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Objective: The osteoclastic bone resorption inhibitors might have positive effect in preventing femoral head collapse in patients with osteonecrosis of the femoral head (ONFH). However, as a novel osteoclastic inhibitor, whether denosumab can prevent collapse in steroid‐induced ONFH remains unknown. This study aims to evaluate the treatment effect of denosumab and the potential protective mechanism. Methods: This was a retrospective study. A total of 161 patients with steroid‐induced ONFH who underwent denosumab treatment were reviewed, and 209 untreated patients were selected as controls. Their clinical characteristics and radiological exam results were obtained. Patients were treated with 60 mg denosumab every 6 months for 2 years. The primary outcome was the incidence of femoral head collapse at 2 years after the initial diagnosis of ONFH. Secondary outcomes included the Harris hip score, progression of osteosclerosis, increase in necrotic area, bone marrow oedema relief, and bone mineral density increase in the femoral head. The Mann–Whitney U test and chi‐square tests were performed to identify the differences between the continuous and categorical variables, respectively. A multivariate logistic regression model was built to identify the factors associated with the treatment effect of denosumab. Results: The incidence of femoral head collapse was 42.24% (68/161) in the denosumab group and 54.07% (113/209) in the control group (χ2 = 5.094, p = 0.024; relative risk = 0.787, 95% CI = 0.627–0.973). The excellent‐good rates of the Harris hip score were 63.98% (103/161) in the denosumab group and 44.98% (94/209) in the control group (χ2 = 13.186, p < 0.001). The incidence of osteosclerosis progression in the denosumab group was 55.28% (89/161), which was significantly higher than that in the control group (43.54%, 91/209, χ2 = 5.016, p = 0.025). Meanwhile, a significant increase in bone mineral density was identified in 29.19% (47/161) and 7.18% (15/209) of patients in the denosumab and control groups, respectively (χ2 = 31.600, p < 0.001). The osteoclastic cytoplasm expression of LC3‐II was more positive in the control group than in the denosumab group (immunohistochemistry scoring: 3.58 ± 2.27 vs 6.33 ± 2.64, Z = −2.684, p = 0.007). A total of three independent factors were considered to be associated with the positive treatment effect of denosumab, the time of first denosumab administration (OR = 2.010, 95% CI = 1.272–3.177), osteosclerosis (OR = 1.583, 95% CI = 1.024–2.445), and the necrotic area before denosumab administration (medium necrotic area: OR = 2.084, 95% CI = 1.245–3.487; large necrotic area: OR = 2.211, 95% CI = 1.255–3.893). Conclusions: The current study demonstrated that denosumab had a positive effect on preventing femoral head collapse in patients with steroid ONFH. This effect might be closely associated with the inhibition of osteoclasts and their autophagy. [ABSTRACT FROM AUTHOR]

Objective: To study the relationship between vascular endothelial cells (VEC) and autophagy, and its regulatory mechanism in steroid‐induced avascular necrosis of the femoral head (SANFH). Methods: In cell experiment, VEC were isolated and cultured from the femoral head of Sprague–Dawley rats and divided into three groups: blank control group (Ctrl), methylprednisolone group (MP), and methylprednisolone+mTOR‐shRNA group (MP + shmTOR). The autophagy formation was observed by transmission electron microscope. The mRNA expression of PI3K, Akt, mTOR, Beclin1 and MAP1LC3 was detected by RT‐PCR and the protein expression was detected by Western blot and immunofluorescence. Expression of the damage marker 6‐keto‐PGF1α was detected by the ELISA method. In vivo experiment, after establishing the model, the grouping method was the same as cell experiment. Autophagosomes were observed by same method, and the expression of related factors was detected by the same method in cell experiment. Results: In the cell experiment, autophagosomes in the MP group were significantly lower than in the Ctrl group, and the autophagosomes in the MP + shmTOR group were intermediate between two groups (P < 0.05). The mRNA expression levels of PI3K, Akt and mTOR in the MP group were significantly higher than in the Ctrl group, while the MP+ shmTOR group presented intermediate levels between these groups (average gray value were 3837.90, 2996.30, 3005.60, F = 428.64, P < 0.05). MRNA expression levels of Beclin1 and MAP1LC3 in the MP group were significantly lower than that in Ctrl group (P < 0.05). The content of 6‐keto‐PGF1α in the MP + shmTOR group was higher than in the Ctrl group and lower than in the MP group at the evaluated time intervals (average absorbance value were 104.98, 206.83, 145.91, F = 352.83, P < 0.01). In vivo experiment, the content of 6‐Keto‐PGF1α in the hormone group increased as time went on; the mTOR‐si group was higher than that in control group, but lower than that in the hormone group (P < 0.01). The mRNA expressions of Beclin1 and MAP1LC3 in the control group were higher than those in the hormone group, while the mRNA expressions of PI3K, Akt and mTOR were lower than those in the mTOR‐si group (P < 0.05). Conclusion: The steroid inhibited the physiological protective effect of autophagy on SANFH by increasing the expression of PI3K/Akt/mTOR signaling pathway related factors and decreasing the expression of Beclin1 and MAP1LC3 in the femoral head VEC. [ABSTRACT FROM AUTHOR]

Diffuse sclerosing osteomyelitis (DSO) is a rare inflammatory disease of the bone with a poorly understood aetiology. We present a case of a 26‐year‐old female with DSO, who has been living with this condition for over 12 years. Many different therapies have been used to attempt to manage her symptoms. She is currently taking oral alendronic acid when she is symptomatic. This case report demonstrates the complexity of managing cases of DSO, as we focus on the multiple treatment modalities used in this case and the response to these. Many cases in literature discuss the use of intravenous bisphosphonates, however, this is linked with a higher risk of medically related osteonecrosis of the jaw. In addition to other reported case studies and research, this case provides further evidence to support the use of oral bisphosphonates in the management of DSO. [ABSTRACT FROM AUTHOR]

The syntheses and structures of ammonium salts of the active pharmaceutical agent (4‐aminium‐1‐hydroxybutylidine)‐1,1‐bisphosphonic acid (alendronic acid, LH5) have been examined. Three deprotonation states of the parent acid were achieved i. e. LH4−, LH32− and LH23−, and crystallisation gave a total of six different structural phases including [NH4][LH4] ⋅ 2(H2O) as two polymorphs 1 a and 1 b, two hydrates of [NH4]2[LH3] ⋅ x(H2O), x=3 (2), x=6 (3), [NH4]5[LH3][LH2] ⋅ 8(H2O) (4) and [NH4]3[LH2] ⋅ 3(H2O) (5). The crystal structures obtained, along with that of the parent acid, enable a direct comparison of competing supramolecular synthons, involving phosphonate‐phosphonate O−H⋅⋅⋅O and ammonium‐phosphonate N−H⋅⋅⋅O hydrogen bonds, in a series displaying progressively decreasing P‐OH with concomitantly increasing RNH3+ moieties. Indeed, the structures show some consistent connectivity patterns of the alendronate units, which thus assemble into substructures such as 2‐D sheets (LH5 ⋅ H2O, 1 a), zig‐zag chains (2, 5) or ladder‐like arrays (3, 4). The occurrence of these motifs appears to correlate with the ionisation level of the parent acid. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy of resistance training (RT) combined with beta‐hydroxy‐beta‐methylbutyric acid (HMB) in the treatment of elderly patients with sarcopenia after hip replacement. Methods: From January 1, 2018 to December 31, 2018, 200 elderly patients (68 men, mean age 76.3 years and 137 women, mean age 79.1 years) who experienced femoral neck fracture with sarcopenia after hip arthroplasty were assigned to four groups: RT + HMB group, RT group, HMB group, and negative control group. Baseline data, body composition, grip strength, Barthel index (BI), Harris hip score (HHS), and visual analog scale score (VAS) were compared among the four groups before and 3 months after surgery. Results: A total of 177 participants completed the trial, including 43 in the HMB + RT group, 44 in the HMB group, 45 in the RT group, and 45 in the negative control group. At the 3‐month follow‐up, the body composition and grip strength of the HMB + RT group and RT group were significantly improved compared with those before operation. The HMB group had no significant change, while the measures in the negative control group significantly decreased. Postoperative BI and HSS did not reach pre‐injury levels in any of the four groups, but postoperative VAS score was significantly improved. However, there was no significant difference in BI, HSS, or VAS among the four groups. Conclusion: RT, with or without HMB supplementation, can effectively improve body composition and grip strength in elderly patients with sarcopenia after hip replacement at short‐term follow‐up. Simultaneously, use of exclusive HMB supplementation alone may also help to prevent decreases in muscle mass and grip strength in these patients. [ABSTRACT FROM AUTHOR]

Aim: Noonan syndrome is an uncommon disorder which can present with developmental delay, short stature and cardiac anomalies. Oro‐facial presentation includes giant cell lesions with secondary aneurysmal bone cysts (ABC). The current case report presents an extensive mandibular ABC managed solely by oral bisphosphonates. Material and methods: This is a single retrospective case report. Results: A stark regression of the ABC was evident following the use of oral bisphosphonates with reformation of mandibular integrity. Conclusion: This case reports highlights the potential value of oral bisphosphonate to manage oral pathology such as an ABC. [ABSTRACT FROM AUTHOR]

Cyclohexanone‐formaldehyde resin and acetophenone‐formaldehyde resin were in situ modified with sodium alendronate and the nanocomposites of cyclohexanone‐formaldehyde resin with sepiolite and montmorillonite by adding the nanoclay into the resin formation media. The analysis of nanocomposites of nanoclay in the resin were carried out with X‐ray diffraction. Exfoliated nanocomposites containing as much as 5 wt% sepiolite were obtained while the nanocomposites of montmorillonite were intercalated. The nanocomposites of alendronic acid‐modified ketone‐formaldehyde resin containing as much as 20 wt% sepiolite or 10 wt% montmorillonite were successfully produced in situ. Fourier transform infrared and nuclear magnetic resonance spectroscopies (NMR) were used for the structural characterization of the modified resins. The alendronic acid modified resins and their nanocomposites with the clays were used to produce reactive non‐toxic fire retardant rigid polyurethane foam. The polyurethane foam containing alendronic acid‐modified acetophenone‐formaldehyde resin had a residue of 20% in the thermogravimetric analysis and was HB‐grade in the horizontal fire test (HB) and self‐extinguished in about 3–5 s during the test. Polyurethane foams containing alendronic acid and the nanoclay with the limiting oxygen index value of 20.8 were achieved. [ABSTRACT FROM AUTHOR]

Background: Actinic keratosis (AK) occurs frequently in sun‐exposed skin while its diagnosis and treatment were still in exploration. Materials and methods: Thirty two patients with facial AK lesions were selected and examined with reflective confocal microscopy (RCM) firstly, followed by biopsy at the same site. RCM was used to observe AK lesions before 5‐aminolevulinic acid photodynamic therapy (ALA‐PDT) treatment, after the first treatment, after 4 treatments, and at 1 and 6 months follow‐up. Retrospective analysis of RCM images was performed. Results: Thirty two AK cases showed initial RCM microscopic features including disorderly arranged epidermal cells (100%), atypical keratinocytes (100%), and blurry border between the epidermis and dermis (100%). 4 patients quitted trail. After treatments, 24 cases showed basically regular arrangement of epidermal cells, absent atypical keratinocytes, and clear border between epidermis and dermis, while 4 cases improved little. At 1 and 6 months follow‐up, 23 cases remained relapse‐free while 1 case developed recurrent symptoms. Effective rate of 4 ALA‐PDT treatments for AK was 100%; recurrence and cure rates were 4.2% and 82.1%, respectively. Conclusion: ALA‐PDT is effective to treat AK, while RCM can be recommended for in vivo evaluating and monitoring the effect of ALA‐PDT on AK. [ABSTRACT FROM AUTHOR]

Management of secondary chronic osteomyelitis (SCO) of the mandible is complex and challenging condition. Antibiotics are often first line treatment but have difficulty penetrating the infected bone and surgical intervention can be extensive, disfiguring and may not provide cure. With increasing reports of successful management of primary chronic osteomyelitis with bisphosphonate therapy, it was considered a viable last line trial medication in a refractory SCO patient for whom surgery was not appropriate. The current case is the first in the literature to report successful management of SCO with oral bisphosphonates. [ABSTRACT FROM AUTHOR]

Alendronic acid is generally a well-tolerated medication, however, there are well-established adverse effects known within dentistry, such as medication-related osteonecrosis of the jaw and upper gastro-intestinal disturbances, particularly erosive oesophagitis. There is growing evidence of bisphosphonate-induced oral ulcerations and this diagnosis needs to be considered for patients presenting with unexplained oral ulceration. An 84-year-old female patient with dementia presented at our emergency dental department with severe, painful oromucosal ulceration. Haematological investigation, including Indirect-immunofluorescence demonstrated no abnormalities. Therefore, the likely diagnosis was that of chemically induced traumatic ulceration. The patient was managed through the cessation of alendronic acid, and the use of both topical and systemic corticosteroids. A 68-year-old female patient with learning difficulties presented with ulceration in the lower buccal sulcus following an urgent referral. The patients carer reported persistent difficulty in the swallowing of medicines, with medications regularly ‘pouched’ in the patients cheeks. Due to patient distress no further investigations were completed. Clinically, the lesion was characteristic of chemically induced traumatic ulceration. We therefore encouraged the continuation of liquid form alendronic acid. At a 2 week review, the ulceration had fully resolved. Alendronic acid-induced ulceration should be considered for patients presenting with oral ulceration, particularly in those with cognitive impairments. There needs to be increased awareness of alendronic acid-induced oral ulceration among prescribers, particularly in patients ‘at risk’. Alternate preparations of this medication such as dispersible tablets and an oral solution are available. [ABSTRACT FROM AUTHOR]

Levodopa (L‐dopa) remains the basis of pharmacological treatment of Parkinson's disease (PD). However, L‐dopa therapy is associated with the development of complications and presents major challenges in the long‐term treatment. Thus, other medications may be suggested to delay and/or reduce the doses of L‐dopa in order to prevent complications. The interpretation of treatment evolution reported in clinical trials on PD may be tricky, especially due to some variability in medications and dose regimens. Some authors have suggested a conversion factor to generate a total L‐dopa equivalent daily dose (LEDD), calculated as a sum of each parkinsonian medication. Therefore, LEDD provides an artificial summary of the total daily medication a patient is receiving, and to date, there is no report focusing on the clinical interpretation of this parameter. Thus, based on a 3‐year, multi‐center retrospective study assessing the impact of second‐line therapy initiation on LEDD in PD patients, the aim of our article was to discuss LEDD as a quantitative outcome to estimate the impact of second‐line therapies on medication regimens; and in the second part of the discussion, to provide a narrative review of the clinical outcomes associated with LEDD in the literature. [ABSTRACT FROM AUTHOR]

Inflammation is a contributing factor in osteocyte apoptosis, which is strongly associated with the development of glucocorticoid‐associated osteonecrosis of the femoral head (GA‐ONFH). Curcumin is a naturally derived drug that regulates immunity and inhibits inflammation. This study aimed to examine the capacity of curcumin to prevent osteocyte apoptosis and GA‐ONFH, while elucidating possible mechanisms of action. C57/BL6 female mice were divided into control, GA‐ONFH, and curcumin‐treated GA‐ONFH groups. We determined the effect of curcumin on the polarization of RAW264.7 and the apoptosis of MLO‐Y4 cells. We found that curcumin reduced the infiltration of M1‐type macrophages in the femoral heads and alleviated systemic inflammation in GA‐ONFH models. Additionally, curcumin decreased the apoptosis of osteocytes in the femoral heads and the ratio of GA‐ONFH in mice. Further, in vitro curcumin intervention inhibited M1‐type polarization via the Janus kinase1/2‐signal transducer and activator of transcription protein1 (JAK1/2‐STAT1) pathway. Taken together, this study demonstrates that curcumin is effective in preventing osteocyte apoptosis and the development of GA‐ONFH in a mouse model. Curcumin prevents inflammatory‐mediated apoptosis of osteocytes in part through inhibition of M1 polarization through the JAK1/2‐STAT1 pathway. These findings provide novel insights as well as a potential preventive agent for GA‐ONFH. This article is protected by copyright. All rights reserved. [ABSTRACT FROM AUTHOR]

There is a concern that bisphosphonates may impair fracture healing because of their inhibitory effects on bone turnover. Here we evaluated the effects of early bisphosphonate therapy on fracture healing and functional outcome following a fracture of the distal radius. The fracture and bisphosphonates (FAB) trial was a double‐blind, randomized, placebo‐controlled trial involving 15 trauma centers in the United Kingdom. We enrolled 421 bisphosphonate‐naive patients aged ≥50 years with a radiographically confirmed fracture of the distal radius and randomized them in a 1:1 ratio to receive alendronic acid 70 mg once weekly (n = 215) or placebo (n = 206) within 14 days of the fracture. The primary outcome measure was the proportion of fractures that had radiologically united at 4 weeks as assessed by an observer, blinded to treatment allocation. Secondary outcomes included the Disabilities of the Arm Shoulder and Hand (DASH) questionnaire, range of wrist movement and grip strength, pain and analgesia requirements, and the rate of malunion. The mean ± SD age of participants was 63 ± 8.5 years and 362 (86%) were female. At 4 weeks, 48 of 202 (23.8%) fractures had united in the alendronic acid group compared with 52 of 187 (27.8%) in the placebo group (observed absolute proportion difference 4.0%; 95% CI, –4.7% to 12.8%; p = 0.36). The absolute proportion difference between groups based on imputed data was 4.5% (95% CI, –4.7% to 13.8%; p = 0.30). There was no significant difference in the proportion of fractures that had united at any other time point and no differences in the DASH score, pain at the fracture site, grip strength, or any other clinical outcome. We conclude that among patients aged 50 years and above with a distal radius fracture, early administration of alendronic acid does not adversely affect fracture union or clinical outcome. These findings suggest bisphosphonate therapy can be safely commenced early after fracture if clinically indicated. © 2019 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Abstract: Diffuse sclerosing osteomyelitis (DSO) is a rare inflammatory disease of bone. The underlying cause is poorly understood and traditional management techniques have struggled to provide patients with adequate relief. A number of reports in the literature have described the use of bisphosphonates to manage DSO; however, these have predominantly been associated with the intravenous formulation. Understandably, there is an element of angst due to its underlying and well‐recognised risk of osteonecrosis of the jaw. In this article, we review the literature for the management of DSO including the novel approach of using bisphosphonates. As an example, we present a case of a 56‐year‐old female with DSO where conventional therapies failed to manage her symptoms; however, treatment with oral alendronic acid led to complete and sustained resolution. This case in conjunction with additional reported cases provides further evidence of the value of bisphosphonates in DSO and highlights that the use of oral bisphosphonates can be successful and could be a viable consideration prior to the use of intravenous versions. [ABSTRACT FROM AUTHOR]

ABSTRACT Alendronic acid modified resol nanocomposite resins (AA-PFNCRs) and sepiolite modified resol nanocomposite resins (SEP-PFNCRs) have been synthesized by in situ method in the presence of base catalyst. Additionally, the synergistic effects of alendronic acid and sepiolite clay (AA-SEP-PFNCR) on the resol resin have been studied. The structure, morphology, and thermal properties of these nanocomposites have been investigated by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), and X-ray Diffraction (XRD). The results demonstrated the interactions between the fillers and resol resin. Thermal properties of nanocomposite resins were improved due to alendronic acid and sepiolite. The obtained samples were also characterized morphologically by Scanning Electron Microscope (SEM). © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43807. [ABSTRACT FROM AUTHOR]

Two bisphosphonates (BPs), namely 1‐hydroxy‐2‐[4‐aminophenyl]ethane‐1,1‐diphosphonic acid (APBP) and 1‐hydroxy‐2‐[3‐indolyl]ethane‐1,1‐diphosphonic acid (IBP), have been synthesized and incorporated to acrylic injectable and self‐curing formulations. Alendronic acid monosodium trihydrated salt (ALN) containing cement was formulated as control. These systems have potential applications in low density hard tissues affected by ailments characterized by a high osteoclastic resorption, i.e. osteoporosis and osteolysis. Values of curing parameters of APBP and IBP were acceptable to obtain pastes with enough fluency to be injected through a biopsy needle into the bone cavity. Working times ranged between 8 and 15 min and maximum temperature was around 50°C. Cured systems stored for a month in synthetic body fluid had compressive strengths between 90 and 96 MPa and modulus between 1.2 and 1.3 GPa, which suggest mechanical stabilization after setting and in the short time. BPs were released in PBS at an initial rate depending on the corresponding chemical structure in the order ALN > APBP > IBP to give final concentrations in PBS of 2.21, 0.44, and 0.19 mol/mL for ALN, APBP, and IBP, respectively. Cytotoxicities of bisphosphonates were evaluated, IC50 values being in the order APBP > ALN > IBP. Absence of cytotoxicity coming from leachables of the cured systems was observed in all cases independently of the BP. An improved cell growth and proliferation for the systems loaded with APBP and IBP compared with that loaded with ALN was observed, as assessed by measuring cell adhesion and proliferation, and total DNA content. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2007 [ABSTRACT FROM AUTHOR]