Worm-eaten-like osteolytic changes in multiple bones of the foot following stable ankle fracture: A case report and literature review

Worm-eaten-like osteolytic changes in multiple bones of the foot following stable ankle fracture: A case report and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Worm-eaten-like osteolytic changes in multiple bones of the foot following stable ankle fracture: A case report and literature review Haotian Wu, Liqing Yao, Xue Yang, Yao Zhou, Zihan Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5348097/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Stable fractures of the ankle joint are common in rehabilitation departments, often resulting in foot and ankle joint dyskinesia. Patients with ankle fractures usually experience pain, stiffness, swelling, limited mobility, lower extremity muscle weakness, and walking abnormalities. However, no reports have been published on stable ankle fractures causing polyostotic osteolytic changes in the foot and the subsequent formation of free bone fragments. In this case report, we described a case of a stable fracture of the right lateral malleolus with pathological alterations characterized by worm-eaten-like osteolytic changes in the distal right tibia, talus, calcaneus, and navicular bones, accompanied by the rare development of free bone fragments in the lateral ankle. Method & Conclusion After an extensive literature review and thorough patient assessment, we concluded that the probable pathological cause was atherosclerosis affecting multiple blood vessels throughout the body due to risk factors such as hypertension and hyperlipidemia. Additionally, the localized trauma-induced fracture led to the foot and ankle swelling and altered bone stress loading, further triggering a cascade of vascular inflammatory reactions and sympathetic excitation within the already atherosclerotic blood vessels. Moreover, these effects were exacerbated by early inappropriate immobilization, which resulted in ischemia and hypoxia of the bone tissues in the injured area. Ultimately, all these factors contributed to the impaired healing of the ankle fracture and osteoporosis development in multiple foot bones. This case report presents a rare manifestation of a common condition, aiming to enhancethe decision-making process of cliniciansand facilitate the formulation ofbetter clinical diagnostic and therapeutic strategies. Rehabilitation rehabilitation therapy ankle fracture fracture prognosis osteoporosis bone loss Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Ankle fractures are prevalent orthopedic conditions that can occur across all ages, accounting for 10.2% of all bone injuries [1]. These fractures have a notably high incidence among older women and younger men [2] and are primarily observed in sports injuries [3]. Furthermore, population aging and the social environment of universal participation in sports have led to an increasing number of ankle fractures annually [4]. The management of ankle fractures involves assessing the stability of the ankle joint, potential complications, and preoperative functional capacity to determine the appropriateness of surgical or nonsurgical intervention [5]. Ankle fractures typically lead to ankle pain, swelling of the affected joint, limited joint movement, and joint stiffness, eventually resulting in decreased muscle strength in the impacted lower limb and gait abnormalities [6, 7]. Therefore, dysfunction after an ankle fracture can affect a patient's ability to perform daily activities as well as their physical and mental health [8]. The pathophysiological processes involved in fracture repair are crucial for identifying suitable management strategies and predicting the outcomes of ankle fractures. Fracture repair encompasses a series of pathophysiological processes that can be delineated into two main stages: primary and secondary healing [9]. After a fracture, the periosteum and bone tissue are disrupted, and a clot is rapidly formed to serve as a provisional matrix for initial repair. Subsequently, an inflammatory phase ensues, where inflammatory cells substantially accumulate and neovascularization is promoted via the proliferation and migration of mesenchymal cells from the periosteum and endosteum. Cartilage formation and intramembranous ossification then contribute to bone formation. In the final stage of the fracture repair process, the original bone is resorbed by osteoclasts to facilitate bone remodeling and restore the bone shape and structure [10]. This fracture repair process and prognosis of ankle fractures are influenced by numerous factors, including sex, age, fracture severity, cartilage damage, vascular supply, and anatomical repositioning [11]. Generally, stable fractures have a favorable prognosis, with approximately 10% developing adverse complications such as delayed healing and malunion [12]. In this case report, we reported a case of a male patient who presented with a closed stable ankle fracture that exhibited poor healing, osteonecrosis, bone fragment formation, and a rare manifestation of osteoporosis affecting multiple foot bones. This case report aims to examine the two primary complications of osteoporosis and osteonecrosis associated with stable ankle fractures and highlight the significance of early recognition, routine monitoring, and vascular health assessment in predicting the outcomes of patients with fractures. Patient and observation Patient characteristics The patient was a 47-year-old male who sustained a right ankle fracture in an automobile accident in May 2023. After the accident, the patient experienced swelling, pain, and limited mobility of the right ankle joint with no open wound. However, the patient initially disregarded these apparent symptoms. The next day following his injury, the patient visited a local hospital and underwent a anteroposterior and lateral X-ray examination(Fig. 1 a). The X-ray results revealed disruption of the cortical continuity and soft tissue swelling of the right lateral ankle, along with the formation of bone spurs at the inferior aspect of the right calcaneus. During the initial conservative treatment at the hospital, the medical staff did not immobilize the patient with support. At 10 days after the fracture, the patient attempted weight-bearing and experienced worsening pain and right ankle swelling. Consequently, the patient sought further treatment by consulting multiple hospitals and clinics. The patient underwent conservative symptomatic therapies such as the external application of Chinese herbs, acupuncture, and ice packs; however, he did not experience any noteworthy improvement in his symptoms. Considering his persistent discomfort, the patient eventually visited our hospital's rehabilitation department in September 2023 for treatment. In terms of his medical history, the patient had a smoking habit for over 30 years (approximately 30 cigarettes/day) and an alcohol drinking habit for over 2 years (approximately 20 ml/day). Moreover, he had elevated blood lipid levels for more than 10 years. Lastly, the patient was diagnosed with hypertension 2 years ago (peak blood pressure: 150/99 mmHg) and was on long-term medication with amlodipine benzenesulfonate tablets. The author has informed the patient and obtained the patient’s consent, and the informed consent form has been signed. Clinical findings Visual examination at our hospital in Septemper demonstrated mild swelling and dark discoloration of the patient's right ankle and foot dorsum. Palpation near the fracture site indicated normal skin temperature on the medial side of the right ankle joint, along with pressure and pain observed in the lateral ankle area of the right foot. Furthermore, regular pulsation of the dorsal pedal artery was palpable. Range of motion assessment of the joint revealed a pronounced limitation in right ankle movement accompanied by notable pain upon pressure. In particular, the joint range of motion measurement showed that the active dorsiflexion of the right ankle joint was 5°, toe flexion was 5°, and internal and external rotation was 0°. Laboratory tests indicated a positive T-SPOT tuberculosis test and elevated total cholesterol and triglyceride levels, whereas other test results were within normal limits. An imaging assessment conducted during the patient's outpatient visit in July 2023 showed emxisting bone conditions in the right foot (Fig. 1 c). After admission to our hospital, the patient underwent additional examinations. Three-dimensional reconstruction of the right ankle joint using computed tomography (CT) revealed multiple bone lesions in the right ankle and soft tissue swelling around the joint. Magnetic resonance imaging (MRI) suggested degenerative changes in the ankle joint, irregular morphology of the lateral malleolus, and possible injuries to the anterior and posterior talofibular ligaments. Additionally, soft tissue edema was observed around the joint and foot dorsum, accompanied by minor joint effusion (Fig. 1 e&f). However, no significant abnormalities were found on chest CT and abdominal ultrasound. Therapeutic intervention The patient was diagnosed with multifocal bone destruction in the right foot, which was potentially exacerbated by delayed treatment due to inadequate monitoring during visits to other hospitals from May to August. Upon presentation to our hospital, a comprehensive laboratory and imaging assessment of the patient was promptly performed. Given the finding of extensive osteolytic bone destruction in the right ankle, standardized treatment protocols were swiftly initiated. The interventions encompassed isometric muscle training, joint mobilization exercise, magnetic therapy, intermediate frequency electrotherapy, ultrasound treatment, and acupuncture to facilitate tissue repair and alleviate pain. Moreover, gradual weight-bearing ambulation was prescribed to incrementally enhance activity levels and promote recovery. By September 28, the patient showed significant improvement in right ankle swelling and functional limitations and was discharged from the hospital. Follow up After 2 months following discharge from our hospital, the patient was admitted to the hospital for coronary artery disease and was subsequently treated with coronary stenting. At 3 months after discharge from our hospital, the patient reported considerable pain in the right ankle during prolonged jogging or walking. A follow-up CT scan of the right ankle showed an old fracture with adjacent loose bone fragments, degenerative changes, and osteoporosis affecting the ankle joint (Fig. 1 g). Discussion Ankle fractures are highly prevalent in adults, constituting 10.2% of all fractures[13]. After the incidence of an ankle fracture, a hematoma is formed at the fracture site, followed by the accumulation of numerous inflammatory cells and mesenchymal stem cells. Next, chondrocytes initiate proliferation and differentiate to transform bone tissue via the action of osteoblasts. This process culminates in the bone remodeling stage, where osteoblasts modulate the bone structure and morphology by resorbing and depositing bone tissue [12]. Ultimately, normal tissue connectivity and function are restored around the ankle joint. The foot and ankle joint region are a tightly packed and functionally intricate structure comprising multiple ligaments, muscles, bones, and blood vessels. In Fig. 2 , we present a simplified anatomical dissection diagram of the ankle joint. The ligaments in the foot and ankle are crucial in maintaining joint stability. Among these, the deltoid ligament supports the medial aspect of the ankle joint and limits valgus motion and stress. The lateral collateral ligament, which consists of the anterior and posterior talofibular ligaments and the calcaneofibular ligament, restricts ankle joint inversion, valgus stress, and rotation [14]. Furthermore, arteries, veins, and their branches intricately traverse the foot and ankle to supply oxygen and nutrients to the tissues, with variations in the arterial anatomy being notably prevalent in this region [15]. Hence, understanding these variations is pivotal for physicians managing patients with fractures and preventing potential complications. In summary, the coordination among ankle muscles, ligaments, and blood vessels contributes to the maintenance of the physiological function of the ankle joint. The ankle joint is critically involved in supporting the weight of the human body. This joint has a large contact area that distributes gravitational stresses [14] and performs an essential weight-bearing function, as evidenced by gait analysis studies. During normal walking, the ankle joint bears approximately five times the body weight. However, forces on the ankle joint during high-impact activities such as running can exceed thirteen times the body weight, underscoring its significant load-bearing capacity [16]. Therefore, considering its role as a weight-bearing joint, immobilization and proper management following ankle fracture are vital [17]. Ankle fractures can result in ischemic osteonecrosis, osteoarthritis, bone nonunion, and cartilage damage [11, 18]. Of these, ischemic osteonecrosis and osteoporosis are more common and frequently mistaken by non-orthopedic physicians; however, they have distinct outcomes and treatments. Ischemic osteonecrosis leads to the collapse of the articular surface and typically necessitates surgical interventions, including medullary decompression, percutaneous drilling, and even joint fusion and arthroplasty in some cases [19, 20]. In contrast, osteoporosis usually increases bone fragility and fracture susceptibility [21] and is often managed using medications such as estrogen, alendronate, and odanacatib [22]. All these results underline that recognizing these distinctions is crucial for non-orthopedic specialists (e.g., rehabilitation physicians) to effectively ameliorate the severe complications following ankle fractures. Hence, we conducted a literature review on the rare manifestations of this common condition, focusing on summarizing osteonecrosis and osteoporosis complications to provide clinicians with valuable diagnostic insights and treatment strategies. 1 Physiopathological processes in the bone tissue Osteoclasts and osteoblasts have distinct physiological roles in the bone tissue. Osteoclasts continuously resorb aged, damaged, and unwanted bone tissue, while osteoblasts perpetually generate new bone tissue [16]. These entire processes are governed by the endocrine and immune systems [23] via signaling pathways such as the RANK-RANKL-OPG and Wnt pathways that collectively regulate bone remodeling [24]. However, aging or specific pathological conditions can disrupt the equilibrium between bone resorption and formation, inducing bone loss and potentially culminating in osteonecrosis or osteoporosis [25, 26]. 1.1 Common causes of bone loss Apart from the aging-related imbalance where bone resorption exceeds bone formation, numerous pathologies such as fractures, skeletal unloading, chronic inflammation, autoimmune disorders (e.g., rheumatoid arthritis), tumors, and hyperparathyroidism can cause bone loss by escalating osteoclast activity and diminishing osteoblast activity [27, 28]. In this literature review, we focus on the primary contributors such as fractures, infections, and tumors (Fig. 3 ). Xuan-Qi et al. outlined the underlying mechanisms of post-fracture bone loss and attributed it to several factors, including immobilization, diminished mechanical stress, impaired blood supply, modulation of the sympathetic nervous system, and muscle and bone interactions [29]. The musculoskeletal system primarily sustains physiological gravitational loads, whereas muscle contraction and movement generate essential force stimuli crucial for maintaining bone health [30]. Skeletal unloading, also termed weightlessness or microgravity, can occur due to immobilization after a fracture. This condition combined with reduced muscle strength and activity can decrease skeletal loading, eventually leading to bone loss. The bones and muscles also regulate osteoclast activation, function, and homeostasis of bone repair through the secretion of factors such as mechanical growth factor, insulin-like growth factor-1, and interleukin-6 (IL-6). Moreover, fractures usually disrupt the blood supply to cause skeletal cell ischemia and hypoxia, ultimately resulting in osteoblast death and subsequent bone loss. Vascular endothelial growth factor is an essential component of this cascade. Bone reconstruction is also regulated by the nervous system via the abundant nerve fibers in the periosteum and the adrenergic receptors present on osteoblasts and osteoclasts [29]. Pain following a fracture incident can trigger sympathetic activation [31]. This activation leads to heightened levels of plasma norepinephrine that interacts with the β-adrenergic receptors on osteoblasts and osteoclasts. Subsequently, these receptors disrupt bone remodeling homeostasis by inhibiting osteogenesis and promoting bone resorption [29]. All these complex factors interact with the pathophysiological process of acute bone loss following fractures. Bone loss can also result from infections, among which Staphylococcus aureus is the most predominant pathogen [32]. Pathogen infections can cause bone destruction through direct and indirect mechanisms. In the direct mechanism, invasive pathogens attack bone tissue cells such as osteoblasts, osteoclasts, and osteocytes, which triggers oxidative stress and the generation of reactive oxygen species to combat these pathogens while also accelerating bone resorption. These alterations ultimately lead to bone destruction. In the case of the indirect mechanism, infections stimulate the production of inflammatory mediators such as tumor necrosis factor-α (TNF-α), IL-1β and IL-6, which interfere with bone metabolism and compromise bone integrity [33]. Currently, the interactions between inflammatory cells and the cells involved in bone healing are widely acknowledged as crucial factors for bone formation, repair, and remodeling [34]. Bone metastases from malignancies, particularly those originating from breast and prostate cancers, are another common cause of bone loss [35]. After tumor cells establish themselves and become active in the bone tissue, they secrete various factors that disrupt normal bone remodeling. Of these factors, parathyroid hormone-related protein has been identified as a key contributor to malignant bone destruction [36], owing to its structural resemblance to the parathyroid hormone. This structural similarity facilitates RANKL expression, thereby enhancing osteoclast activity and bone resorption [37]. Moreover, tumor-released factors can impede bone formation. For instance, Dickkopf-1 (DKK-1) is a factor that inhibits osteoblast activity by antagonizing Wnt protein family actions on osteoblasts [36]. Furthermore, a strong link has been demonstrated between atherosclerosis and the skeletal system [38]. Recent research has indicated that lipid metabolism alterations may disrupt bone remodeling homeostasis by interfering with critical signaling pathways. For example, elevated cholesterol or triglyceride levels may affect the regulation of the RANKL/RANK/OPG and Wnt signaling pathways. Adipocyte-secreted adipokines, such as leptin and lipocalins, may also modulate bone metabolism. The resulting lipid metabolism disorders may cause abnormalities in vascular endothelial cells and increase thrombosis, consequently affecting bone microcirculation [39]. Panagiotis et al. have suggested that dyslipidemia can induce oxidative stress and inflammation, which in turn promote bone resorption while inhibiting bone formation [40]. Current studies have also indicated that the development of atherosclerosis and osteoporosis may be influenced by aging, smoking, sedentary lifestyle, estrogen levels, oxidative stress, and various factors such as the nuclear hormone receptor transcription factor PPARγ2, IL-1, IL-6, TNF-α, osteoprotegerin, fibroblast growth factor-23, sclerostin, adipokines, and bone morphogenetic proteins [39, 41, 42]. 2. Osteonecrosis 2.1 Concept of osteonecrosis Osteonecrosis, also known as ischemic bone necrosis, bone infarction, or aseptic bone necrosis, typically results from the disruption of skeletal blood supply that causes ischemia and hypoxia of bone tissue, ultimately leading to tissue death. Osteonecrosis in the foot and ankle is less frequent than that in the femoral head, wrist, knee, and shoulder joints. The primary pathological process of this condition involves increased intracortical pressure within the bone cortex, disruption of the vascular system, and heightened mechanical stress on the bone cells, which collectively contribute to osteonecrosis development[43]. Various factors can induce osteonecrosis, with trauma being the most prevalent trigger [44]. Moreover, glucocorticoid use, systemic lupus erythematosus, hematologic disorders, excessive alcohol consumption, smoking, and infections are recognized non-traumatic risk factors for osteonecrosis [45]. We further explored the rare etiology and clinical presentations of foot and ankle osteonecrosis by reviewing the 92 case reports (including 102 patients) that documented this necrotic condition over the last decade (2013.11.17–2023.11.17) from databases including PubMed, Embase, CBM, Cochrane, and CNKI (Fig. 4 ). 2.2 Etiology of osteonecrosis In our analysis, the predominant risk factors for osteonecrosis in the foot and ankle were identified as fracture, sprain, idiopathic origin, medical interventions, and glucocorticoid use, which were consistent with its common causes of fractures, sprains, or ligament tears resulting from trauma or accidents (Fig. 5 a). Hence, clinicians should meticulously assess the history of trauma in patients presenting with foot and ankle pain. This approach aids in the early identification of latent injuries, thereby facilitating prompt interventions to prevent osteonecrosis onset in this region. However, the diagnosis and treatment of idiopathic osteonecrosis is relatively complicated because it typically lacks clear external triggers. For instance, the ischemic necrosis of the navicular bone, which is termed Kohler's disease in children, often resolves spontaneously with a favorable prognosis. In contrast, this necrosis in adults, which is known as Müller–Weiss disease, carries a relatively poor prognosis [20]. Additionally, conditions including Freiberg's disease that affects the foot and the second or third metatarsal head or Preiser's disease in the wrist can present unique challenges. Generally, patients with idiopathic osteonecrosis present to hospitals with non-traumatic foot pain, necessitating evaluation by clinicians and imaging examination. Furthermore, foot and ankle osteonecrosis arising from medical causes occupies a significant proportion and is primarily linked to vascular damage during surgical procedures or infections. Therefore, clinicians should remain vigilant for the potential incidence of osteonecrosis during medical interventions such as surgery and therapeutic procedures and possess a comprehensive understanding of its etiology to ensure the implementation of effective therapeutic strategies. Finally, glucocorticoid-induced osteonecrosis and its mechanisms have been extensively investigated, with genetic susceptibility, vascular damage, adipocyte dysfunction, increased intraosseous pressure, and bone marrow ischemia being implicated in this condition [46]. The presence of a dose-dependent relationship between osteonecrosis development and glucocorticoids is well-established [47–49]. For example, a previous study has demonstrated the induction of osteonecrosis following cumulative doses of prednisone or its glucocorticoid equivalents ranging from 480 to 4320 mg [50]. However, numerous confounding variables have made it challenging to determine a safe threshold for glucocorticoid usage [47]. Therefore, clinicians should exercise caution when treating with cumulative steroid doses to mitigate osteonecrosis risk. For instance, high-dose methylprednisolone therapy should not exceed 5 days if administered at a dose of ≥ 1 g/day. As observed in our investigation (Fig. 5 b), foot and ankle osteonecrosis may also manifest concurrently with necrosis at anatomical sites other than the foot and ankle. Pierre et al. concluded that bone infarctions are typically multifocal and frequently coexist with multiple areas of ischemic osteonecrosis [51]. In such cases, osteonecrosis is considered multifocal when it is observed at three or more sites[52]. Moreover, the femoral head represents the most commonly affected site, followed by the knee, shoulder, and ankle bones[53]. Although glucocorticoid use constitutes the predominant etiological factor [54] of osteonecrosis, conditions such as lymphoma, HIV infection, and leukemia may also serve as causative factors[52, 55]. Therefore, clinicians should carefully consider all these factors when screening for the potential occurrence of multiple osteonecrosis during the management of non-traumatic osteonecrosis. 2.3 Imaging features of osteonecrosis Imaging tests such as X-rays, CT scans, and MRIs are crucial in diagnosing bone diseases. The use of “etc.” at the end of a list that is already introduced by “such as/including” is redundant. However, the imaging findings can be unremarkable in the early stages of osteonecrosis, with the earliest radiologic sign being a radiolucent crescent [47]. In contrast, advanced stages of osteonecrosis are more easily identifiable. Osteonecrosis is characterized by osteosclerosis, which can be identified based on increased bone density on radiographic and CT images. Additionally, MRI images of osteonecrosis show a characteristic double-line sign presenting as a low-signal ring between necrotic and healthy bone tissue [56]. 2.4 Summary In this case report, the CT scan of our patient conducted in 2024 indicated an old fracture of the right lateral ankle with characteristic peripheral free bone fragmentation shadows and a hyperdense shadow adjacent to the right talus, suggesting osteonecrosis. After reviewing the patient's medical history, the osteonecrosis of the right ankle joint was suggested to have stemmed from the early inadequate immobilization and support initially provided to the patient. Furthermore, the patient had a medical history of hypertension, hyperlipidemia, and prolonged alcohol consumption and smoking, which can contribute to endothelial damage and coagulation abnormalities. Early imaging data in July 2023 further revealed injuries to the anterior and posterior talofibular ligaments of the right ankle and the deltoid ligaments of the medial malleolus. These ligamentous injuries compromised the stability of the ankle. All these factors influenced the bone tissue to undergo ischemia and hypoxia, ultimately resulting in osteonecrosis and the formation of free bone fragments. 3. Osteoporosis 3.1 Concept of osteoporosis Osteoporosis is a chronic skeletal disease characterized by the deterioration of bone tissue microarchitecture and a reduction in bone mineral density [21]. This condition significantly increases bone fragility and susceptibility to fractures [57] and is estimated to have a higher prevalence than cardiovascular disease and cancer [58]. Moreover, osteoporosis onset has been found to impair motor and cognitive functions, potentially increasing the mortality risk in affected individuals [59]. Consequently, osteoporosis imposes a substantial burden at the individual and societal levels. 3.2 Causes of osteoporosis after fracture incidence The fundamental pathology of osteoporosis involves the disruption of the equilibrium between bone formation and resorption. Apart from the well-established understanding that aging and menopause lead to bone resorption rates surpassing those of bone formation, several factors such as genetic predisposition, medication use, fractures, immobilization, chronic inflammation, endocrine disorders, and hematologic conditions can also contribute to osteoporosis by elevating osteoclast activity and diminishing osteoblast function[60]. 3.3 Imaging features of osteoporosis In osteoporosis imaging, the reduction in bone density associated with osteoporosis presents as relative hypointensity. This imaging feature is discernible through techniques such as dual-energy X-ray absorptiometry and quantitative CT. Additionally, high-resolution imaging techniques such as MRI allow the assessment of structural degeneration in osteoporosis, revealing thinning of the trabeculae and cortical bone [61]. 3.4 Summary The patient in our case report was diagnosed with delayed fracture healing accompanied by osteonecrosis development in multiple foot bones and osteoporosis. Immobilization is crucial for patients with stable ankle fractures, and the application of casts and splints can reduce the rehabilitation duration and enhance clinical outcomes [62]. Furthermore, proper immobilization fosters a conducive environment for fracture healing, potentially preventing the exacerbation of the initial injury and secondary complications. In our patient, inadequate immobilization significantly contributed to his unfavorable prognosis. Moreover, the early onset of ankle pain and swelling prompted the patient to engage in non-standard weight-bearing activities to mitigate discomfort. However, this approach resulted in additional injury, swelling of the ankle ligaments and surrounding soft tissues, and compression of the vascular network in the foot and ankle of the patient. Another noteworthy aspect of this case report is that our patient was diagnosed with coronary artery disease and subsequently underwent stent placement during the second month of follow-up. Previous research has confirmed a robust association between coronary artery disease and osteoporosis [63]. Thus, we could gain novel perspectives in managing our patient's condition. Our patient also presented with hypertension, hyperlipidemia, and unhealthy lifestyle behaviors of smoking and alcohol consumption, all of which are established risk factors for atherosclerosis. These factors can contribute to the narrowing of the blood vessels in the foot and ankle, resulting in decreased blood flow. Additionally, specific conditions can cause the rupture of atherosclerotic plaques, which then form emboli that occlude blood vessels. Furthermore, adequate blood supply is vital for body tissue development and repair. Oxygen, nutrients, growth factors, and signaling molecules crucial for osteoblasts are delivered to bone tissues through blood circulation [64]. Hence, any interruptions or inadequate blood supply to bone tissues can induce ischemia and hypoxia, thereby disrupting cellular metabolism and escalating susceptibility to cellular damage and death. Moreover, cell death, damage, and hypoxia can activate immune cells that trigger the release of inflammatory mediators such as TNF-α, IL-1β, and IL-11, which in turn can induce heightened bone destruction and decreased bone formation [33]. Once the inflammatory response is initiated, it can propagate within the bone marrow to elicit a widespread inflammatory cascade. 4 Case analysis In our patient, the combination of the previously mentioned factors contributed to diminished blood flow to the right foot, causing ischemia and hypoxia in the skeletal tissues. Consequently, these changes impaired fracture healing and led to the formation of free bone fragments and osteoporosis development. During this process, the interaction of factors, such as post-injury stress, triggered sympathetic nerve excitation, skeletal muscle injury, and minimized or impaired the normal load-bearing capacity of the bones, further exacerbating osteoporosis in the foot and ankle. After completing the comprehensive rehabilitation treatment at our hospital, the patient exhibited considerable improvement in the localized swelling and restricted movement of the right ankle. Our patient-tailored therapeutic approach encompassed acupuncture, magnetic therapy, intermediate frequency electrotherapy, and isokinetic muscle exercise. These interventions were aimed at promoting local blood and lymphatic circulation, reducing soft tissue swelling and adhesions, alleviating local inflammatory responses, and improving the patient's pain management and joint mobility and stability while also mitigating risks such as deep vein thrombosis. Although rehabilitation therapy has been proven beneficial for adults recovering from ankle fractures, available findings on the effects of rehabilitation are heterogeneous. Therefore, outcomes could vary based on individual differences [65]. Currently, literature on the rehabilitation of post-ankle fractures remains relatively limited and is supported by only a modest level of evidence. A consensus on the effective rehabilitation methodologies and their specific efficacy for these particular fractures is still lacking. Hence, further research endeavors are warranted to advance our understanding and comprehensively identify optimal rehabilitation strategies for managing ankle fractures. Conclusion Based on the clinical, imaging, and laboratory analyses of our patient, we strongly suspect that the root cause of the patient's osteonecrosis, formation of free bone fragments, and osteoporosis was atherosclerosis in the blood vessels and inadequate blood supply to the foot during the early non-standardized treatment. During the second month of follow-up, the patient underwent coronary artery stenting after being diagnosed with coronary artery disease. This development provided additional valuable insights into the patient's status. Considering these conditions, the interplay of atherosclerosis affecting vasculature across the body and secondary ankle injury due to early inadequate immobilization and irregular exercise may have together contributed to the patient's unfavorable clinical outcome. Our case report offers substantial clinical implications. Along with paying meticulous attention to the treatment and exercise regimen, the vigilant monitoring of vascular health is crucial when managing patients with fractures, especially those with persistent swelling and pain occurrence following fractures. Lastly, regular patient assessment and consideration of systemic conditions are imperative and may provide pivotal guidance for mitigating complications and enhancing patient prognosis. Declarations Funding: This work was supported by the Major Science and Technology Projects in Yunnan Province (Grant number 2018zf016); Rehabilitation Clinical Medical Centre of Yunnan Province (Grant number[zx2019-04-02); National Key Research and Development Program of China (Grant number 2018YFC2002301); Jiajie Expert Workstation of Yunnan Province (Grant number 2019IC034); Study on a New Model of Comprehensive Intervention in Rehabilitation and Psychology of "Brain and Heart together" (Grant number 202203AC100007-6); Science and Technology Talent and Platform Program (Academician and Expert Workstation) (Grant number 202305AF150032); Research and Development of Integrated Chinese and Western Medicine Rehabilitation Technology and Multi-modal Monitoring System for movement Disorders (Grant number 2022YFC2009700); Scientific Research Fund project of Education Department of Yunnan Province (Grant number 2024J0383). Ethical Approval: This study has been performed in accordance with the ethical standards in the 1964 Declaration of Helsinki and has been carried out in accordance with relevant regulations of the US Health Insurance Portability and Accountability Act (HIPAA). The author has informed the patient and obtained the patient’s consent, and the informed consent form has been signed. Consent to Publish declaration: The author has informed the patient and obtained the patient’s consent, and the informed consent form has been signed. Availability of data and materials: The datasets generated and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request. Clinical Trial Number: Not applicable Competing interests: Not applicable Funding: This work was supported by the Major Science and Technology Projects in Yunnan Province (Grant number 2018zf016); Rehabilitation Clinical Medical Centre of Yunnan Province (Grant number[zx2019-04-02); National Key Research and Development Program of China (Grant number 2018YFC2002301); Jiajie Expert Workstation of Yunnan Province (Grant number 2019IC034); Study on a New Model of Comprehensive Intervention in Rehabilitation and Psychology of "Brain and Heart together" (Grant number 202203AC100007-6); Science and Technology Talent and Platform Program (Academician and Expert Workstation) (Grant number 202305AF150032); Research and Development of Integrated Chinese and Western Medicine Rehabilitation Technology and Multi-modal Monitoring System for movement Disorders (Grant number 2022YFC2009700); Scientific Research Fund project of Education Department of Yunnan Province (Grant number 2024J0383). Authors' Contributions: Hao-Tian Wu is responsible for collecting, plotting, writing and editing the relevant data in the article. Li-Qing Yao was responsible for reviewing and editing the paper. Xue Yang for data collection and editing Zhou Yao and Chen Zihan supported the data query and plotting. Acknowledgements The authors would like to thank all the participants in the study. References Kang, H.J., et al., Epidemiology of Ankle Fractures in Korea: A Nationwide Population-Based Study. Journal of Korean Medical Science, 2022. 37 (38). Court-Brown, C.M. and B. Caesar, Epidemiology of adult fractures: A review. Injury, 2006. 37 (8): p. 691-697. Kyriacou, H., et al., Principles and guidelines in the management of ankle fractures in adults. Journal of Perioperative Practice, 2021. 31 (11): p. 427-434. Larsen, P., M. Al-Bayati, and R. Elsøe, The Foot and Ankle Outcome Score (FAOS) During Early Recovery After Ankle Fracture. Foot & Ankle International, 2021. 42 (9): p. 1179-1184. 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Denaro, Vertebroplasty versus conservative treatment for vertebral fractures. The Lancet, 2010. 376 (9758). Stirling, P., et al., Patient-reported functional outcomes and health-related quality of life following fractures of the talus. The Annals of The Royal College of Surgeons of England, 2019. 101 (6): p. 399-404. Issa, K., et al., Clinical Characteristics of Early-Stage Osteonecrosis of the Ankle and Treatment Outcomes. Journal of Bone and Joint Surgery, 2014. 96 (9). Greenhagen, R.M., et al., Bilateral Osteonecrosis of the Navicular and Medial Cuneiform in a Patient with Systemic Lupus Erythematosus. Foot & Ankle Specialist, 2012. 5 (3): p. 180-184. Ensrud, K.E. and C.J. Crandall, Osteoporosis. Annals of Internal Medicine, 2017. 167 (3). Khosla, S. and L.C. Hofbauer, Osteoporosis treatment: recent developments and ongoing challenges. The Lancet Diabetes & Endocrinology, 2017. 5 (11): p. 898-907. Pietschmann, P., et al., Immunology of Osteoporosis: A Mini-Review. Gerontology, 2016. 62 (2): p. 128-137. Weitzmann, M.N. and I. Ofotokun, Physiological and pathophysiological bone turnover — role of the immune system. Nature Reviews Endocrinology, 2016. 12 (9): p. 518-532. Ma, M., et al., Osteoimmunology and osteonecrosis of the femoral head. Bone & Joint Research, 2022. 11 (1): p. 26-28. Wang, L.-T., L.-R. Chen, and K.-H. Chen, Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview. International Journal of Molecular Sciences, 2023. 24 (6). Buettmann, E.G., et al., Similarities Between Disuse and Age ‐Induced Bone Loss. Journal of Bone and Mineral Research, 2022. 37 (8): p. 1417-1434. Brent, M.B., Pharmaceutical treatment of bone loss: From animal models and drug development to future treatment strategies. Pharmacology & Therapeutics, 2023. 244 . Zheng, X.-Q., et al., Pathophysiological mechanism of acute bone loss after fracture. Journal of Advanced Research, 2023. 49 : p. 63-80. Herrmann, M., et al., Interactions between Muscle and Bone—Where Physics Meets Biology. Biomolecules, 2020. 10 (3). Li, H., et al., Protein kinase G signaling pathway is involved in sympathetically maintained pain by modulating ATP-sensitive potassium channels. Regional Anesthesia & Pain Medicine, 2021. 46 (11): p. 1006-1011. Dudareva, M., et al., The microbiology of chronic osteomyelitis: Changes over ten years. Journal of Infection, 2019. 79 (3): p. 189-198. Oliveira, T.C., M.S. Gomes, and A.C. Gomes, The Crossroads between Infection and Bone Loss. Microorganisms, 2020. 8 (11). Loi, F., et al., Inflammation, fracture and bone repair. Bone, 2016. 86 : p. 119-130. Clézardin, P., et al., Bone metastasis: mechanisms, therapies, and biomarkers. PHYSIOLOGICAL REVIEWS, 2021. 101 : p. 797-855. Weilbaecher, K.N., T.A. Guise, and L.K. McCauley, Cancer to bone: a fatal attraction. Nature Reviews Cancer, 2011. 11 (6): p. 411-425. Clézardin, P., Pathophysiology of bone metastases from solid malignancies. Joint Bone Spine, 2017. 84 (6): p. 677-684. Burnett, J.R. and S.D. Vasikaran, Cardiovascular disease and osteoporosis: is there a link between lipids and bone? The Association of Clinical Biochemists, 2002. 39 : p. 203-210. Tian, L.I. and X. Yu, Lipid metabolism disorders and bone dysfunction-interrelated and mutually regulated (Review). Molecular Medicine Reports, 2015. 12 (1): p. 783-794. Anagnostis, P., et al., Bone Health in Patients with Dyslipidemias: An Underestimated Aspect. International Journal of Molecular Sciences, 2022. 23 (3). Laroche, M., et al., Osteoporosis and ischemic cardiovascular disease. Joint Bone Spine, 2017. 84 (4): p. 427-432. Szekanecz, Z., et al., Common mechanisms and holistic care in atherosclerosis and osteoporosis. Arthritis Research & Therapy, 2019. 21 (1). Bickley, M.K.J., et al., Avascular necrosis of the foot and ankle: aetiology, investigation and management. Orthopaedics and Trauma, 2023. 37 (1): p. 40-48. Moon, D.K., Epidemiology, Etiology, and Anatomy of Osteonecrosis of the Foot and Ankle. Foot and Ankle Clinics, 2019. 24 (1): p. 1-16. Assouline-Dayan, Y., et al., Pathogenesis and Natural History of Osteonecrosis. Seminars in Arthritis and Rheumatism, 2002. 32 (1): p. 94-124. Motta, F., et al., Steroid-induced osteonecrosis. Journal of Translational Autoimmunity, 2022. 5 . Chang, C., A. Greenspan, and M.E. Gershwin, The pathogenesis, diagnosis and clinical manifestations of steroid-induced osteonecrosis. Journal of Autoimmunity, 2020. 110 . Konarski, W., et al., Osteonecrosis Related to Steroid and Alcohol Use—An Update on Pathogenesis. Healthcare, 2023. 11 (13). Chen, S., A. Kavanagh, and C. Zarick, Steroid-Induced Avascular Necrosis in the Foot and Ankle—Pathophysiology, Surgical, and Nonsurgical Therapies: Case Study and Literature Review. Foot & Ankle Specialist, 2021. Powell, C., et al., Steroid induced osteonecrosis: An analysis of steroid dosing risk. Autoimmunity Reviews, 2010. 9 (11): p. 721-743. Lafforgue, P. and S. Trijau, Bone infarcts: Unsuspected gray areas? Joint Bone Spine, 2016. 83 (5): p. 495-499. Torrente Segarra, V. and M. Bonet, Multifocal osteonecrosis in systemic lupus erythematosus: Two case reports and literature review. European Journal of Rheumatology, 2021. 8 (1): p. 46-47. Sun, W., et al., The pathogenesis of multifocal osteonecrosis. Scientific Reports, 2016. 6 (1). Gallart Úbeda, V., et al., Osteonecrosis multifocal. Actualización y caso clínico. Rehabilitación, 2020. 54 (1): p. 63-67. Cajiao, K., F.J. Setoain, and P. Peris, Multifocal Osteonecrosis. JCR: Journal of Clinical Rheumatology, 2021. 27 (5): p. e196-e197. Couturier, S. and G. Gold, Imaging Features of Avascular Necrosis of the Foot and Ankle. Foot and Ankle Clinics, 2019. 24 (1): p. 17-33. Cooper, C., et al., The epidemiology of osteoporosis. British Medical Bulletin, 2020. Sozen, T., L. Ozisik, and N. Calik Basaran, An overview and management of osteoporosis. European Journal of Rheumatology, 2017. 4 (1): p. 46-56. Barnsley, J., et al., Pathophysiology and treatment of osteoporosis: challenges for clinical practice in older people. Aging Clinical and Experimental Research, 2021. 33 (4): p. 759-773. Noh, J.-Y., Y. Yang, and H. Jung, Molecular Mechanisms and Emerging Therapeutics for Osteoporosis. International Journal of Molecular Sciences, 2020. 21 (20). Link, T.M. and S. Majumdar, Osteoporosis imaging. Radiologic Clinics of North America, 2003. 41 (4): p. 813-839. PORT, A.M., et al., Comparison of two conservative methods of treating an isolated fracture of the lateral malleolus. J Bone Joint Surg, 1996. 78 : p. 568-572. Azeez, T.A., Osteoporosis and cardiovascular disease: a review. Molecular Biology Reports, 2022. 50 (2): p. 1753-1763. Stegen, S. and G. Carmeliet, The skeletal vascular system – Breathing life into bone tissue. Bone, 2018. 115 : p. 50-58. Lin, C.-W.C., et al., Rehabilitation for ankle fractures in adults , in Cochrane Database of Systematic Reviews . 2012. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5348097","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":378854356,"identity":"b0d98a1c-3893-4ed2-b1bd-411d8e13a7c2","order_by":0,"name":"Haotian Wu","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Haotian","middleName":"","lastName":"Wu","suffix":""},{"id":378854357,"identity":"07ea76ac-2e9b-42b8-93ee-eac3536b85ae","order_by":1,"name":"Liqing Yao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAklEQVRIiWNgGAWjYHACxgMJDBIMDOzNx39+MLDh4edvIKwHooXnWIK0REGajOSMA0RoAZMSOQYSPB8O2xg0JOBXbnD88IEDD8os8uQj0hIMJAzO8xgwHGD88DEHj5YzaQkHEs5JFBueeXwgocDgNo85cwOz5MxteLQcyDE4kNgmkbixHahXAqjFsuEAGzMvPi3n30C1NOQYNvAYnOMxOJBAQMsNqC3zOXKMGYDqCWuRvPEM7JfEDTzH0pglDJJ5JGccbMbrF77zyQcf/iirS5zf3nyM8cMfO3t+/uaDHz7i0aJwAESygcIBLsbYgFs9EMg3QLXI41c3CkbBKBgFIxkAALq5XQw+dSsqAAAAAElFTkSuQmCC","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":true,"prefix":"","firstName":"Liqing","middleName":"","lastName":"Yao","suffix":""},{"id":378854358,"identity":"051ea0a6-27b0-4620-911a-732ff6d9384f","order_by":2,"name":"Xue Yang","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"Yang","suffix":""},{"id":378854359,"identity":"6142254e-2dd1-418f-aa40-6d5a62864487","order_by":3,"name":"Yao Zhou","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yao","middleName":"","lastName":"Zhou","suffix":""},{"id":378854360,"identity":"2db38c9a-fba2-42b6-b6b6-c461fb4b84b2","order_by":4,"name":"Zihan Chen","email":"","orcid":"","institution":"Second Affiliated Hospital of Kunming Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zihan","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-10-28 14:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5348097/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5348097/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70964296,"identity":"b8b14de5-cddc-4d47-8181-04f5b30833ea","added_by":"auto","created_at":"2024-12-09 15:56:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8684318,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTimeline of patient diagnosis and relevant radiological imaging: \u003c/strong\u003eThe left side of the figure illustrates the timeline of the patient's clinical course, while the right side corresponds to the radiological findings at specific time points. The blue arrow in the image indicates the site of the fracture, the red arrow points to the area of bone destruction, and the yellow arrow identifies the location of ligament damage.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5348097/v1/a12067bb7ed730b1f38d97d7.png"},{"id":70963416,"identity":"829c2054-81be-43ba-adf9-5ff44818f5ca","added_by":"auto","created_at":"2024-12-09 15:48:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":371658,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnatomy of the blood vessels and ligaments in the foot and ankle joint region\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5348097/v1/2a09265152a479f430275842.png"},{"id":70964297,"identity":"f364e4c3-0bed-4336-98b6-273790cc715a","added_by":"auto","created_at":"2024-12-09 15:56:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2445339,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiagram depicting the different causes of partial bone loss：(a)\u003c/strong\u003e Various factors that influence the mechanisms of bone loss post-fracture, including immobilization, mechanical stress reduction, vascular damage, sympathetic stimulation, and interactions between the muscles and bones. \u003cstrong\u003e(b)\u003c/strong\u003e Direct and indirect pathways through which infection by pathogenic microorganisms can affect bone remodeling and cause bone loss. \u003cstrong\u003e(c)\u003c/strong\u003e Variedtumor-secreted factors that affect osteoblasts and osteoclasts. \u003cstrong\u003e(d)\u003c/strong\u003e The relationship between lipid metabolism disorders and bone loss, as demonstrated by the molecular mechanisms involved in the related pathophysiological processes.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5348097/v1/ec4fcb2fb30e73ee8da700b0.png"},{"id":70964295,"identity":"db550211-d07a-454d-8d8a-52ed45bbdcd4","added_by":"auto","created_at":"2024-12-09 15:56:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":683650,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLiterature screening process for selecting case reports of\u003c/strong\u003e \u003cstrong\u003efoot and ankle osteonecrosis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5348097/v1/03a224e71224368cd97d9e32.png"},{"id":70963418,"identity":"543f7c24-49d7-40eb-9ffa-d873a8b36f79","added_by":"auto","created_at":"2024-12-09 15:48:32","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1753505,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStatistical analysis of the etiology (a) and location (b) of avascular necrosis in the foot and ankle. \u003c/strong\u003eSLE: Systemic Lupus Erythematosus; HVEI: High Voltage Electrical Injury; HIV: Human Immunodeficiency Virus; OSID: Other Systemic Immune Disorders; IAOD: Iliac Artery Occlusive Disease.\u003c/p\u003e","description":"","filename":"figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5348097/v1/45467a507481e4c84a74c1d9.png"},{"id":70963421,"identity":"f7dbbe64-efc7-455d-b784-b8af35e27abc","added_by":"auto","created_at":"2024-12-09 15:48:32","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2766135,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDiagram illustrating osteoporosis in multiple bones of the patient's foot: \u003c/strong\u003eMultiple factors of the patient that disrupted the balance between osteoblasts and osteoclasts, thereby causing bone resorption to exceed bone formation. Ultimately, osteoporosis developed in multiple bones of the foot.\u003c/p\u003e","description":"","filename":"figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-5348097/v1/83ccdc6b9c62a53ec60297c7.png"},{"id":90794937,"identity":"58203454-9428-443c-9936-378f70c3fece","added_by":"auto","created_at":"2025-09-08 08:47:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":18276896,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5348097/v1/839149e6-643a-4425-9cb5-6b7539b3d492.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Worm-eaten-like osteolytic changes in multiple bones of the foot following stable ankle fracture: A case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnkle fractures are prevalent orthopedic conditions that can occur across all ages, accounting for 10.2% of all bone injuries [1]. These fractures have a notably high incidence among older women and younger men [2] and are primarily observed in sports injuries [3]. Furthermore, population aging and the social environment of universal participation in sports have led to an increasing number of ankle fractures annually [4]. The management of ankle fractures involves assessing the stability of the ankle joint, potential complications, and preoperative functional capacity to determine the appropriateness of surgical or nonsurgical intervention [5]. Ankle fractures typically lead to ankle pain, swelling of the affected joint, limited joint movement, and joint stiffness, eventually resulting in decreased muscle strength in the impacted lower limb and gait abnormalities [6, 7]. Therefore, dysfunction after an ankle fracture can affect a patient's ability to perform daily activities as well as their physical and mental health [8].\u003c/p\u003e \u003cp\u003eThe pathophysiological processes involved in fracture repair are crucial for identifying suitable management strategies and predicting the outcomes of ankle fractures. Fracture repair encompasses a series of pathophysiological processes that can be delineated into two main stages: primary and secondary healing [9]. After a fracture, the periosteum and bone tissue are disrupted, and a clot is rapidly formed to serve as a provisional matrix for initial repair. Subsequently, an inflammatory phase ensues, where inflammatory cells substantially accumulate and neovascularization is promoted via the proliferation and migration of mesenchymal cells from the periosteum and endosteum. Cartilage formation and intramembranous ossification then contribute to bone formation. In the final stage of the fracture repair process, the original bone is resorbed by osteoclasts to facilitate bone remodeling and restore the bone shape and structure [10]. This fracture repair process and prognosis of ankle fractures are influenced by numerous factors, including sex, age, fracture severity, cartilage damage, vascular supply, and anatomical repositioning [11].\u003c/p\u003e \u003cp\u003eGenerally, stable fractures have a favorable prognosis, with approximately 10% developing adverse complications such as delayed healing and malunion [12]. In this case report, we reported a case of a male patient who presented with a closed stable ankle fracture that exhibited poor healing, osteonecrosis, bone fragment formation, and a rare manifestation of osteoporosis affecting multiple foot bones. This case report aims to examine the two primary complications of osteoporosis and osteonecrosis associated with stable ankle fractures and highlight the significance of early recognition, routine monitoring, and vascular health assessment in predicting the outcomes of patients with fractures.\u003c/p\u003e"},{"header":"Patient and observation","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e \u003cp\u003eThe patient was a 47-year-old male who sustained a right ankle fracture in an automobile accident in May 2023. After the accident, the patient experienced swelling, pain, and limited mobility of the right ankle joint with no open wound. However, the patient initially disregarded these apparent symptoms. The next day following his injury, the patient visited a local hospital and underwent a anteroposterior and lateral X-ray examination(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The X-ray results revealed disruption of the cortical continuity and soft tissue swelling of the right lateral ankle, along with the formation of bone spurs at the inferior aspect of the right calcaneus. During the initial conservative treatment at the hospital, the medical staff did not immobilize the patient with support. At 10 days after the fracture, the patient attempted weight-bearing and experienced worsening pain and right ankle swelling. Consequently, the patient sought further treatment by consulting multiple hospitals and clinics. The patient underwent conservative symptomatic therapies such as the external application of Chinese herbs, acupuncture, and ice packs; however, he did not experience any noteworthy improvement in his symptoms. Considering his persistent discomfort, the patient eventually visited our hospital's rehabilitation department in September 2023 for treatment. In terms of his medical history, the patient had a smoking habit for over 30 years (approximately 30 cigarettes/day) and an alcohol drinking habit for over 2 years (approximately 20 ml/day). Moreover, he had elevated blood lipid levels for more than 10 years. Lastly, the patient was diagnosed with hypertension 2 years ago (peak blood pressure: 150/99 mmHg) and was on long-term medication with amlodipine benzenesulfonate tablets. The author has informed the patient and obtained the patient\u0026rsquo;s consent, and the informed consent form has been signed.\u003c/p\u003e \u003cp\u003eClinical findings\u003c/p\u003e \u003cp\u003eVisual examination at our hospital in Septemper demonstrated mild swelling and dark discoloration of the patient's right ankle and foot dorsum. Palpation near the fracture site indicated normal skin temperature on the medial side of the right ankle joint, along with pressure and pain observed in the lateral ankle area of the right foot. Furthermore, regular pulsation of the dorsal pedal artery was palpable. Range of motion assessment of the joint revealed a pronounced limitation in right ankle movement accompanied by notable pain upon pressure. In particular, the joint range of motion measurement showed that the active dorsiflexion of the right ankle joint was 5\u0026deg;, toe flexion was 5\u0026deg;, and internal and external rotation was 0\u0026deg;. Laboratory tests indicated a positive T-SPOT tuberculosis test and elevated total cholesterol and triglyceride levels, whereas other test results were within normal limits. An imaging assessment conducted during the patient's outpatient visit in July 2023 showed emxisting bone conditions in the right foot (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003eAfter admission to our hospital, the patient underwent additional examinations. Three-dimensional reconstruction of the right ankle joint using computed tomography (CT) revealed multiple bone lesions in the right ankle and soft tissue swelling around the joint. Magnetic resonance imaging (MRI) suggested degenerative changes in the ankle joint, irregular morphology of the lateral malleolus, and possible injuries to the anterior and posterior talofibular ligaments. Additionally, soft tissue edema was observed around the joint and foot dorsum, accompanied by minor joint effusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee\u0026amp;f). However, no significant abnormalities were found on chest CT and abdominal ultrasound.\u003c/p\u003e \u003cp\u003eTherapeutic intervention\u003c/p\u003e \u003cp\u003eThe patient was diagnosed with multifocal bone destruction in the right foot, which was potentially exacerbated by delayed treatment due to inadequate monitoring during visits to other hospitals from May to August. Upon presentation to our hospital, a comprehensive laboratory and imaging assessment of the patient was promptly performed. Given the finding of extensive osteolytic bone destruction in the right ankle, standardized treatment protocols were swiftly initiated. The interventions encompassed isometric muscle training, joint mobilization exercise, magnetic therapy, intermediate frequency electrotherapy, ultrasound treatment, and acupuncture to facilitate tissue repair and alleviate pain. Moreover, gradual weight-bearing ambulation was prescribed to incrementally enhance activity levels and promote recovery. By September 28, the patient showed significant improvement in right ankle swelling and functional limitations and was discharged from the hospital.\u003c/p\u003e \u003cp\u003eFollow up\u003c/p\u003e \u003cp\u003eAfter 2 months following discharge from our hospital, the patient was admitted to the hospital for coronary artery disease and was subsequently treated with coronary stenting. At 3 months after discharge from our hospital, the patient reported considerable pain in the right ankle during prolonged jogging or walking. A follow-up CT scan of the right ankle showed an old fracture with adjacent loose bone fragments, degenerative changes, and osteoporosis affecting the ankle joint (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eg).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAnkle fractures are highly prevalent in adults, constituting 10.2% of all fractures[13]. After the incidence of an ankle fracture, a hematoma is formed at the fracture site, followed by the accumulation of numerous inflammatory cells and mesenchymal stem cells. Next, chondrocytes initiate proliferation and differentiate to transform bone tissue via the action of osteoblasts. This process culminates in the bone remodeling stage, where osteoblasts modulate the bone structure and morphology by resorbing and depositing bone tissue [12]. Ultimately, normal tissue connectivity and function are restored around the ankle joint.\u003c/p\u003e\n\u003cp\u003eThe foot and ankle joint region are a tightly packed and functionally intricate structure comprising multiple ligaments, muscles, bones, and blood vessels. In Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, we present a simplified anatomical dissection diagram of the ankle joint. The ligaments in the foot and ankle are crucial in maintaining joint stability. Among these, the deltoid ligament supports the medial aspect of the ankle joint and limits valgus motion and stress. The lateral collateral ligament, which consists of the anterior and posterior talofibular ligaments and the calcaneofibular ligament, restricts ankle joint inversion, valgus stress, and rotation [14]. Furthermore, arteries, veins, and their branches intricately traverse the foot and ankle to supply oxygen and nutrients to the tissues, with variations in the arterial anatomy being notably prevalent in this region [15]. Hence, understanding these variations is pivotal for physicians managing patients with fractures and preventing potential complications. In summary, the coordination among ankle muscles, ligaments, and blood vessels contributes to the maintenance of the physiological function of the ankle joint.\u003c/p\u003e\n\u003cp\u003eThe ankle joint is critically involved in supporting the weight of the human body. This joint has a large contact area that distributes gravitational stresses [14] and performs an essential weight-bearing function, as evidenced by gait analysis studies. During normal walking, the ankle joint bears approximately five times the body weight. However, forces on the ankle joint during high-impact activities such as running can exceed thirteen times the body weight, underscoring its significant load-bearing capacity [16]. Therefore, considering its role as a weight-bearing joint, immobilization and proper management following ankle fracture are vital [17].\u003c/p\u003e\n\u003cp\u003eAnkle fractures can result in ischemic osteonecrosis, osteoarthritis, bone nonunion, and cartilage damage [11, 18]. Of these, ischemic osteonecrosis and osteoporosis are more common and frequently mistaken by non-orthopedic physicians; however, they have distinct outcomes and treatments. Ischemic osteonecrosis leads to the collapse of the articular surface and typically necessitates surgical interventions, including medullary decompression, percutaneous drilling, and even joint fusion and arthroplasty in some cases [19, 20]. In contrast, osteoporosis usually increases bone fragility and fracture susceptibility [21] and is often managed using medications such as estrogen, alendronate, and odanacatib [22]. All these results underline that recognizing these distinctions is crucial for non-orthopedic specialists (e.g., rehabilitation physicians) to effectively ameliorate the severe complications following ankle fractures. Hence, we conducted a literature review on the rare manifestations of this common condition, focusing on summarizing osteonecrosis and osteoporosis complications to provide clinicians with valuable diagnostic insights and treatment strategies.\u003c/p\u003e\n\u003cp\u003e1 Physiopathological processes in the bone tissue\u003c/p\u003e\n\u003cp\u003eOsteoclasts and osteoblasts have distinct physiological roles in the bone tissue. Osteoclasts continuously resorb aged, damaged, and unwanted bone tissue, while osteoblasts perpetually generate new bone tissue [16]. These entire processes are governed by the endocrine and immune systems [23] via signaling pathways such as the RANK-RANKL-OPG and Wnt pathways that collectively regulate bone remodeling [24]. However, aging or specific pathological conditions can disrupt the equilibrium between bone resorption and formation, inducing bone loss and potentially culminating in osteonecrosis or osteoporosis [25, 26].\u003c/p\u003e\n\u003cp\u003e1.1 Common causes of bone loss\u003c/p\u003e\n\u003cp\u003eApart from the aging-related imbalance where bone resorption exceeds bone formation, numerous pathologies such as fractures, skeletal unloading, chronic inflammation, autoimmune disorders (e.g., rheumatoid arthritis), tumors, and hyperparathyroidism can cause bone loss by escalating osteoclast activity and diminishing osteoblast activity [27, 28]. In this literature review, we focus on the primary contributors such as fractures, infections, and tumors (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eXuan-Qi et al. outlined the underlying mechanisms of post-fracture bone loss and attributed it to several factors, including immobilization, diminished mechanical stress, impaired blood supply, modulation of the sympathetic nervous system, and muscle and bone interactions [29]. The musculoskeletal system primarily sustains physiological gravitational loads, whereas muscle contraction and movement generate essential force stimuli crucial for maintaining bone health [30]. Skeletal unloading, also termed weightlessness or microgravity, can occur due to immobilization after a fracture. This condition combined with reduced muscle strength and activity can decrease skeletal loading, eventually leading to bone loss. The bones and muscles also regulate osteoclast activation, function, and homeostasis of bone repair through the secretion of factors such as mechanical growth factor, insulin-like growth factor-1, and interleukin-6 (IL-6). Moreover, fractures usually disrupt the blood supply to cause skeletal cell ischemia and hypoxia, ultimately resulting in osteoblast death and subsequent bone loss. Vascular endothelial growth factor is an essential component of this cascade. Bone reconstruction is also regulated by the nervous system via the abundant nerve fibers in the periosteum and the adrenergic receptors present on osteoblasts and osteoclasts [29]. Pain following a fracture incident can trigger sympathetic activation [31]. This activation leads to heightened levels of plasma norepinephrine that interacts with the \u0026beta;-adrenergic receptors on osteoblasts and osteoclasts. Subsequently, these receptors disrupt bone remodeling homeostasis by inhibiting osteogenesis and promoting bone resorption [29]. All these complex factors interact with the pathophysiological process of acute bone loss following fractures.\u003c/p\u003e\n\u003cp\u003eBone loss can also result from infections, among which \u003cem\u003eStaphylococcus aureus\u003c/em\u003e is the most predominant pathogen [32]. Pathogen infections can cause bone destruction through direct and indirect mechanisms. In the direct mechanism, invasive pathogens attack bone tissue cells such as osteoblasts, osteoclasts, and osteocytes, which triggers oxidative stress and the generation of reactive oxygen species to combat these pathogens while also accelerating bone resorption. These alterations ultimately lead to bone destruction. In the case of the indirect mechanism, infections stimulate the production of inflammatory mediators such as tumor necrosis factor-\u0026alpha; (TNF-\u0026alpha;), IL-1\u0026beta; and IL-6, which interfere with bone metabolism and compromise bone integrity [33]. Currently, the interactions between inflammatory cells and the cells involved in bone healing are widely acknowledged as crucial factors for bone formation, repair, and remodeling [34].\u003c/p\u003e\n\u003cp\u003eBone metastases from malignancies, particularly those originating from breast and prostate cancers, are another common cause of bone loss [35]. After tumor cells establish themselves and become active in the bone tissue, they secrete various factors that disrupt normal bone remodeling. Of these factors, parathyroid hormone-related protein has been identified as a key contributor to malignant bone destruction [36], owing to its structural resemblance to the parathyroid hormone. This structural similarity facilitates RANKL expression, thereby enhancing osteoclast activity and bone resorption [37]. Moreover, tumor-released factors can impede bone formation. For instance, Dickkopf-1 (DKK-1) is a factor that inhibits osteoblast activity by antagonizing Wnt protein family actions on osteoblasts [36].\u003c/p\u003e\n\u003cp\u003eFurthermore, a strong link has been demonstrated between atherosclerosis and the skeletal system [38]. Recent research has indicated that lipid metabolism alterations may disrupt bone remodeling homeostasis by interfering with critical signaling pathways. For example, elevated cholesterol or triglyceride levels may affect the regulation of the RANKL/RANK/OPG and Wnt signaling pathways. Adipocyte-secreted adipokines, such as leptin and lipocalins, may also modulate bone metabolism. The resulting lipid metabolism disorders may cause abnormalities in vascular endothelial cells and increase thrombosis, consequently affecting bone microcirculation [39]. Panagiotis et al. have suggested that dyslipidemia can induce oxidative stress and inflammation, which in turn promote bone resorption while inhibiting bone formation [40]. Current studies have also indicated that the development of atherosclerosis and osteoporosis may be influenced by aging, smoking, sedentary lifestyle, estrogen levels, oxidative stress, and various factors such as the nuclear hormone receptor transcription factor PPAR\u0026gamma;2, IL-1, IL-6, TNF-\u0026alpha;, osteoprotegerin, fibroblast growth factor-23, sclerostin, adipokines, and bone morphogenetic proteins [39, 41, 42].\u003c/p\u003e\n\u003cp\u003e2. Osteonecrosis\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e2.1 Concept of osteonecrosis\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eOsteonecrosis, also known as ischemic bone necrosis, bone infarction, or aseptic bone necrosis, typically results from the disruption of skeletal blood supply that causes ischemia and hypoxia of bone tissue, ultimately leading to tissue death. Osteonecrosis in the foot and ankle is less frequent than that in the femoral head, wrist, knee, and shoulder joints. The primary pathological process of this condition involves increased intracortical pressure within the bone cortex, disruption of the vascular system, and heightened mechanical stress on the bone cells, which collectively contribute to osteonecrosis development[43]. Various factors can induce osteonecrosis, with trauma being the most prevalent trigger [44]. Moreover, glucocorticoid use, systemic lupus erythematosus, hematologic disorders, excessive alcohol consumption, smoking, and infections are recognized non-traumatic risk factors for osteonecrosis [45]. We further explored the rare etiology and clinical presentations of foot and ankle osteonecrosis by reviewing the 92 case reports (including 102 patients) that documented this necrotic condition over the last decade (2013.11.17\u0026ndash;2023.11.17) from databases including PubMed, Embase, CBM, Cochrane, and CNKI (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e2.2 Etiology of osteonecrosis\u003c/p\u003e\n\u003cp\u003eIn our analysis, the predominant risk factors for osteonecrosis in the foot and ankle were identified as fracture, sprain, idiopathic origin, medical interventions, and glucocorticoid use, which were consistent with its common causes of fractures, sprains, or ligament tears resulting from trauma or accidents (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ea). Hence, clinicians should meticulously assess the history of trauma in patients presenting with foot and ankle pain. This approach aids in the early identification of latent injuries, thereby facilitating prompt interventions to prevent osteonecrosis onset in this region. However, the diagnosis and treatment of idiopathic osteonecrosis is relatively complicated because it typically lacks clear external triggers. For instance, the ischemic necrosis of the navicular bone, which is termed Kohler\u0026apos;s disease in children, often resolves spontaneously with a favorable prognosis. In contrast, this necrosis in adults, which is known as M\u0026uuml;ller\u0026ndash;Weiss disease, carries a relatively poor prognosis [20]. Additionally, conditions including Freiberg\u0026apos;s disease that affects the foot and the second or third metatarsal head or Preiser\u0026apos;s disease in the wrist can present unique challenges. Generally, patients with idiopathic osteonecrosis present to hospitals with non-traumatic foot pain, necessitating evaluation by clinicians and imaging examination. Furthermore, foot and ankle osteonecrosis arising from medical causes occupies a significant proportion and is primarily linked to vascular damage during surgical procedures or infections. Therefore, clinicians should remain vigilant for the potential incidence of osteonecrosis during medical interventions such as surgery and therapeutic procedures and possess a comprehensive understanding of its etiology to ensure the implementation of effective therapeutic strategies. Finally, glucocorticoid-induced osteonecrosis and its mechanisms have been extensively investigated, with genetic susceptibility, vascular damage, adipocyte dysfunction, increased intraosseous pressure, and bone marrow ischemia being implicated in this condition [46]. The presence of a dose-dependent relationship between osteonecrosis development and glucocorticoids is well-established [47\u0026ndash;49]. For example, a previous study has demonstrated the induction of osteonecrosis following cumulative doses of prednisone or its glucocorticoid equivalents ranging from 480 to 4320 mg [50]. However, numerous confounding variables have made it challenging to determine a safe threshold for glucocorticoid usage [47]. Therefore, clinicians should exercise caution when treating with cumulative steroid doses to mitigate osteonecrosis risk. For instance, high-dose methylprednisolone therapy should not exceed 5 days if administered at a dose of \u0026ge;\u0026thinsp;1 g/day.\u003c/p\u003e\n\u003cp\u003eAs observed in our investigation (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eb), foot and ankle osteonecrosis may also manifest concurrently with necrosis at anatomical sites other than the foot and ankle. Pierre et al. concluded that bone infarctions are typically multifocal and frequently coexist with multiple areas of ischemic osteonecrosis [51]. In such cases, osteonecrosis is considered multifocal when it is observed at three or more sites[52]. Moreover, the femoral head represents the most commonly affected site, followed by the knee, shoulder, and ankle bones[53]. Although glucocorticoid use constitutes the predominant etiological factor [54] of osteonecrosis, conditions such as lymphoma, HIV infection, and leukemia may also serve as causative factors[52, 55]. Therefore, clinicians should carefully consider all these factors when screening for the potential occurrence of multiple osteonecrosis during the management of non-traumatic osteonecrosis.\u003c/p\u003e\n\u003cp\u003e2.3 Imaging features of osteonecrosis\u003c/p\u003e\n\u003cp\u003eImaging tests such as X-rays, CT scans, and MRIs are crucial in diagnosing bone diseases. The use of \u0026ldquo;etc.\u0026rdquo; at the end of a list that is already introduced by \u0026ldquo;such as/including\u0026rdquo; is redundant.\u003c/p\u003e\n\u003cp\u003eHowever, the imaging findings can be unremarkable in the early stages of osteonecrosis, with the earliest radiologic sign being a radiolucent crescent [47]. In contrast, advanced stages of osteonecrosis are more easily identifiable. Osteonecrosis is characterized by osteosclerosis, which can be identified based on increased bone density on radiographic and CT images. Additionally, MRI images of osteonecrosis show a characteristic double-line sign presenting as a low-signal ring between necrotic and healthy bone tissue [56].\u003c/p\u003e\n\u003cp\u003e2.4 Summary\u003c/p\u003e\n\u003cp\u003eIn this case report, the CT scan of our patient conducted in 2024 indicated an old fracture of the right lateral ankle with characteristic peripheral free bone fragmentation shadows and a hyperdense shadow adjacent to the right talus, suggesting osteonecrosis. After reviewing the patient\u0026apos;s medical history, the osteonecrosis of the right ankle joint was suggested to have stemmed from the early inadequate immobilization and support initially provided to the patient. Furthermore, the patient had a medical history of hypertension, hyperlipidemia, and prolonged alcohol consumption and smoking, which can contribute to endothelial damage and coagulation abnormalities. Early imaging data in July 2023 further revealed injuries to the anterior and posterior talofibular ligaments of the right ankle and the deltoid ligaments of the medial malleolus. These ligamentous injuries compromised the stability of the ankle. All these factors influenced the bone tissue to undergo ischemia and hypoxia, ultimately resulting in osteonecrosis and the formation of free bone fragments.\u003c/p\u003e\n\u003cp\u003e3. Osteoporosis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cspan\u003e3.1 Concept of osteoporosis\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eOsteoporosis is a chronic skeletal disease characterized by the deterioration of bone tissue microarchitecture and a reduction in bone mineral density [21]. This condition significantly increases bone fragility and susceptibility to fractures [57] and is estimated to have a higher prevalence than cardiovascular disease and cancer [58]. Moreover, osteoporosis onset has been found to impair motor and cognitive functions, potentially increasing the mortality risk in affected individuals [59]. Consequently, osteoporosis imposes a substantial burden at the individual and societal levels.\u003c/p\u003e\n\u003cp\u003e3.2 Causes of osteoporosis after fracture incidence\u003c/p\u003e\n\u003cp\u003eThe fundamental pathology of osteoporosis involves the disruption of the equilibrium between bone formation and resorption. Apart from the well-established understanding that aging and menopause lead to bone resorption rates surpassing those of bone formation, several factors such as genetic predisposition, medication use, fractures, immobilization, chronic inflammation, endocrine disorders, and hematologic conditions can also contribute to osteoporosis by elevating osteoclast activity and diminishing osteoblast function[60].\u003c/p\u003e\n\u003cp\u003e3.3 Imaging features of osteoporosis\u003c/p\u003e\n\u003cp\u003eIn osteoporosis imaging, the reduction in bone density associated with osteoporosis presents as relative hypointensity. This imaging feature is discernible through techniques such as dual-energy X-ray absorptiometry and quantitative CT. Additionally, high-resolution imaging techniques such as MRI allow the assessment of structural degeneration in osteoporosis, revealing thinning of the trabeculae and cortical bone [61].\u003c/p\u003e\n\u003cp\u003e3.4 Summary\u003c/p\u003e\n\u003cp\u003eThe patient in our case report was diagnosed with delayed fracture healing accompanied by osteonecrosis development in multiple foot bones and osteoporosis. Immobilization is crucial for patients with stable ankle fractures, and the application of casts and splints can reduce the rehabilitation duration and enhance clinical outcomes [62]. Furthermore, proper immobilization fosters a conducive environment for fracture healing, potentially preventing the exacerbation of the initial injury and secondary complications. In our patient, inadequate immobilization significantly contributed to his unfavorable prognosis. Moreover, the early onset of ankle pain and swelling prompted the patient to engage in non-standard weight-bearing activities to mitigate discomfort. However, this approach resulted in additional injury, swelling of the ankle ligaments and surrounding soft tissues, and compression of the vascular network in the foot and ankle of the patient.\u003c/p\u003e\n\u003cp\u003eAnother noteworthy aspect of this case report is that our patient was diagnosed with coronary artery disease and subsequently underwent stent placement during the second month of follow-up. Previous research has confirmed a robust association between coronary artery disease and osteoporosis [63]. Thus, we could gain novel perspectives in managing our patient\u0026apos;s condition. Our patient also presented with hypertension, hyperlipidemia, and unhealthy lifestyle behaviors of smoking and alcohol consumption, all of which are established risk factors for atherosclerosis. These factors can contribute to the narrowing of the blood vessels in the foot and ankle, resulting in decreased blood flow. Additionally, specific conditions can cause the rupture of atherosclerotic plaques, which then form emboli that occlude blood vessels. Furthermore, adequate blood supply is vital for body tissue development and repair. Oxygen, nutrients, growth factors, and signaling molecules crucial for osteoblasts are delivered to bone tissues through blood circulation [64]. Hence, any interruptions or inadequate blood supply to bone tissues can induce ischemia and hypoxia, thereby disrupting cellular metabolism and escalating susceptibility to cellular damage and death. Moreover, cell death, damage, and hypoxia can activate immune cells that trigger the release of inflammatory mediators such as TNF-\u0026alpha;, IL-1\u0026beta;, and IL-11, which in turn can induce heightened bone destruction and decreased bone formation [33]. Once the inflammatory response is initiated, it can propagate within the bone marrow to elicit a widespread inflammatory cascade.\u003c/p\u003e\n\u003cp\u003e4 Case analysis\u003c/p\u003e\n\u003cp\u003eIn our patient, the combination of the previously mentioned factors contributed to diminished blood flow to the right foot, causing ischemia and hypoxia in the skeletal tissues. Consequently, these changes impaired fracture healing and led to the formation of free bone fragments and osteoporosis development. During this process, the interaction of factors, such as post-injury stress, triggered sympathetic nerve excitation, skeletal muscle injury, and minimized or impaired the normal load-bearing capacity of the bones, further exacerbating osteoporosis in the foot and ankle.\u003c/p\u003e\n\u003cp\u003eAfter completing the comprehensive rehabilitation treatment at our hospital, the patient exhibited considerable improvement in the localized swelling and restricted movement of the right ankle. Our patient-tailored therapeutic approach encompassed acupuncture, magnetic therapy, intermediate frequency electrotherapy, and isokinetic muscle exercise. These interventions were aimed at promoting local blood and lymphatic circulation, reducing soft tissue swelling and adhesions, alleviating local inflammatory responses, and improving the patient\u0026apos;s pain management and joint mobility and stability while also mitigating risks such as deep vein thrombosis. Although rehabilitation therapy has been proven beneficial for adults recovering from ankle fractures, available findings on the effects of rehabilitation are heterogeneous. Therefore, outcomes could vary based on individual differences [65]. Currently, literature on the rehabilitation of post-ankle fractures remains relatively limited and is supported by only a modest level of evidence. A consensus on the effective rehabilitation methodologies and their specific efficacy for these particular fractures is still lacking. Hence, further research endeavors are warranted to advance our understanding and comprehensively identify optimal rehabilitation strategies for managing ankle fractures.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on the clinical, imaging, and laboratory analyses of our patient, we strongly suspect that the root cause of the patient's osteonecrosis, formation of free bone fragments, and osteoporosis was atherosclerosis in the blood vessels and inadequate blood supply to the foot during the early non-standardized treatment. During the second month of follow-up, the patient underwent coronary artery stenting after being diagnosed with coronary artery disease. This development provided additional valuable insights into the patient's status. Considering these conditions, the interplay of atherosclerosis affecting vasculature across the body and secondary ankle injury due to early inadequate immobilization and irregular exercise may have together contributed to the patient's unfavorable clinical outcome. Our case report offers substantial clinical implications. Along with paying meticulous attention to the treatment and exercise regimen, the vigilant monitoring of vascular health is crucial when managing patients with fractures, especially those with persistent swelling and pain occurrence following fractures. Lastly, regular patient assessment and consideration of systemic conditions are imperative and may provide pivotal guidance for mitigating complications and enhancing patient prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Major Science and Technology Projects in Yunnan Province (Grant number 2018zf016); Rehabilitation Clinical Medical Centre of Yunnan Province (Grant number[zx2019-04-02); National Key Research and Development Program of China (Grant number 2018YFC2002301); Jiajie Expert Workstation of Yunnan Province (Grant number 2019IC034); Study on a New Model of Comprehensive Intervention in Rehabilitation and Psychology of \u0026quot;Brain and Heart together\u0026quot; (Grant number 202203AC100007-6); Science and Technology Talent and Platform Program (Academician and Expert Workstation) (Grant number 202305AF150032); Research and Development of Integrated Chinese and Western Medicine Rehabilitation Technology and Multi-modal Monitoring System for movement Disorders (Grant number 2022YFC2009700); Scientific Research Fund project of Education Department of Yunnan Province (Grant number 2024J0383).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been performed in accordance with the ethical standards in the 1964 Declaration of Helsinki and has been carried out in accordance with relevant regulations of the US Health Insurance Portability and Accountability Act (HIPAA). The author has informed the patient and obtained the patient\u0026rsquo;s consent, and the informed consent form has been signed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author has informed the patient and obtained the patient\u0026rsquo;s consent, and the informed consent form has been signed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient \u0026nbsp;data and anonymity but are available from the corresponding author on \u0026nbsp;reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Major Science and Technology Projects in Yunnan Province (Grant number 2018zf016); Rehabilitation Clinical Medical Centre of Yunnan Province (Grant number[zx2019-04-02); National Key Research and Development Program of China (Grant number 2018YFC2002301); Jiajie Expert Workstation of Yunnan Province (Grant number 2019IC034); Study on a New Model of Comprehensive Intervention in Rehabilitation and Psychology of \u0026quot;Brain and Heart together\u0026quot; (Grant number 202203AC100007-6); Science and Technology Talent and Platform Program (Academician and Expert Workstation) (Grant number 202305AF150032); Research and Development of Integrated Chinese and Western Medicine Rehabilitation Technology and Multi-modal Monitoring System for movement Disorders (Grant number 2022YFC2009700); Scientific Research Fund project of Education Department of Yunnan Province (Grant number 2024J0383).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHao-Tian Wu is responsible for collecting, plotting, writing and editing the relevant data in the article.\u003c/p\u003e\n\u003cp\u003eLi-Qing Yao was responsible for reviewing and editing the paper.\u003c/p\u003e\n\u003cp\u003eXue Yang for data collection and editing\u003c/p\u003e\n\u003cp\u003eZhou Yao and Chen Zihan supported the data query and plotting.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all the participants in the study.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKang, H.J., et al., \u003cem\u003eEpidemiology of Ankle Fractures in Korea: A Nationwide Population-Based Study.\u003c/em\u003e Journal of Korean Medical Science, 2022. \u003cstrong\u003e37\u003c/strong\u003e(38).\u003c/li\u003e\n\u003cli\u003eCourt-Brown, C.M. and B. 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Carmeliet, \u003cem\u003eThe skeletal vascular system \u0026ndash; Breathing life into bone tissue.\u003c/em\u003e Bone, 2018. \u003cstrong\u003e115\u003c/strong\u003e: p. 50-58.\u003c/li\u003e\n\u003cli\u003eLin, C.-W.C., et al., \u003cem\u003eRehabilitation for ankle fractures in adults\u003c/em\u003e, in \u003cem\u003eCochrane Database of Systematic Reviews\u003c/em\u003e. 2012.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rehabilitation, rehabilitation therapy, ankle fracture, fracture prognosis, osteoporosis, bone loss","lastPublishedDoi":"10.21203/rs.3.rs-5348097/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5348097/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e Stable fractures of the ankle joint are common in rehabilitation departments, often resulting in foot and ankle joint dyskinesia. Patients with ankle fractures usually experience pain, stiffness, swelling, limited mobility, lower extremity muscle weakness, and walking abnormalities. However, no reports have been published on stable ankle fractures causing polyostotic osteolytic changes in the foot and the subsequent formation of free bone fragments. In this case report, we described a case of a stable fracture of the right lateral malleolus with pathological alterations characterized by worm-eaten-like osteolytic changes in the distal right tibia, talus, calcaneus, and navicular bones, accompanied by the rare development of free bone fragments in the lateral ankle.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod \u0026amp; Conclusion \u003c/strong\u003eAfter an extensive literature review and thorough patient assessment, we concluded that the probable pathological cause was atherosclerosis affecting multiple blood vessels throughout the body due to risk factors such as hypertension and hyperlipidemia. Additionally, the localized trauma-induced fracture led to the foot and ankle swelling and altered bone stress loading, further triggering a cascade of vascular inflammatory reactions and sympathetic excitation within the already atherosclerotic blood vessels. Moreover, these effects were exacerbated by early inappropriate immobilization, which resulted in ischemia and hypoxia of the bone tissues in the injured area. Ultimately, all these factors contributed to the impaired healing of the ankle fracture and osteoporosis development in multiple foot bones. This case report presents a rare manifestation of a common condition, aiming to enhancethe decision-making process of cliniciansand facilitate the formulation ofbetter clinical diagnostic and therapeutic strategies.\u003c/p\u003e","manuscriptTitle":"Worm-eaten-like osteolytic changes in multiple bones of the foot following stable ankle fracture: A case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-09 15:48:26","doi":"10.21203/rs.3.rs-5348097/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f4c8525a-26aa-4a7a-9941-ff0f5f0807b3","owner":[],"postedDate":"December 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T08:39:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-09 15:48:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5348097","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5348097","identity":"rs-5348097","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}