the antibiotics to be used in the prophylaxis of fracture infection on the union of the fracture. MATERIALS AND METHODS: A total of 48 male Wistar rats were divided into four groups as two-week control (C2) and cephalexin (CEP2) and four-week control (C4) and cephalexin (CEP4). After establishment of standard fracture model on right femurs, 60 mg/kg/day of cephalexin was applied to CEP2 and CEP4 by oral gavage. Radiological, biomechanical, histopathological, immunohistochemical, and histomorphometric examinations were performed on amputated femurs. RESULTS: Callus volume of CEP4 group significantly increased compared to CEP2 group (p=0.005), while no significant difference was found in the bone mineral density and callus/bone volume among the groups (p>0.05). There was no significant difference in flexural strength between the C4 and CEP4 groups (p=0.093). Histological healing scores increased from Week 2 to Week 4 (p=0.002) and inflammation scores decreased in both control and cephalexin groups (p=0.010 and p=0.008); however, no significant difference was found in healing and inflammation scores (p>0.05). The CD34+ immunoreactivity in the CEP2 group was significantly higher than the C2 group (p=0.029). Collagen type III level was significantly lower in the CEP2 and CEP4 groups compared to the corresponding control groups (p=0.008 and p=0.016, respectively). CONCLUSION: Cephalexin did not exert any radiological, histopathological, histomorphometric, biomechanical, and immunohistochemical adverse effects on the femoral fracture healing model in rats; however, it showed positive effects on CD34 and Collagen type III levels. Based on these findings, antibiotherapy with cephalexin may be considered as a safe treatment for fracture union.

Diclofenac, a NSAID, delays fracture healing in aged mice.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, belong to the most prescribed analgesic medication after traumatic injuries. However, there is accumulating evidence that NSAIDs impair fracture healing. Because bone regeneration in aged patients is subject to significant changes in cell differentiation and proliferation as well as a markedly altered pharmacological action of drugs, we herein analyzed the effects of diclofenac on bone healing in aged mice using a stable closed femoral facture model. Thirty-three mice (male n = 14, female n = 19) received a daily intraperitoneal injection of diclofenac (5 mg/kg body weight). Vehicle-treated mice (n = 29; male n = 13, female n = 16) served as controls. Fractured mice femora were analyzed by means of X-ray, biomechanics, micro computed tomography (µCT), histology and Western blotting. Biomechanical analyses revealed a significantly reduced bending stiffness in diclofenac-treated animals at 5 weeks after fracture when compared to vehicle-treated controls. Moreover, the callus tissue in diclofenac-treated aged animals exhibited a significantly reduced amount of bone tissue and higher amounts of fibrous tissue. Further histological analyses demonstrated less lamellar bone after diclofenac treatment, indicating a delay in callus remodeling. This was associated with a decreased number of osteoclasts and an increased expression of osteoprotegerin (OPG) during the early phase of fracture healing. These findings indicate that diclofenac delays fracture healing in aged mice by affecting osteogenic growth factor expression and bone formation as well as osteoclast activity and callus remodeling.

The effect of teriparatide on fracture healing after atypical femoral fracture: A systematic review and meta-analysis.

This meta-analysis demonstrated that a greater prevalence of delayed union and nonunion and a longer time to fracture healing in the group that did not receive TPTD treatment after AFFs than in the group that received TPTD treatment. PURPOSE: To date, there is no hard evidence for medical management after atypical femoral fracture (AFF), even though weak data indicate faster healing with teriparatide (TPTD). Herein, we aimed to investigate the effect of postfracture TPTD treatment on AFF healing using a pairwise meta-analysis focusing on delayed union, nonunion, and fracture healing time. METHODS: A systematic search of the MEDLINE (PUBMED), Embase, and Cochrane Library databases was performed for studies investigating the effect of TPTD after AFF up to October 11, 2022. We compared the incidence of delayed union and nonunion and the time of fracture healing between the TPTD ( +) and TPTD (-) groups. RESULTS: The 6 studies analyzed a total of 214 AFF patients, including 93 who received TPTD therapy after AFF and 121 who did not. The pooled analysis showed a significantly higher rate of delayed union in the TPTD (-) group than in the TPTD ( +) group (OR, 0.24; 95% CI, 0.11-0.52; P < 0.01; I2 = 0%), and a higher nonunion rate was observed in the TPTD (-) group than in the TPTD ( +) group with low heterogeneity (OR, 0.21; 95% CI, 0.06-0.78; P = 0.02; I2 = 0%). The TPTD (-) group required 1.69 months longer to achieve fracture union than the TPTD ( +) group, with statistical significance (MD = - 1.69, 95% CI: - 2.44 to - 0.95, P < 0.01; I2 = 13%). Subgroup analysis for patients with complete AFF showed that the TPTD (-) group had a higher rate of delayed union with low heterogeneity (OR, 0.22; 95% CI, 0.10-0.51; P < 0.01; I2 = 0%), but there was no significant difference in the nonunion rate between TPTD ( +) and TPTD (-) groups (OR, 0.35; 95% CI, 0.06-2.21; P = 0.25; I2 = 0%). Fracture healing took significantly longer in the TPTD (-) group (MD = - 1.81, 95% CI: - 2.55 to - 1.08; P < 0.01; I2 = 48%). The reoperation rate showed no significant difference between the two groups (OR, 0.29; 95% CI, 0.07-1.20; P = 0.09; I2 = 0%). CONCLUSIONS: The current meta-analysis supported the hypothesis that TPTD treatment following AFF might benefit fracture healing, lowering the rate of delayed union and nonunion and shortening the fracture healing time.

Antibiotic cement-coated rigid locked nails in infected femoral and tibial nonunion. Reoperation rates of commercial versus custom-made nails.

INTRODUCTION: The objective of this study is to assess bone union, infection control, and reoperation rates in a series of patients with infected femoral or tibial nonunion treated with antibiotic-cement-coated rigid nails and to compare the results obtained with custom-made nails versus commercial nails. METHODS: We retrospectively analyzed a series of consecutive patients with infected nonunion of the femur or the tibia treated with antibiotic-cement-coated rigid nails between January 2010 and 2020. We assessed patients' distinctive characteristics, initial injury, type of nail used (custom-made nail with vancomycin or commercial nail with gentamicin), success rate (bone union + infection control), reoperation rate, and failure rate. Comparative analyses were conducted between reoperated and non-reoperated patients regarding the type of nail used. A multivariate regression analysis was performed to assess the risk variables that impacted reoperation rates. RESULTS: We included 54 patients with 22 (40.74%) infected femoral nonunions and 32 (59.25%) tibial nonunions, who were treated with 38 (70.37%) custom-made antibiotic-cement coated nails and 16 (29.62%) commercial nails. Bone union and infection control were achieved in 51 (94.44%) cases. The reoperation rate was 40.74% (n = 22), and the failure rate was 5.55% (n = 3). The use of custom-made nails was associated with a higher risk of reoperation (Odds Ratio 4.71; 95% Confidence Interval 1.10 - 20.17; p = 0.036). CONCLUSION: Antibiotic-cement-coated nails reached a 94.44% success rate. Nails manufactured in the OR coated with vancomycin cement were associated with a higher risk of reoperation than commercial nails loaded with gentamicin cement. LEVEL OF EVIDENCE: III comparative, observational, non-randomized.

Effect of Vancomycin Applied to the Surgical Site on Fracture Healing in a Diabetic Rat Model.

BACKGROUND: Prophylactic vancomycin treatment decreases the prevalence of surgical site and deep infections by >70% in diabetic patients undergoing reconstructive foot and ankle surgery. Thus, determining whether clinically relevant local vancomycin doses affect diabetic fracture healing is of medical interest. We hypothesized that application of vancomycin powder to the fracture site during surgery would not affect healing outcomes, but continuous exposure of vancomycin would inhibit differentiation of osteoblast precursor cells and their osteogenic activity in vitro. METHODS: The vancomycin dose used to treat the diabetic rats was a modest increase to routine surgical site vancomycin application of 1 to 2 g for a 70-kg adult (21 mg/kg). After femur fracture in BB-Wistar type 1 diabetic rats, powdered vancomycin (25 mg/kg) was administered to the fracture site. Bone marrow and periosteal cells isolated from diabetic bones were cultured and treated with increasing levels of vancomycin (0, 5, 50, 500, or 5000 µg/mL). RESULTS: Radiographic scoring, micro-computed tomography (µCT) analysis, and torsion mechanical testing failed to identify any statistical difference between the vancomycin-treated and the untreated fractured femurs 6 weeks postfracture. Low to moderate levels of vancomycin treatment (5 and 50 µg/mL) did not impair cell viability, osteoblast differentiation, or calcium deposition in either the periosteum or bone marrow-derived cell cultures. In contrast, high doses of vancomycin (5000 µg/mL) did impair viability, differentiation, and calcium deposition. CLINICAL RELEVANCE: In this diabetic rodent fracture model, vancomycin powder application at clinically relevant doses did not affect fracture healing or osteogenesis.

Race, Gender, and Primary Language Were Not Associated With Changes in Opioid Prescribing in Children: Results From a Single Institution, 2010 to 2020.

BACKGROUND: Patients should be prescribed medication based on their medical condition, without prejudice because of their race, gender, or primary language. However, previous research has shown that men are prescribed more medication than women, patients who are White are prescribed more medications than patients who are non-White, and English-speaking people are prescribed more medications than non-English-speaking patients. However, it is unclear whether these differences also occur in pediatric orthopaedic populations. QUESTIONS/PURPOSES: We asked: (1) Was the amount of opiates prescribed at discharge associated with patient age, gender, race, or primary language? (2) Did the amount of opiates prescribed to patients at discharge change from 2010 to 2020? METHODS: In a single center, between January 2010 and December 2019, we treated 331 patients younger than 18 years surgically for upper and lower long-bone extremity fractures. Patients were considered eligible if they had a nonpathologic fracture. Femur fractures were not included. Based on these criteria, all patients were eligible. The mean age was 12 ± 4 years. The mean weight was 57 ± 33 kg. Among these patients, 76% (253 of 331) were boys and 24% (78 of 331) were girls. From the hospital discharge records, we recorded the amount of opiates prescribed at the time of discharge as measured by morphine milligram equivalents (MMEs). We examined the association of age, gender, race, primary language, weight, and year of treatment using this measurement. We determined a patient's race retrospectively by information given by their parents at time of admission. We did not attempt to contact patients to obtain more nuanced information about their racial background. These data were obtained from the electronic health record. The Wilcoxon rank sum test, t-test, or chi-square test was used to assess associations depending on the distribution of variables, as appropriate. Because opioids as measured in MMEs is zero-inflated, a two-part model analysis was used to adjust for confounding variables. One component of the model was for the probability of having any opiate prescription and another was for the mean number of opioids received. Findings were considered statistically significant if p values were < 0.05. RESULTS: In total, 57% (189 of 331) of children were prescribed opiates at discharge after surgery for long-bone fractures. Opiate MMEs increased with patient age (r = 0.38; p < 0.01). Boys and girls showed no difference in the amounts of pain medication (adjusted odds ratio [OR] 1.38 [95% confidence interval (CI) 0.80 to 2.39]; p = 0.71; adjusted opioid difference: 0.35 MME [95% CI -51.7 to 52.4]; p = 0.99), nor were there differences between patients who were White and those who were non-White (adjusted OR 0.78 [95% CI 0.49 to 1.23]; p = 0.28; adjusted opioid difference: 21.5 MME [95% CI -19.3 to 62.4]; p = 0.30), or between patients for whom English was there primary language and those for whom English was not their primary language (adjusted OR 1.16 [95% CI 0.52 to 2.57]; p = 0.71; adjusted opioid difference: 22.7 MME [95% CI -55.7 to 101.3]; p = 0.57) when adjusted for age and weight. There was no change in opioid prescription amounts from 2010 to 2020 after adjusting for changes in patient age across years (Spearman r = -0.08; p = 0.16). CONCLUSION: Fairness in opioid prescribing based on race, gender, or primary language is possible. Additional research is needed to determine what factors in our institution led to this result. We suggest that prescribers should apply consistent protocols based on factors such as weight or injury type rather than making individual decisions for each patient. This will lead to fairer opioid prescribing to patients from different race and gender groups. LEVEL OF EVIDENCE: Level III, therapeutic study.

Unveiling the Time Course Mechanism of Bone Fracture Healing by Transcriptional Profiles.

BACKGROUND: Bone fracture healing is a time-consuming and high-priority orthopedic problem worldwide. OBJECTIVE: Discovering the potential mechanism of bone healing at a time course and transcriptional level may better help manage bone fracture. METHODS: In this study, we analyze a time-course bone fracture healing transcriptional dataset in a rat model (GSE592, GSE594, and GSE1371) of Gene Expression Omnibus (GEO). RNA was obtained from female Sprague-Dawley rats with a femoral fracture at the initial time (day 3) as well as early (week 1), middle (week 2), and late (week 4) time periods, with nonfracture rats used as control. Gene Ontology (GO) functional analysis and pathway examinations were performed for further measurements of GSEA and hub genes. RESULTS: Results indicated that the four stages of bone fracture healing at the initial, early, middle, and late time periods represent the phases of hematoma formation, callus formation, callus molding, and mature lamellar bone formation, respectively. Extracellular organization was positively employed throughout the four stages. At the hematoma formation phase, the muscle contraction process was downregulated. Antibacterial peptide pathway was downregulated at all phases. The upregulation of Fn1 (initial, early, middle, and late time periods), Col3a1 (initial, early, and middle time periods), Col11a1 (initial and early time periods), Mmp9 (middle and late time periods), Mmp13 (early, middle, and late time periods) and the downregulation of RatNP-3b (initial, early, middle, and late time periods) were possible symbols for bone fracture healing and may be used as therapeutic targets. CONCLUSION: These findings suggest some new potential pathways and genes in the process of bone fracture healing and further provide insights that can be used in targeted molecular therapy for bone fracture healing.

Risks of femoral localized periosteal thickening in patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. METHODS: We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). RESULTS: LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. CONCLUSIONS: LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.

Local zinc treatment enhances fracture callus properties in diabetic rats.

The effects of locally applied zinc chloride (ZnCl2 ) on early and late-stage parameters of fracture healing were evaluated in a diabetic rat model. Type 1 Diabetes has been shown to negatively impact mechanical parameters of bone as well as biologic markers associated with bone healing. Zinc treatments have been shown to reverse those outcomes in tests of nondiabetic and diabetic animals. This study is the first to assess the efficacy of a noncarrier mediated ZnCl2 on bony healing in diabetic animals. This is a promising basic science approach which may lead to benefits for diabetic patients in the future. Treatment and healing were assessed through quantification of callus zinc, radiographic scoring, microcomputed tomography (µCT), histomorphometry, and mechanical testing. Local ZnCl2 treatment increased callus zinc levels at 1 and 3 days after fracture (p ≤ 0.025). Femur fractures treated with ZnCl2 showed increased mechanical properties after 4 and 6 weeks of healing. Histomorphometry of the ZnCl2 -treated fractures found increased callus cartilage area at Day 7 (p = 0.033) and increased callus bone area at Day 10 (p = 0.038). In contrast, callus cartilage area was decreased (p < 0.01) after 14 days in the ZnCl2 -treated rats. µCT analysis showed increased bone volume in the fracture callus of ZnCl2 -treated rats at 6 weeks (p = 0.0012) with an associated increase in the proportion of µCT voxel axial projections (Z-rays) spanning the fracture site. The results suggest that local ZnCl2 administration improves callus chondrogenesis leading to greater callus bone formation and improved fracture healing in diabetic rats.

Factors affecting healing and progression of conservatively treated incomplete atypical femoral fractures: retrospective observational study.

INTRODUCTION: Incomplete atypical femoral fractures (iAFF) may occur with prolonged bisphosphonate usage. Factors influencing iAFF healing and progression are not well understood. This study of conservatively managed iAFF assessed factors influencing iAFF healing and progression including the effects of bisphosphonates and teriparatide use. MATERIALS AND METHODS: Single-center retrospective observational study of 69 consecutive patients with 78 radiographically confirmed iAFF from 2002 to 2017. Serial radiographs assessed for focal cortical thickening, dreaded black line (DBL) and complete fracture. Chief outcome measures were DBL healing and complete fracture. RESULTS: DBL had a significant association (p < 0.05) with fracture progression by multivariable logistic regression (55.8% versus 25.7%, odds ratio [OR] 26.57 (95% CI 1.40-504.78)) and shorter fracture-free survival (mean 3.21 versus 6.27 years). Presence of symptoms was associated with shorter fracture-free survival (mean 2.68 versus 5.98 years). Discontinuing bisphosphonates had significant associations (p < 0.001) by multivariable logistic regression with decreased fracture rate (11.6% versus 92.0%; OR 0.00, 95% CI 0.00-0.08) and longer fracture-free survival (mean 7.52 versus 1.99 years). DBL healing occurred in 36.4%, only when bisphosphonates were discontinued. Age, sex, race, fracture site, glucocorticoid use, teriparatide supplementation and duration of bisphosphonate use showed no statistically significant effect although teriparatide use appeared to improve DBL healing (50% versus 17.9%, p = 0.188). CONCLUSIONS: In conservatively managed iAFF, DBL healing occurred in 36.4% if bisphosphonates were discontinued. Bisphosphonates and DBL were significantly associated with fracture progression and together with symptoms with fracture survival.

Sedative use and incidence of falls and hip fractures among older adults in an outpatient geriatric clinic / Perfil de uso de sedativos e ocorrência de quedas e fratura de fêmur entre idosos em um ambulatório de geriatria

OBJECTIVE: To investigate the use of sedatives by older adults attending a private outpatient geriatric clinic in Belo Horizonte (MG), Brazil, and its association with falls and hip fractures. METHODS: Using a longitudinal design, the prevalence of benzodiazepine and nonbenzodiazepine ("z-drugs") intake by older adults was described and their association with the incidence of falls and fractures (30 days after the initial visit) was evaluated through logistic regression. RESULTS: A total of 7821 older adults were included in the study, most of them women (72.50%), with a mean age of 77.5 years and a mean Clinical-Functional Vulnerability Index (IVCF-20) score of 16.5. The overall prevalence of sedative use (any sedative) was 6.19%, with 4.48% benzodiazepines and 1.98% z-drugs. The most widely used sedatives were clonazepam (29.04%), zolpidem (28.65%), and alprazolam (23.44%). Falls were reported for 182 patients (2.33%), with a higher incidence among users of any sedatives (4.34; p = 0.002; OR = 1.94, adjusted for sex, age, and IVCF-20) and benzodiazepines (5.14%; p < 0.001; OR = 2.28) than among non-users (2.19%). Hip fractures occurred in 33 patients (0.42%), and again were more frequent among users of sedatives (1.03%; p = 0.032; OR = 2.57) and benzodiazepines (1.43%; p = 0.003; OR = 3.45) than among non-users (0.38%). CONCLUSIONS: The use of sedatives, especially benzodiazepines, is associated with an increased incidence of falls and hip fractures in older adults

OBJETIVO: Investigar a utilização de sedativos entre idosos atendidos em ambulatório privado de geriatria em Belo Horizonte (MG), bem como sua associação com quedas e fraturas de fêmur. METODOLOGIA: Trata-se de estudo longitudinal, no qual foi descrita a prevalência de uso de benzodiazepínicos e drogas Z entre idosos (60 anos ou mais) e avaliada sua associação com a incidência de queda e fratura (30 dias após consulta inicial) por meio de regressão logística. RESULTADOS: Foram incluídos no estudo 7821 idosos, com maioria feminina (72,50%), idade média de 77,5 anos e Índice de Vulnerabilidade Clínico Funcional (IVCF-20) médio de 16,5 pontos. A prevalência de uso de sedativos em geral foi de 6,19%, sendo 4,48% de benzodiazepínicos e 1,98% de drogas Z. Os medicamentos sedativos mais utilizados foram clonazepam (29,04%), zolpidem (28,65%) e alprazolam (23,44%). Relatou-se queda para 182 idosos (2,33%), com incidência maior entre usuários de sedativos (4,34; p = 0,002; OR = 1,94 ajustada por sexo, idade e IVCF-20) e de benzodiazepínicos (5,14%; p < 0,001; OR = 2,28) do que entre não usuários (2,19%). Identificou-se fratura de fêmur em 33 idosos (0,42%), sendo mais frequente entre usuários de sedativos (1,03%; p = 0,032; OR = 2,57) e de benzodiazepínicos (1,43%; p = 0,003; OR = 3,45) do que entre não usuários (0,38%). CONCLUSÃO: Concluiu-se que a incidência de quedas e fraturas de fêmur em idosos possui associação com o uso de medicamentos sedativos, em especial os benzodiazepínicos

Case report: Clinical characteristics and treatment of secondary osteoporosis induced by X-linked congenital adrenal dysplasia.

Objective: To summarize the clinical features and bone complications in a patient from a large family with X-linked congenital adrenocortical hypoplasia (AHC) and evaluate the efficacy of different treatment regimens on the prognosis of secondary osteoporosis caused by AHC at a 5-year follow-up. Methods: A large family with AHC was recruited, and the causative gene mutation was identified by Sanger sequencing in the proband. Clinical features as well as radiological examinations and laboratory indices of osteoporosis secondary to AHC were analyzed in this study. Meanwhile, the proband was treated with classical antiresorptive drugs (bisphosphonates) for 2 years and switched to a vitamin K2 analogue for another 3 years, during which the efficacy of the drugs was evaluated. Results: The proband was identified as carrying a homozygous insertion mutation (p. Thr193GlyfsX13) in the NR0B1 (nuclear receptor subfamily 0, group B, member 1) gene, resulting in a premature stop codon due to a frameshift mutation. During treatment and follow-up, the proband did not respond well to bisphosphonate and developed atypical femoral fractures. Vitamin K2 improved clinical symptoms. In terms of bone mineral density (BMD), there is no evidence of any effect of vitamin K2 on the neck of femur, though some minor effects on spinal BMD cannot be excluded. Conclusions: Secondary osteoporosis induced by AHC deserves clinical attention. Unlike in primary osteoporosis, the curative effect of bisphosphonates was unsatisfactory and was more likely to cause atypical femoral fractures in long-term treatment. It is suggested that bone anabolic drugs may be better alternatives.

The effect of combined drug therapy in lateral fragility fractures of the femur: a prospective observational study.

OBJECTIVE: Due to a growing number of lateral fragility fractures, and their high economic and social impact, we evaluated the combined drug therapy effectiveness in lateral fragility femur fractures treated by intramedullary nailing surgery comparing the clinical and radiological results of two groups of patients. PATIENTS AND METHODS: From May 2019 to March 2020, we carried out a prospective observational study comparing the results of patients with femoral lateral fractures treated by the same intramedullary nail (PFNA Synthes®) using Clodronic acid and Vitamin D (study group, 25 patients) compared to patients with the same fractures treated with Vitamin D alone (control group, 25 patients). The evaluations were based on bone biochemical markers (serum calcium level, serum phosphate level, parathyroid hormone, Vitamin D, serum C-terminal telopeptide), Visual Analogic Scale and HHS (Harris Hip Score) score, and femur densitometric views. In order to evaluate the femur neck mineral bone density (BMD), two areas have been identified on the Anterior-Posterior view: the Region of Interest (ROI)1 (under the head screw) and the ROI2 (above the femoral screw). The BMD has been calculated using femur densitometric views at T0 (1st day post-surgery) and at T1 (12 months later). RESULTS: As far as the BMD average of ROI1 is concerned, we found a significant statistical increase at T1 in the study group (0.93±0.07 gr/cm2) vs. control group (0.88±0.08 gr/cm2), p=0.04. Both biochemical and densitometric values were statistically increased in the study group from T0 to T1 (p<0.05), while control group showed an improvement in the biochemical values only. CONCLUSIONS: Thanks to a one year follow-up, we are able to demonstrate that the administration of an adequate drug therapy after surgery can lead to a better control of the bone remodeling and reabsorption process.

Tranexamic acid in pertrochanteric fractures: a retrospective analysis of perioperative outcomes after fixation with a proximal femoral nail.

BACKGROUND: Treatment of pertrochanteric femoral fractures is often associated with significant blood loss. It has already been demonstrated that the administration of tranexamic acid (TXA) for endoprosthetic procedures reduces blood losses and leads to a decreased frequency of postoperative complications. The aim of this study is to demonstrate whether the administration of TXA as part of osteosynthesis treatment for pertrochanteric fractures using a proximal femoral nail reduces perioperative blood losses and haemorrhage-related complications. METHODS: In a two-centre retrospective cohort study, 1 g TXA i.v. was administered preoperatively to 294 patients who had suffered from pertrochanteric femoral fractures. The subjects were compared clinically to a historical control group who did not receive TXA (nonTXA). Outcomes were evaluated on the basis of perioperative blood loss, transfusion requirement, and occurrence of complications. RESULTS: The TXA group showed evidence of a reduction in blood loss (TXA = 0.97 ± 0.47 l; nonTXA = 1.06 ± 0.47 l; p = 0.004) and a lower frequency of transfusion (TXA = 20%; nonTXA = 31%; p = 0.032) as compared to the nonTXA group. However, evidence of this therapeutic effect could only be demonstrated at one of the centres on subgroup comparison between the two centres. At the second centre, the data did not show a significant difference. A trend could be seen towards a reduction in postoperative renal failure. No complications occurred resulting from the administration of tranexamic acid. CONCLUSION: Preoperative administration of TXA does not lead to an increased rate of thromboembolic complications when applied for treatment of pertrochanteric femoral fractures. Evidence of a positive effect could be seen in principle in relation to the reduction in perioperative blood loss and the frequency of transfusion. The difference in effect between the two centres remains to be clarified: for this reason, it is possible to assume that further factors influencing the efficacy of TXA administration are at play which were not taken into account in this study.

Kefir peptides promote osteogenic differentiation to enhance bone fracture healing in rats.

AIMS: Fractures are the result of fragile bone structures after trauma caused by direct or indirect external impact or strong muscular contraction. Most fracture patients undergo surgical fixation to accelerate the healing process and restore the function of mutilated bone. Promoting the healing process remains an important issue for the treatment of bone fractures. Our previous studies demonstrated the remarkable bone-protective effects of kefir peptides (KPs) in ovariectomized rats and mice. In this study, we further evaluate the efficacy of KPs on fracture healing using a rat model of femoral fracture. MAIN METHODS: Fifteen 8-week-old male Sprague Dawley (SD) rats were divided into the sham, mock, and KPs groups, in which the mock and the KPs groups underwent femur-fracture surgery with nail fixation, while the sham group underwent a sham operation. The next day, rats were orally administered with daily 400 mg/kg of KPs (KPs group) or distilled water (sham and mock groups) for four weeks. X-ray imaging, histochemical staining and serum osteogenic markers were applied for fracture healing evaluation. In vitro, mouse bone marrow mesenchymal stem cells (BMMSCs) and MC3T3-E1 line were subjected to osteoblast differentiation in the presence of KPs and compared with no KPs treatment. KEY FINDINGS: The results demonstrated that KPs treatment improved the progression of the fracture healing process (p < 0.05) and significantly increased the expressions of Col1a1, Alp, Spp1, Vegfa and Cox2 mRNA in the femurs of the KPs-treated fractured rats compared to those of the mock-treated fracture rats. In vitro, KPs treatment promoted bone regeneration factor (Col1a1, Alp, M-csf and Phospho1) expression in MC3T3-E1-derived osteoblast cultures (on Day 3) and enhanced osteogenic differentiation and mineralization in BMMSC-derived osteoblast cultures (on Day 17 and Day 21). SIGNIFICANCE: This is the first study to show that KPs can help with fracture healing by promoting osteogenic differentiation, and it also suggests that KPs can be used as a nutritional supplement to accelerate fracture healing.