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SummaryA post-menopausal Caucasian woman sustained an atypical femoral fracture (AFF) after 5-years continuous denosumab for osteoporosis without prior bisphosphonate exposure. This is only the fifth case reported of AFF in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should consider AFF in patients taking denosumab even without prior bisphosphonate exposure.IntroductionDenosumab has demonstrated overwhelmingly favourable skeletal benefit/risk profile in managing post-menopausal osteoporosis with up to 10-year exposure in the extension of the pivotal FREEDOM randomised placebo-controlled trial. Four previous cases of atypical femoral fracture have been reported in bisphosphonate-naïve patients receiving denosumab for osteoporosis.MethodsWe present an 85-year-old Caucasian post-menopausal woman without prior fragility fracture who sustained unilateral atypical femoral fracture after 5-years continuous subcutaneous denosumab for osteoporosis. She had no prior bisphosphonate or glucocorticoid exposure and had known chronic kidney disease.ResultsX-ray scan demonstrated complete, non-comminuted left proximal femoral shaft fracture meeting radiographic criteria for an atypical femoral fracture. Computed tomography (CT) scan lower limbs revealed unusual side-by-side appearance of proximal and distal fragments of left proximal femur. DXA BMD was artefactually elevated at lumbar spine (1.504 g/cm2, T-score + 2.5) and low-normal at right femoral neck (0.856 g/cm2, T-score -1.0). Serum biochemistry showed renal impairment at baseline (eGFR 30 mL/min/1.73m2). Low-normal serum C telopeptide of type 1 collagen (CTX) (230 ng/L) indicated therapeutic suppression of bone resorption.ConclusionThe patient underwent intramedullary nailing of the femur and denosumab was ceased. This is only the fifth case reported of atypical femoral fracture in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should maintain a high index of suspicion for atypical femoral fracture in a patient taking denosumab even without prior bisphosphonate exposure.

IntroductionNovel strategies are needed to address the rising burden of osteoporosis and fragility fractures. High-intensity resistance and impact (HiRIT) exercise has shown benefit in improving bone density in postmenopausal women with osteoporosis/osteopenia. Whether HiRIT can enhance the therapeutic effects of osteoporosis pharmacotherapy has not been established. ROLEX-DUO is a randomised controlled trial designed to assess the efficacy of romosozumab on various bone and muscle outcomes in combination with different exercise interventions in women with postmenopausal osteoporosis/osteopenia.Methods and analysisROLEX-DUO is an 8-month randomised placebo-controlled trial conducted at two tertiary referral centres for patients with osteoporosis/osteopenia in Sydney, New South Wales, Australia. The study is implementing the combination of romosozumab or placebo with different forms of exercise in postmenopausal women with osteoporosis/osteopenia without recent fragility fracture (n=102). Eligible women will be randomised 1:1:1 into one of three groups: (1) romosozumab with supervised HiRIT, (2) romosozumab with unsupervised low-intensity exercise or (3) placebo with unsupervised low-intensity exercise. Co-primary outcomes are the mean percentage change in lumbar spine bone mineral density (BMD), and mean change in five times sit-to-stand test performance (seconds) at 8 months. Secondary/exploratory outcomes include BMD changes at the femoral neck, total hip and distal radius, three-dimensional dual-energy X-ray absorptiometry (DXA) hip outcomes, DXA-derived lean and fat mass, serum markers of bone turnover (procollagen type 1 peptide, C-telopeptide of type 1 collagen) and bone biomarkers (dickkopf-1), serum extracellular vesicle analyses, 36-Item Short Form Survey (SF-36) quality-of-life scores, Menopause-Specific Quality Of Life (MENQOL) Questionnaire menopause symptom burden scores, number of falls and fractures. Mixed-effects models will be performed to compare longitudinal outcome results between groups using intention-to-treat analysis.Ethics and disseminationThe trial was approved by the Northern Sydney Local Health District Human Research Ethics Committee (2022/ETH01794, protocol V.8, dated 03 July 2024). Participants will provide written informed consent prior to inclusion. Findings will be disseminated via peer-reviewed journals, scientific conferences and summary reports to funding bodies.Trial registration numberACTRN12623000867695.

Summary In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed. Purpose/introduction In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover. Methods We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers. Results Patients experienced a ~ 5–22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment. Conclusions A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk.

Abstract Bisphosphonates and denosumab have demonstrated overwhelmingly favorable skeletal benefit/risk profile in managing postmenopausal osteoporosis. External auditory canal osteonecrosis is a rare skeletal complication of antiresorptives previously described in 11 patients with bisphosphonate exposure and 1 bisphosphonate-naïve patient on denosumab. We present 2 patients who developed external auditory canal osteonecrosis while taking antiresorptives for postmenopausal osteoporosis; a 79-year-old asymptomatic bisphosphonate-naïve woman with 2-year exposure to denosumab, and a 64-year-old woman with otalgia after 5 years of risedronate and 5 years of denosumab treatment. Neither patient had previous exposure to glucocorticoids or local radiotherapy. Otoscopy performed by an ear/nose/throat (ENT) surgeon revealed exposed areas of bone in external auditory canal in both patients. Computed tomography of temporal bones found no evidence of bone erosion. Bone turnover markers were suppressed. Both patients ceased denosumab and were managed conservatively, with stable external auditory canal findings after 12 months. Although external auditory canal osteonecrosis is a rare skeletal complication of antiresorptive use, development of localizing symptoms in the ear should alert physicians to this rare clinical entity and prompt ENT surgical referral for early diagnosis and initiation of management.

Syphilis is increasingly prevalent in the community. The protean manifestations of neurosyphilis make the recognition, diagnosis and early initiation of treatment challenging. We report a case of early syphilitic meningitis presenting with multiple cranial neuropathies. Cerebrospinal fluid (CSF) examination was inflammatory with predominant lymphocytosis. The patient was diagnosed with neurosyphilis based on serum as well as CSF testing. Intravenous benzylpenicillin treatment resulted in rapid improvement of neurological symptoms. Neurosyphilis should be considered in immunocompetent patients presenting with multiple cranial neuropathies, or isolated cranial neuropathies without vascular risk factors.

Purpose of Review This review summarises the latest evidence on effects of exercise on falls prevention, bone mineral density (BMD) and fragility fracture risk in postmenopausal women, explores hypotheses underpinning exercise-mediated effects on BMD and sheds light on innovative concepts to better understand and harness the skeletal benefits of exercise. Recent Findings Multimodal exercise programs incorporating challenging balance exercises can prevent falls. Emerging clinical trial evidence indicates supervised progressive high-intensity resistance and impact training (HiRIT) is efficacious in increasing lumbar spine BMD and is safe and well-tolerated in postmenopausal women with osteoporosis/osteopenia. There remains uncertainty regarding durability of this load-induced osteogenic response and safety in patients with recent fractures. Muscle-derived myokines and small circulating extracellular vesicles have emerged as potential sources of exercise-induced muscle-bone crosstalk but require validation in postmenopausal women. Summary Exercise has the potential for multi-modal skeletal benefits with i) HiRIT to build bone, and ii) challenging balance exercises to prevent falls, and ultimately fractures. The therapeutic effect of such exercise in combination with osteoporosis pharmacotherapy should be considered in future trials.

Accelerated sub-lesional bone loss is common in the first 2–3 years after traumatic spinal cord injury (TSCI), particularly in the distal femur and proximal tibia. Few studies have explored efficacy of antiresorptives for acute bone loss prevention post-TSCI, with limited data for knee bone mineral density (BMD) or beyond two years follow-up. An open-label non-randomized study was performed at Royal North Shore Hospital and Royal Rehab Centre, Sydney between 2018 and 2023. An ‘acute interventional cohort’ (n = 11) with TSCI (duration ≤ 12-weeks) received a single infusion of 4 mg zoledronic acid (ZOL) at baseline. A ‘chronic non-interventional cohort’ (n = 9) with TSCI (duration 1–5-years) did not receive ZOL. All participants underwent baseline and 6-monthly blood tests (including CTx and P1NP) and 12-monthly DXA BMD scans (including distal femur and proximal tibia). Participants were predominantly Caucasian and male (mean age 38.4 years). At baseline, the ‘acute’ cohort had higher serum CTx, P1NP and sclerostin concentrations, while the ‘chronic’ cohort had lower left hip and knee BMD. Majority with acute TSCI experienced an acute phase reaction after ZOL (9/11; 82%). In the acute cohort, left hip BMD fell by mean ~ 15% by 48 months. Left distal femoral and proximal tibial BMD declined by mean ~ 6–13% at 12 months and ~ 20–23% at 48 months, with a tendency towards greater BMD loss in motor-complete TSCI. A single early ZOL infusion in acute TSCI could not attenuate rapidly declining hip and knee BMD. Prospective controlled studies are required to establish the optimal strategy for preventing early bone loss after acute TSCI.

BackgroundSyphilis is increasing in prevalence in the community.1 2 Neurosyphilis has protean manifestations making recognition, diagnosis and early initiation of treatment challenging.Methods/ResultsWe present a case of early syphilitic meningitis in a 37-year-old female presenting with multiple cranial neuropathies (V, VI, VII, VIII and XII) developing over the course of two weeks. This began with a sensation of disequilibrium and unsteady gait, and progressed to difficulty closing both eyes, right lip numbness, bilateral hearing impairment (right, followed by left), and dysarthria. She did not report headache, meningism, features of primary syphilis infection or risk factors for sexually transmitted infections (STIs). Examination confirmed the presence of right-sided trigeminal, bilateral abducens, facial, vestibulocochlear and hypoglossal nerve palsies. Cerebrospinal fluid (CSF) examination was inflammatory (protein 1.28 g/L, glucose 3.8mmol/L) with predominant lymphocytosis (76%, WCC 441 x 106/L). Magnetic resonance imaging (MRI) demonstrated post-contrast enhancement of the trigeminal nerve at the pons, as well as facial and vestibulocochlear nerves at the geniculate ganglion with no leptomeningeal enhancement. Our patient was diagnosed with neurosyphilis on serum and CSF serological testing (Serum Treponema pallidum particle agglutination assay (TPPA) positive, chemiluminescent microparticle immunoassay (CMIA) IgG and IgM positive, rapid plasma reagen 1:32. CSF TPPA positive, Venereal Disease Research Laboratory test titre of 1:8). She was treated with intravenous benzylpenicillin with rapid improvement in her cranial neuropathies.ConclusionsThis is the most extensive cranial neuropathy reported with syphilitic infections to date. Neurosyphilis should be considered as a differential in patients presenting with multiple cranial neuropathies.ReferencesKojima N, Klausner J. An update on the global epidemiology of syphilis. Curr Epidemiol Rep 2018;5(1):24–38.Ghanem K, Ram S, Rice P. The modern epidemic of syphilis. N Engl J Med 2020;382(24):2379–80.

Abstract Pheochromocytomas are rare catecholamine-secreting neuroendocrine tumors of the adrenal medulla chromaffin cells, usually associated with features of catecholamine excess. Clinically and biochemically silent pheochromocytoma without adrenergic symptoms or elevated catecholamine concentrations are rare. A 71-year-old female presented with acute right flank pain with abdominal computed tomography (CT) scan revealing a hemorrhagic right adrenal mass. She had no preceding adrenergic symptoms, and normal serum electrolytes, on a background of well-controlled hypertension on amlodipine monotherapy. After conservative management and discharge, an outpatient CT adrenal scan confirmed an 88 × 64 mm right adrenal mass demonstrating intense avidity (maximum standardized uptake value, 20.2) on fluorodeoxyglucose F 18-positron emission tomography (FDG-PET)/CT scan. Biochemical screening supported a nonfunctional adrenal lesion with normal-range plasma normetanephrines and metanephrines. She underwent a right adrenalectomy for presumed nonfunctioning adrenocortical cancer; however, histopathology demonstrated a 120-mm pheochromocytoma. Succinate dehydrogenase subunit B (SDHB) and fumarate hydratase (FH) staining were retained; however, weakly positive 2SC staining raised concerns for FH-deficient pheochromocytoma. Germline DNA sequencing was negative for pathogenic RET, VHL, SDHB, SDHD, or FH variants. Tumor cells stained positive for tyrosine hydroxylase and negative for dopamine β hydroxylase. Four months postoperatively, progress FDG-PET/CT scan demonstrated no focal avidity. Massive biochemically silent pheochromocytomas are exceedingly rare, and we discuss various mechanisms that may predispose patients to this phenomenon.