Bilateral Atypical Femoral Fracture in a Bisphosphonate-Naïve Patient with Prior Long-Term Denosumab Therapy: A Case Report of the Management Strategy and a Literature Review.

The benefits of denosumab as an antiresorptive therapy and in reducing fragility fractures are well documented. However, its association with atypical femur fractures (AFFs), especially in the absence of prior bisphosphonate use, remains poorly understood and warrants further investigation. This case report presents a rare instance of bilateral AFFs in a 78-year-old bisphosphonate-naïve patient with a history of long-term denosumab therapy for previous metastatic breast cancer. Management involved intramedullary nail fixation after initial presentation with a unilateral AFF and a recommendation to cease denosumab therapy. However, the patient subsequently experienced a contralateral periprosthetic AFF below a total hip implant 5 months thereafter and was treated with open reduction internal fixation. This case report highlights the critical need for orthopedic surgeons to maintain a high level of suspicion and vigilance in screening for impending AFFs, especially in patients with a prolonged history of denosumab therapy without prior bisphosphonate use. Furthermore, the growing report of such cases emphasizes the urgent need for comprehensive research aimed at refining treatment protocols that balance the therapeutic benefits of denosumab and its associated risks of AFFs.

Effects of osteopathic manipulative treatment and bio-electromagnetic energy regulation therapy on lower back pain.

CONTEXT: Lower back pain (LBP) is prevalent and is a leading contributor to disease burden worldwide. Osteopathic manipulative treatment (OMT) can alleviate alterations in the body that leads to musculoskeletal disorders such as LBP. Bio-electromagnetic Energy Regulation (BEMER; BEMER International AG), which has also been shown to relieve musculoskeletal pain, is a therapeutic modality that deploys a biorhythmically defined stimulus through a pulsed electromagnetic field (PEMF). Therefore, it is possible that combined OMT and BEMER therapy could reduce low back pain in adults more than the effect of either treatment modality alone. OBJECTIVES: To investigate the individual and combined effects of OMT and BEMER therapy on LBP in adults. METHODS: Employees and students at a medical college were recruited to this study by email. Participants were included if they self-reported chronic LBP of 3 months' duration or longer; participants were excluded if they were experiencing acute LBP of 2 weeks' duration or less, were currently being treated for LBP, were pregnant, or had a known medical history of several conditions. Ultimately, 40 participants were randomly assigned to four treatment groups: an OMT only, BEMER only, OMT+BEMER, or control (light touch and sham). Treatments were given regularly over a 3 week period. Data on LBP and quality of life were gathered through the Visual Analog Scale (VAS), Short Form 12 item (SF-12) health survey, and Oswestry Low Back Pain Questionnaire/Oswestry Disability Index prior to treatment and immediately after the 3 week intervention protocol. One-way analysis of variance (ANOVA) was performed retrospectively and absolute changes for each participant were calculated. Normal distribution and equal variances were confirmed by Shapiro-Wilk test (p>0.05) and Brown-Forsythe, respectively. Significance was set at p<0.05. RESULTS: Despite a lack of statistical significance between groups, subjective reports of pain reported on the VAS showed a substantial mean percentage decrease (50.8%) from baseline in the OMT+BEMER group, compared with a 10.2% decrease in the OMT-only and 9.8% in BEMER-only groups when comparing the difference in VAS ratings from preintervention to postintervention. Participants also reported in quality of life assessed on the Oswestry Low Back Pain Questionnaire/Oswestry Disability Index, with the OMT+BEMER group showing a decrease of 30.3% in score, the most among all groups. The OMT+BEMER group also reported the greatest improvement in score in the physical component of the SF-12, with an increase of 21.8%. CONCLUSIONS: The initial data from this study shows a potential additive effect of combination therapy (OMT and BEMER) for management of LBP, though the results did not achieve statistical significance.

Plant α-glucan phosphatases SEX4 and LSF2 display different affinity for amylopectin and amylose.

The plant glucan phosphatases Starch EXcess 4 (SEX4) and Like Sex Four2 (LSF2) apply different starch binding mechanisms. SEX4 contains a carbohydrate binding module, and LSF2 has two surface binding sites (SBSs). We determined KDapp for amylopectin and amylose, and KD for ß-cyclodextrin and validated binding site mutants deploying affinity gel electrophoresis (AGE) and surface plasmon resonance. SEX4 has a higher affinity for amylopectin; LSF2 prefers amylose and ß-cyclodextrin. SEX4 has 50-fold lower KDapp for amylopectin compared to LSF2. Molecular dynamics simulations and AGE data both support long-distance mutual effects of binding at SBSs and the active site in LSF2.

Mechanistic Insights into Glucan Phosphatase Activity against Polyglucan Substrates.

Glucan phosphatases are central to the regulation of starch and glycogen metabolism. Plants contain two known glucan phosphatases, Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2), which dephosphorylate starch. Starch is water-insoluble and reversible phosphorylation solubilizes its outer surface allowing processive degradation. Vertebrates contain a single known glucan phosphatase, laforin, that dephosphorylates glycogen. In the absence of laforin, water-soluble glycogen becomes insoluble, leading to the neurodegenerative disorder Lafora Disease. Because of their essential role in starch and glycogen metabolism glucan phosphatases are of significant interest, yet a comparative analysis of their activities against diverse glucan substrates has not been established. We identify active site residues required for specific glucan dephosphorylation, defining a glucan phosphatase signature motif (CζAGΨGR) in the active site loop. We further explore the basis for phosphate position-specific activity of these enzymes and determine that their diverse phosphate position-specific activity is governed by the phosphatase domain. In addition, we find key differences in glucan phosphatase activity toward soluble and insoluble polyglucan substrates, resulting from the participation of ancillary glucan-binding domains. Together, these data provide fundamental insights into the specific activity of glucan phosphatases against diverse polyglucan substrates.

Structural mechanism of laforin function in glycogen dephosphorylation and lafora disease.

Glycogen is the major mammalian glucose storage cache and is critical for energy homeostasis. Glycogen synthesis in neurons must be tightly controlled due to neuronal sensitivity to perturbations in glycogen metabolism. Lafora disease (LD) is a fatal, congenital, neurodegenerative epilepsy. Mutations in the gene encoding the glycogen phosphatase laforin result in hyperphosphorylated glycogen that forms water-insoluble inclusions called Lafora bodies (LBs). LBs induce neuronal apoptosis and are the causative agent of LD. The mechanism of glycogen dephosphorylation by laforin and dysfunction in LD is unknown. We report the crystal structure of laforin bound to phosphoglucan product, revealing its unique integrated tertiary and quaternary structure. Structure-guided mutagenesis combined with biophysical and biochemical analyses reveal the basis for normal function of laforin in glycogen metabolism. Analyses of LD patient mutations define the mechanism by which subsets of mutations disrupt laforin function. These data provide fundamental insights connecting glycogen metabolism to neurodegenerative disease.