Cilostazol and Tocopherol in the Management of Medication-Related Osteonecrosis of the Jaw: New Insights From a Case Report

Esdras Façanha de Carvalho, Maitê Bertotti, Cesar Augusto Migliorati, André Caroli Rocha

J Oral Maxillofac Surg . 2021 Jul 8;S0278-2391(21)00655-8. doi: 10.1016/j.joms.2021.06.036. Online ahead of print.


Several treatment protocols for medication-related osteonecrosis of the jaw (MRONJ) have been published. Despite the efficacy of surgical therapy of approximately 90% as primary therapy, the role of other agents, such as drug administration, should not be underestimated. Based on previous experience with osteoradionecrosis, the association of pentoxifylline and tocopherol has shown encouraging results in MRONJ patients. Despite the need for long-term use of the combination, compliance has been good. However, studies in breast cancer patients revealed that pentoxifylline can require dose reduction or discontinuation due to nausea and epigastric pain. Cilostazol has been used as a substitute for pentoxifylline in peripheral artery disease. Herein we report a case in which cilostazol replaced pentoxifylline at a dose of 100mg, 2 times/day with tocopherol 500UI, 2 times/day, in a 77-year-old female patient that could not tolerate pentoxifylline for the management of MRONJ. After an uneventful 22 months of follow-up, a cone-beam computed tomography revealed complete bone formation and no signs of recurrence. Cilostazol may be a useful and safe alternative to pentoxifylline as part of MRONJ management protocols.

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Association Between Vitamin E and Handgrip Strength in the Korean General Population in KNHANES VII (2018

Nodam Park, Soo A Kim, Kiyoung Oh, Yuntae Kim, Siha Park, Joon Yeop Kim, Namhun Heo

Ann Rehabil Med . 2021 Jun 14. doi: 10.5535/arm.21038. Online ahead of print.


Objective: To investigate the association between vitamin E and handgrip strength (HGS) with multiple factors.

Methods: A total of 1,814 participants were included (822 men and 981 women) from the Korean subjects of the 7th Korea National Health and Nutrition Examination Survey in 2018. Data were analyzed using multiple logistic regression to determine the correlation between vitamin E and HGS with potential confounding factors.

Results: In the multiple logistic regression model, only the young age group (19-40 years) of men showed a positive relationship between vitamin E and HGS. However, in older age groups (41-80 years) of men and all age groups of women, there was no statistically significant result. After adjusting for confounding factors, young men showed higher vitamin E levels and higher HGS. Conversely, women and older age groups did not show significant results after adjusting for confounding factors.

Conclusion: In this study, the serum vitamin E level had a positive effect on HGS in young men (<40 years). Further research is needed on this topic regarding vitamin E intake and other objective measures.

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Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Karl Michaëlsson, Susanna C Larsson

Nutrients . 2021 Jun 5;13(6):1940. doi: 10.3390/nu13061940.


Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10-8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

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Dietary Intake of Vitamin E and Fats Associated with Sarcopenia in Community-Dwelling Older Japanese People: A Cross-Sectional Study from the Fifth Survey of the ROAD Study

Yuta Otsuka, Toshiko Iidaka, Chiaki Horii, Shigeyuki Muraki, Hiroyuki Oka, Kozo Nakamura, Takayuki Izumo, Tomohiro Rogi, Hiroshi Shibata, Sakae Tanaka, Noriko Yoshimura

Nutrients . 2021 May 20;13(5):1730. doi: 10.3390/nu13051730.


Dietary habits are of considerable interest as a modifiable factor for the maintenance of muscle health, especially sarcopenia. The present study aimed to investigate the association between dietary intake and sarcopenia prevalence in community-dwelling Japanese subjects. This cross-sectional study was conducted using data from the fifth survey of the Research on Osteoarthritis/Osteoporosis against Disability (ROAD) study, and 1345 participants (437 men and 908 women) aged ≥60 years were included in the analysis. Sarcopenia was determined by the definition of the Asian Working Group for Sarcopenia established in 2014, and dietary intake was assessed with the brief-type self-administered diet history questionnaire. Overall, 77 subjects (5.7%) were identified as having sarcopenia, 5.0% of men and 6.1% of women. Multiple logistic regression analysis showed that the odds ratios of sarcopenia for the dietary intake of vitamin E (α-tocopherol, 0.14 (CI 0.04-0.49), β-tocopherol (0.24, CI 0.07-0.78), γ-tocopherol (0.28, CI 0.09-0.87), and fats (fat 0.27, CI 0.08-0.96; monounsaturated fatty acids, 0.22, CI 0.07-0.72, polyunsaturated fatty acids, 0.28, CI 0.09-0.89) at the highest quantile were significantly lower compared with those at the lowest quantile. Therefore, higher dietary intakes of vitamin E and fats would be associated with a lower prevalence of sarcopenia.

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Low Serum Vitamin E Level Associated with Low Hand Grip Strength in Community-Dwelling Adults: Korean National Health and Nutrition Examination Survey (KNHANES VII) 2016-2018

Yongjae Kim, Sungjae Shin, Namki Hong, Yumie Rhee

Nutrients . 2021 May 11;13(5):1598. doi: 10.3390/nu13051598.


This study assessed the association between serum vitamin E levels and hand grip strength (HGS) in community-dwelling adults data of 1011 men aged 50 years and older and 1144 postmenopausal women were analyzed. Low HGS was defined as HGS below the sex-stratified median value. Proportion of low HGS was the greatest in the lowest quintile of serum vitamin E level (<10.51 mg/L, 57.1%), with a decreasing trend toward the highest vitamin E quintile (>17.81 mg/L, 43.6%; p < 0.001). A one-unit (mg/L) decrease in vitamin E levels was associated with lower HGS in men (adjusted beta coefficient -0.10, 95% confidence interval [CI] -0.18 to -0.02, p = 0.019), but not in women (-0.01, 95% CI -0.06 to 0.03, p = 0.550). Compared with the middle quintile (Q3; 12.59-14.69 mg/L), the lowest vitamin E quintile (Q1) was associated with elevated odds of low HGS (adjusted odds ratio [aOR]: 1.38, p = 0.045), independent of sociodemographic factors, health-related lifestyles, comorbidities, dietary intake, and cholesterol level. However, the odds of low HGS did not differ significantly in other vitamin E quintiles (Q2, aOR 1.12; Q4, aOR 1.38; Q5, aOR 1.12; p > 0.05). Individuals with the lowest quintile vitamin E level had elevated odds of low HGS independent of covariates, findings which merit further validation.

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Therapeutic potential of annatto tocotrienol with self-emulsifying drug delivery system in a rat model of postmenopausal bone loss

Nur-Vaizura Mohamad, Soelaiman Ima-Nirwana, Kok-Yong Chin

Biomed Pharmacother . 2021 Feb 11;137:111368. doi: 10.1016/j.biopha.2021.111368. Online ahead of print.


Tocotrienol has been shown to prevent bone loss in animal models of postmenopausal osteoporosis, but the low oral bioavailability might limit its use. A self-emulsifying drug delivery system (SEDDS) could increase the bioavailability of tocotrienol. However, evidence of this system in improving the skeletal effects of tocotrienol is scanty. This study aims to evaluate the therapeutic efficacy of annatto tocotrienol with SEDDS in a rat model of postmenopausal bone loss. Ten-month-old female Sprague Dawley rats were randomized into six groups. The baseline group was euthanatized at the onset of the study. Four other groups underwent ovariectomy to induce estrogen deficiency. The sham underwent similar surgery procedure, but their ovaries were retained. Eight weeks after surgery, the ovariectomized rats received one of the four different regimens orally daily: (a) SEDDS, (b) annatto tocotrienol [60 mg/kg body weight (b.w.)] without SEDDS, (c) annatto-tocotrienol (60 mg/kg b.w.) with SEDDS, (d) raloxifene (1 mg/kg b.w.). After eight weeks of treatment, blood was collected for the measurement of delta-tocotrienol level and oxidative stress markers. The rats were euthanized and their bones were harvested for the evaluation of the bone microstructure, calcium content and strength. Circulating delta-tocotrienol level was significantly higher in rats receiving annatto tocotrienol with SEDDS compared to the group receiving unformulated annatto-tocotrienol (p < 0.05). Treatment with unformulated or SEDDS-formulated annatto tocotrienol improved cortical bone thickness, preserved bone calcium content, increased bone biomechanical strength and increased antioxidant enzyme activities compared with the ovariectomized group (p < 0.05). Only SEDDS-formulated annatto tocotrienol improved trabecular microstructure, bone stiffness and lowered malondialdehyde level (p < 0.05 vs the ovariectomized group). The improvement caused by annatto tocotrienol was comparable to raloxifene. In conclusion, SEDDS improves the bioavailability and skeletal therapeutic effects of annatto tocotrienol in a rat model of postmenopausal bone loss. This formulation should be tested in a human clinical trial to validate its efficacy.

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Vitamin E-infused highly cross-linked polyethylene did not reduce the number of in vivo wear particles in total knee arthroplasty

Kumi Orita, Yukihide Minoda, Ryo Sugama, Yoichi Ohta, Hideki Ueyama, Susumu Takemura, Hiroaki Nakamura

Carbohydr Polym . 2021 Jan 1;251:116988. doi: 10.1016/j.carbpol.2020.116988. Epub 2020 Aug 30.


Aims: Vitamin E-infused highly cross-linked polyethylene (E1) has recently been introduced in total knee arthroplasty (TKA). An in vitro wear simulator study showed that E1 reduced polyethylene wear. However there is no published information regarding in vivo wear. Previous reports suggest that newly introduced materials which reduce in vitro polyethylene wear do not necessarily reduce in vivo polyethylene wear. To assist in the evaluation of the newly introduced material before widespread use, we established an in vivo polyethylene wear particle analysis for TKA. The aim of this study was to compare in vivo polyethylene wear particle generation between E1 and conventional polyethylene (ArCom) in TKA.

Methods: A total of 34 knees undergoing TKA (17 each with ArCom or E1) were investigated. Except for the polyethylene insert material, the prostheses used for both groups were identical. Synovial fluid was obtained at a mean of 3.4 years (SD 1.3) postoperatively. The in vivo polyethylene wear particles were isolated from the synovial fluid using a previously validated method and examined by scanning electron microscopy.

Results: The total number of polyethylene wear particles obtained from the knees with E1 (mean 6.9, SD 4.0 × 107 counts/knee) was greater than that obtained from those with ArCom (mean 2.2, SD 2.6 × 107 counts/knee) (p = 0.001). The particle size (equivalent circle of diameter) from the knees with E1 was smaller (mean 0.5 μm, SD 0.1) than that of knees with ArCom (mean 1.5, SD 0.3 μm) (p = 0.001). The aspect ratio of particles from the knees with E1 (mean 1.3, SD 0.1) was smaller than that with ArCom (mean 1.4, SD 0.1) (p < 0.001 ).

Conclusion: This is the first report of in vivo wear particle analysis of E1. E1 polyethylene did not reduce the number of in vivo polyethylene wear particles compared with ArCom in early clinical stage. Further careful follow-up of newly introduced E1 for TKA should be carried out. Cite this article: Bone Joint J 2020;102-B(11):1527-1534.

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Pentoxifylline, tocopherol, and sequestrectomy are effective for the management of advanced osteoradionecrosis of the jaws-a case series

Raíssa Soares Dos Anjos, Giovana Nóbrega de Pádua Walfrido, Rômulo Oliveira de Hollanda Valente, Luiz Alcino Gueiros, Alessandra Albuquerque Tavares Carvalho, Preeyan Patel, Stephen Porter, Jair Carneiro Leão, Igor Henrique Morais Silva

Support Care Cancer . 2020 Oct 27. doi: 10.1007/s00520-020-05847-6. Online ahead of print.


Background: The aim of the present study was to evaluate the efficacy of pentoxifylline and tocopherol for the management of osteoradionecrosis of the jaws.

Methods: Twenty-five patients diagnosed with osteoradionecrosis of the jaws treated with pentoxifylline 400 mg + tocopherol 400 mg three times daily (tid) were evaluated. Clinical records and image tests were reviewed. All patients were previously submitted to head and neck radiation therapy and presented with a clinical and radiographic diagnosis of osteoradionecrosis of the jaws.

Results: Following therapy with pentoxifylline and tocopherol, 76% (19/25) of the patients showed complete mucosal healing, in which 47.3% (9/19) did not undergo sequestrectomy. From this particular group, 77.7% (7/9) were in stage I and 33.3% (3/9) used the protocol for up to 3 months. Among those who underwent to sequestrectomy, complete mucosal healing was observed in 52.7% (10/19). Among these, 60% (6/10) were in stage I and 100% of the patients were using the protocol for more than 3 months. In all other patients, partial healing of the mucosa was observed since they presented advanced disease. These represented 24% of the sample (6/25), 66.6% (4/6) were in stage III, and 60% (4/6) used the protocol for over 6 months.

Conclusion: Pentoxifylline and tocopherol may provide effective management of osteoradionecrosis of the jaws, and the association with sequestrectomy may avoid major surgical procedures.

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Quercetin and vitamin E alleviate ovariectomy-induced osteoporosis by modulating autophagy and apoptosis in rat bone cells

Sina Vakili, Fatemeh Zal, Zohreh Mostafavi-Pour, Amir Savardashtaki, Farhad Koohpeyma

J Cell Physiol . 2020 Oct 8. doi: 10.1002/jcp.30087. Online ahead of print.


Osteoporosis is the most prevalent metabolic bone disease and one of the most important postmenopausal consequences. The aim of this study was to investigate the effects of quercetin (Q) and vitamin E (vitE) on ovariectomy-induced osteoporosis. Animals were ovariectomized and treated with Q (15 mg/kg/day), vitE (60 mg/kg/day), estradiol (10 µg/kg/day), and Q (7.5 mg/kg/day) + vitE (30 mg/kg/day) for 10 weeks by gavage, and osteoporosis markers and messenger RNA (mRNA) expression of autophagy and apoptosis-related genes were analyzed in serum and tibia of rats. Data indicated that ovariectomy resulted in development of osteoporosis as demonstrated by reduction in serum calcium, bone weight, bone volume, trabeculae volume, and the total number of osteocytes and osteoblasts, and increase in the total number of osteoclasts and serum osteocalcin. Total mRNA expressions of LC3, beclin1, and caspase 3 were also increased and bcl2 expression was decreased in the tibia. By reversing these changes, treatment with Q and vitE markedly improved osteoporosis. In conclusion, Q, and to a lesser extent, vitE, prevented osteoporosis by regulating the total number of bone cells, maybe through regulating autophagy and apoptosis.

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Pentoxifylline and tocopherol protocol to treat medication-related osteonecrosis of the jaw: A systematic literature review

Rafael Correia Cavalcante, Guilherme Tomasetti

J Craniomaxillofac Surg . 2020 Sep 18;S1010-5182(20)30206-7. doi: 10.1016/j.jcms.2020.09.008. Online ahead of print.


Purpose: Medication-related osteonecrosis of the jaw (MRONJ) is a previously described debilitating condition in which patients experience progressive bone destruction in the maxilla and/or mandible after exposure to certain drugs. Clinical management of MRONJ remains controversial, with no established guidelines. The aim of our study was to conduct a literature review on the effectiveness of pentoxifylline (PTX) and tocopherol (PENTO protocol) on MRONJ.

Study design: A literature review was conducted, using two different scientific databases, to evaluate the effects of PTX and tocopherol on MRONJ.

Discussion: PENTO protocol prescription to treat MRONJ was reported to be well tolerated, with minimal side-effects, and non-expensive when compared with other non-surgical treatment modalities. It was shown to relieve painful symptoms in all patients, and significant new bone formation was observed at final follow-up.

Conclusion: Observational and case-series studies have demonstrated that pentoxifylline and tocopherol are potentially useful in the non-surgical management of MRONJ.

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