Peptide Functionalised Nanocarriers for Bone Specific Delivery of PTH (1-34) in Osteoporosis

: Osteoporosis represents a major public health burden especially considering the aging population worldwide. Treatment modalities for osteoporosis are classified into two categories based on the effect on bone remodelling: anabolic drugs and antiresorptive drugs. Anabolic drugs are preferred as it stimulates new bone formation. Currently, PTH (1-34) is the only peptide-based drug approved as an anabolic agent for the treatment of osteoporosis by both USFDA as well as EMA. However, its non-specific delivery results in prolonged kidney exposure, causing hypercalcemia. Nanotechnology-based drug delivery systems functionalized by conjugating it with homing moieties, such as peptides, offer an advantage of targeted delivery with reduced off-target effects. Here, we propose an innovative and targeted nanovesicle approach to efficiently deliver PTH (1-34) to the bone surface using peptides as a homing moiety. The proposed innovative delivery approach will augment the specific interaction between the drug and bone surface without producing side effects. This will reduce the off-target effects of PTH (1-34), and at the same time, it will also improve the outcome of anabolic therapy. Therefore, we postulate that the proposed innovative drug delivery approach for PTH (1-34) will establish as a promising therapy for osteoporotic patients, specifically in postmenopausal women who are at greater risk of bone fracture.

Impact of Antiresorptive Agents on Maxillary Bones: a Narrative Literature Review

Antiresorptive drugs operate in the bone metabolism modulation and are widely used in the treatment of bone metastases and bone losses related to hormonal deficiency. Although this therapy shows satisfactory results, there are adverse effects associated with its use, such as osteonecrosis of the jaws. Medication-related osteonecrosis of the jaws (MRONJ) is, therefore, a serious and challenging condition with important implications in dentistry. The aim was to conduct a narrative literature review on anti-resorptive drugs and their latest repercussions on the maxillary bones. The review was carried out through a bibliographic search using Decs/Mesh descriptors of interest, in Portuguese and English, in the PubMed, Virtual Health Library (VHL) and Scielo databases. After applying the inclusion and exclusion criteria, a total of 33 studies were selected for analysis. It can be noticed that therapy with anti-resorptive agents is complex, especially in dental practice, since MRONJ is a complication that is difficult to manage. Regarding the therapeutic options, these are divided into conservative, surgical or adjuvant therapy, however, there are no protocols in the literature, and there is no consistency regarding the indication of the suspension of the drug administration - "Drug Holiday". Thus, it is important that the multidisciplinary team seeks strategies that minimize complications and promote control over the use of these drugs. In addition, there is a need for investigations that contribute with guidelines for the management and control of adverse effects resulting from therapy with antiresorptive drugs. Keywords: Bone Density Conservation Agents. Diphosphonates. Denosumab. Bisphosphonate-Associated Osteonecrosis of the Jaw. ResumoAs drogas antirreabsortivas atuam na modulação do metabolismo ósseo e são indicadas para o tratamento de metástases ósseas e perdas ósseas relacionadas à deficiência hormonal. Ainda que esta terapia apresente resultados satisfatórios, observam-se efeitos adversos associados ao seu uso, como a osteonecrose dos maxilares. A osteonecrose dos maxilares associada ao uso de medicamentos (OMAM) é, portanto, uma condição séria e desafiadora com implicações importantes na Odontologia. O objetivo foi realizar uma revisão narrativa de literatura sobre as drogas antirreabsortivas e suas respectivas repercussões nos ossos maxilares. A revisão foi realizada através de busca bibliográfica utilizando descritores Decs/Mesh de interesse, em português e inglês, nas bases de dados PubMed, Biblioteca Virtual de Saúde (BVS) e Scielo. Após aplicação dos critérios de inclusão e exclusão, um total de 33 trabalhos foram selecionados para análise. Pode-se constatar que a terapia com agentes antirreabsortivos é complexa, sobretudo na prática odontológica, visto que a OMAM é uma complicação de difícil manejo. Em relação às condutas terapêuticas para esta condição, divide-se em terapia conservadora, cirúrgica ou adjuvante, todavia, não existem protocolos validados na literatura, bem como não há consistência quanto à indicação do intervalo de suspensão da administração da droga - “Drug Holiday”. Desse modo, é importante que a equipe multidisciplinar busque estratégias que minimizem as complicações e promovam o controle no uso dessas drogas. Além disso, nota-se a necessidade de realizar investigações que contribuam com diretrizes para o manejo e controle dos efeitos adversos decorrentes da terapia com medicamentos antirreabsortivos. Palavras-chave: Conservadores da Densidade Óssea. Bisfosfonatos. Denosumabe. Osteonecrose Associada a Bisfosfonatos.

Real-world Study of Antiresorptive-Related Osteonecrosis of Jaw Based on the US Food and Drug Administration Adverse Event Reporting System (FAERS) database

Objective To explore the risk signals of osteonecrosis of jaw induced by antiresorptive drugs and provide references for the clinical safety application. Method Based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to June 2021, We chosen ‘Osteonecrosis of jaw’ as Preferred Terms (PT) and antiresorptive drugs. We used proportional reporting ratio (PRR), odds ratio (reporting odds ratio, ROR), Bayesian confidence propagation neural network (BCPNN) and multi-item Gamma-Poisson contraction (MGPS) algorithm to evaluate the association between drugs and adverse events. Results 27,065 reports related to osteonecrosis of the jaw in the FAERS dated from January 2004 to June 2021 . A total of 9 antiresorptive agents were included in the analysis. Affected patients tended to be older than 65 years. Most cases were reported from North America (39.82%) and Europe (36.15%) and were submitted by health-care professionals (81.44%). Pamidronate and clodronic acid showed a higher score than the other agents in every method. Zoledronic acid and denosumab were reported more than other agents.. Rate of hospitalization due to antiresorptive-related osteonecrosis of the jaw was from 7.66% to 28.78%; rate of fatality was from 0 to 12.78%. Conclusion All antiresorptive drugs may cause ONJ, and ONJ can be effectively prevented. Practitioners should consider the factors that may increase the likelihood of ONJ. The findings support a continued surveillance and risk factor identification studies.

Denosumab-related osteonecrosis of the external auditory canal—benefit of the early surgical management

Background: Antiresorptive drugs are widely used to reduce bone mineral loss in patients with osteoporosis and to prevent skeletal-related events in patients with metastatic cancers and multiple myeloma (MM). Both the bisphosphonates (BP) and denosumab typically used in this indication were shown to be effective and relatively safe. Obviously, this medication could have some adverse effects; one of them is osteonecrosis of the external auditory canal. Only sporadic cases of external auditory canal osteonecrosis have been published yet. Here, we provide a case of denosumab-related osteonecrosis of the external auditory canal successfully treated surgically in the early stage of the disease. Case report: A 68-year-old patient with breast cancer underwent comprehensive oncological treatment, including denosumab administration. She was diagnosed with osteonecroses in the jaw and ear canal. The necrotic bones in both regions were resected with primary wound closure. Both affected sites healed well with no signs of necrosis recurrence. Conclusions: Osteonecrosis of the external auditory canal is a rare but probably underdiagnosed complication of antiresorptive medication. It has a negative impact on patient quality of life if left untreated. Early surgical treatment appears to be effective. The authors highlight several similarities with medication-related osteonecrosis of the jaw. Therefore, an analogous disease staging and treatment rationale is suggested.

Local and generalized bone loss in rheumatoid arthritis

The article presents a review of cross-sectional studies and long-term prospective observations dedicated to changes in bone mineral density (BMD) in patients with rheumatoid arthritis (RA) and factors influencing it. The relationship between local bone loss (erosion count) and generalized BMD loss was noted. It is indicated that existing RA treatment strategies are aimed at suppressing inflammation rather than preventing bone resorption. There is evidence that anti-inflammatory therapy using glucocorticoids, methotrexate, and biologic DMARDs in combination with antiresorptive drugs (bisphosphonates and denosumab) helps prevent BMD loss and the progression of erosions. It is emphasized that osteoporosis in RA, which belongs to the immune-mediated secondary osteopathies, is one of the most frequent and serious complications of RA, which determine the unfavorable course and prognosis of the underlying disease.

Atypical Femoral Fracture in a Patient without Bisphosphonate or Denosumab Exposure-A Case Report

Introduction: Atypical femoral fractures (AFF) are associated with the use of bisphosphonates (BPs) or denosumab. However, few cases that meet the characteristics of these fractures, as established by the American Society of Bone and Mineral Research, have occurred in patients who have never used antiresorptive drugs. Case Report:We report a case of AFF in a 67-year-old woman who had never used antiresorptive medications. The history and comorbidities of the patient, the characteristics of the fracture, and the subsequent treatment are presented. Conclusion: AFFs may occur even in patients who have never been exposed to BPs or denosumab. The absence of antiresorptive osteoporosis therapy and the lack of radiographic focal periosteal reaction in the lateral femoral cortex, as in our case, can make it difficult to detect and prevent the disorder. Prolonged use of proton pump inhibitors and Vitamin D deficiency-related osteomalacia may contribute to the occurrence of these fractures. Further studies are required to accurately understand all inciting factors contributing to the development of AFFs. Keywords: Atypical femoral fractures, subtrochanteric fractures, denosumab, bisphosphonates, antiresorptive drugs.

Management of patients under Bone Anti-Resorptive Drugs- A Survey among Dental Practitioners

Introduction: Bone antiresorptive drugs are commonly prescribed for osteoporosis, Paget's disease, multiple myeloma, metastasis-associated with breast/prostate cancer. The most common complication of these drugs is the risk of developing osteonecrosis of the jaw. Maximum precautions should be taken in these patients before undertaking invasive dental procedures as they are at risk of developing osteonecrosis of the jaw. Thus, the purpose of this study is to assess the knowledge and practice among the dental practitioners in managing patients on these group of drugs. Aim: To assess the knowledge and practice regarding the management of patients under bone anti-resorptive therapy among dental practitioners in Saveetha Dental College. Materials and methods: A cross-sectional survey was conducted using a self-prepared and pre-validated questionnaire containing 13 close-ended questions on knowledge and practice among 150 dental practitioners in Saveetha Dental College. Results: Out of 150 Dental practitioners, 69% were female and 31% were male. About 33% of dentists had more than 2 years of experience while 67% had less than 2 years of experience. Qualification distribution revealed 50.7% of dental specialists and 49.3% dental graduates. The mean score of Knowledge and practice was high among males when compared to females, high among dental specialists with more than 2 years of experience. Conclusion: The practitioners are aware of the antiresorptive group of drugs, its indication, and oral complication. The management protocol, precautions needed to treat these patients for any invasive dental procedures are well understood by the Dental practitioners.

Different Presentation and Outcomes in the Surgical Treatment of Advanced MRONJ in Oncological and Nononcological Patients Taking or Not Corticosteroid Therapy

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect caused by antiangiogenic antiresorptive drugs used to treat various oncological and non oncological diseases. The clinical and radiological characteristics of MRONJ depend on the type of causative drug, the time of administration, and its dosage. Proven systemic risk factors like anemia, uncontrolled diabetes, corticosteroid therapy, and chemotherapy in neoplastic diseases (e.g., high doses of methotrexate up to 30 mg daily) significantly increase the chances of acquiring MRONJ. The risk factors themselves can affect treatment outcomes. Although the main scientific societies have recently disseminated good practice rules on the patient’s prevention, diagnosis, and management, there are still no guidelines on shared therapeutic strategies. In general, if conservative treatment fails, surgical treatment is considered, including local debridement, osteoplasty, and marginal or segmental osteotomy. In literature, cohorts of heterogeneous patients with MRONJ have been analyzed for a long time, resulting in a lack of uniformity of information and difficulties interpreting the data. According to the American Association of Oral and Maxillofacial Surgeons criteria, this retrospective study evaluates the surgical treatment outcomes of 64 patients with stage II-III MRONJ, evaluated at the Department of Maxillofacial Surgery of the University of Turin (Italy). The first objective of this retrospective study is to evaluate treatment results for stages II-III in all cases; the second objective is to evaluate the same results by dividing the sample into different cohorts of patients: first, based on the underlying pathology, i.e., oncological and non oncological, and secondly, based on the drug or combination of drugs they took.

Overview of the Pharmacological Management of Osteoporosis in Postmenopausal Women

Aim: The aim of the study is to assess the Pharmacological management of osteoporosis in postmenopausal women. Objective: The purpose of this study is to evaluate the treatment of osteoporosis in postmenopausal women. Methodology: This is an observational prospective study, carried out in a tertiary care hospital. Results: A total of 300 postmenopausal women were enrolled in the study. The mean ± standard deviation, of the age of postmenopausal women included in this study was 55.5 ± 5.0 years. 68.1% were prescribed with the combinational therapy of Teriparatide+Bisphosphonates. 39.2% of subjects were using acetaminophen for pain. Conclusion: Antiresorptive drugs (hormonal therapy, bisphosphonates, and denosumab) and, the anabolic agents (teriparatide) are commonly prescribed, in this study it is obvious that Sequential Therapy is highly prevailing in the clinical practice, with 68.1%.