Bisphosphonate-Induced Orbital Cellulitis in a Patient With Suspected Parathyroid Carcinoma: A Case Report.

Bisphosphonates are widely used for a number of metabolic bone conditions. Orbital inflammation is a very rare side effect of bisphosphonate therapy that can risk permanent visual loss. We describe the complex case and successful treatment of a 79-year-old man who developed orbital cellulitis following the use of intravenous pamidronate disodium for severe hypercalcaemia. The challenges regarding the diagnosis of parathyroid carcinoma are also discussed.

The Use of Steroids to Treat Hypercalcemia Due to Granulomatous Disease From Disseminated Coccidioidomycosis.

The clinical course and treatment of hypercalcemia from a granulomatous disease in the setting of an infectious etiology, namely disseminated coccidioidomycosis, remains incompletely understood. The mechanism and treatment of hypercalcemia have been documented in most granulomatous disorders, with sarcoidosis being the most well-understood so far. We discuss a case of a patient with a recent diagnosis of disseminated coccidioidomycosis who presented with hypercalcemia despite adequate infection control. The treatment course involved combinatorial-calcitonin, low-dose bisphosphonates, and corticosteroids, which led to a favorable outcome.

The Healing and therapeutic effects of perioperative bisphosphonate use in patients with fragility fractures: meta-analysis of 19 clinical trials.

OBJECTIVES: Previous evidence suggests that bisphosphonates (BPs) may lower the risk of recurrent fractures and enhance functional recovery in patients with fractures. However, there has been controversy regarding the optimal timing of treatment initiation for patients with fragility fractures. We conducted a meta-analysis to evaluate the available evidence on the use of BPs during the perioperative period and compared it to both non-perioperative periods and non-usage. METHODS: Electronic searches were performed using PubMed, EMBASE, Web of Science and the Cochrane Library published before February 2023, without any language restrictions. The primary outcomes included fracture healing rate, healing time, and new fractures. We also examined a wide range of secondary outcomes. Random effects meta-analysis was used. RESULTS: A total of 19 clinical trials involving 2543 patients were included in this meta-analysis. When comparing patients with non-perioperative BPs use in 4-6 weeks and approximately 10-12 weeks post-surgically, the overall risk ratios (RRs) of perioperative BPs use for healing rate were 1.06 (95% CI: 0.81, 1.38, p=0.69) and 1.02 (95% CI: 0.94, 1.11, p=0.65), respectively, suggesting no difference in healing rate between perioperative and non-perioperative BP initiation. For healing time, the overall mean difference between perioperative and non-perioperative periods was -0.19 week (95% CI: -1.03, 0.64, p=0.65) at approximately 10-12 weeks, indicating no significant impact of perioperative BP initiation on healing time. In terms of new fractures, the overall RR with BP use was 0.35 (95% CI: 0.17-0.73, p=0.005), when compared to patients without BPs use. This suggests a protective impact of BP use against new fractures compared to patients without BP use. Perioperative BP use was associated with a markedly higher likelihood of having adverse experiences, including fever (RR: 23.78, 95% CI: 8.29, 68.21, p< 0.001), arthralgia (RR: 10.20, 95% CI: 2.41, 43.16, p=0.002), and myalgia (RR: 9.42, 95% CI: 2.54, 34.87, p< 0.001), compared with non-BPs use. CONCLUSIONS: Treatment with BP during the perioperative period does not affect the healing process and has positive effects on therapy for patients with fragility fractures. These compelling findings underscore the potential efficacy of BP use during the perioperative period as a viable treatment option for patients with fragility fractures.

Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures.

BACKGROUND: Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). METHODS: We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected P-values <0.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. RESULTS: In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal, were in linkage disequilibrium (R2 ≥ 0.2) with a SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. CONCLUSIONS: While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2 and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF.

We investigated the genetic factors contributing to atypical femur fractures (AFF), which are rare and unusual fractures in the thigh bone These fractures are related to the use of bisphosphonates, which are prescribed to prevent fractures caused by osteoporosis. Previous studies suggested potential genetic links, but their findings were not confirmed in larger groups. To address this, we analyzed genetic data from 139 European individuals with AFF and 196 individuals without AFF, all of whom used bisphosphonates, using a genetic technique called whole exome sequencing (WES). Our results suggested three genes­XRN2, SORD, and PLOD2­might be linked to AFF, although the evidence was not conclusive. Importantly, our findings suggest that AFF may be caused by different genes in different individuals. A much larger sample size is now needed to fully understand the genetic architecture of AFF. These findings may guide future research into the genetic causes of AFF.

Osteoporosis and Apical Periodontitis Prevalence: A Systematic Review.

Osteoporosis is a common systemic bone disorder in the elderly, characterized by low bone mineral density and deterioration of bone structure. Apical periodontitis is an inflammatory response to the microbial infection of root canals, typically characterized by apical bone destruction surrounding the tooth's apex. This systematic review aimed to determine if osteoporosis affects the prevalence of apical periodontitis in adults. PRISMA guidelines have been followed. It included randomized clinical trials, cross-sectional, cohort, and case-control studies, and excluded non-relevant investigations and various secondary sources. A comprehensive search was performed in PubMed, Scopus, and Web of Science, until 13 March 2024. The Newcastle-Ottawa Scale was used to assess the quality of the three selected studies: two cross-sectional studies and one case-control study. One investigation only included post-menopausal women recruited at a dental university clinic, the other integrated data from the total hospital patients' population, and the third selected patients referred to the university dental clinic from the university hospital. The findings varied: one study noted a marginal association between low bone mineral density and apical periodontitis, another found a significant association, and the third, with the lowest risk of bias, reported no link. The main limitations were the scarcity of eligible studies and their overall quality. The review was registered in the PROSPERO database (CRD42024523705), applied strict inclusion criteria and thorough searches by experienced and independent reviewers. There is no strong evidence that adult individuals with osteoporosis have a higher probability of developing apical periodontitis. However, clinicians should remain cautious of osteoporosis's potential impact on apical periodontitis development.

Role of osteoclast inhibitors in prostate cancer bone metastasis; a narrative review.

OBJECTIVE: To study the role of Osteoclast inhibitors in advanced prostate cancer metastasis treatment and their efficacy in reducing skeletal related events. METHODS: DATA SOURCE: A comprehensive search was done using search terms as "osteoclast inhibitors" "Bisphosphonates" "Zoledronic acid" " pamidronate" " Alendronate" "Denosumab" " Prostate cancer metastasis" in pubmed and Google scholar. Relevant articles were screened and collected . The collected articles were used to frame the review and data showing use of Osteoclast inhibitors In prostate cancer bone metastasis was collected. DATA SUMMARY: Prostate cancer metastasizes most commonly to the skeleton thus leading to significant morbidity ranging from pain, pathological fractures to spinal cord compression and are the primary cause of patient disability and reduced quality of life.Initially, radiation therapy and radiopharmaceuticals were the mainstay of treatment however the role of Bisphosphonates and denosumab has become an integral part of therapy to manage metastatic prostate cancer. These agents significantly decrease skeletal related events and enhance patients quality of life. Emerging therapies like Radium-223 have also shown promise in reducing skeletal related events and also improving survival rates in patients with bone metastasis. Other treatment options which are being used are systemic agents like Docetaxel, cabazitaxel, hormonal therapies like abiraterone and enzalutamide. Immunotherapy with sipuleucel-T has demonstrated a reduction in mortality among prostate cancer patients with metastasis, highlighting the need for further research in this area. Ongoing studies are investigating novel agents that target both tumor cells and the bone microenvironment. CONCLUSION: Osteoclast inhibitors are effective in reducing skeletal related events in advanced bone metastasis and improve the quality of life of patients.

[Dynamics of mandibular density during therapy with zolendronic acid]. / Dinamika plotnosti nizhnei chelyusti v protsesse terapii zolendronovoi kislotoi.

THE AIM OF THE STUDY: Was to investigate the dynamics of mandibular density in cancer patients during therapy with zolendronic acid. MATERIALS AND METHODS: The study comprised 14 patients who received zolendronic acid at a dosage of 4 mg once every 28 days for bone metastases. In all 14 patients, measurements of mandibular density values on CT scans were performed over time. RESULTS: Using multiple linear regression analysis, a model was developed to predict the effect of the number of zolendronic acid injections «X1¼ on the dynamics of mandibular density «Y¼. The resulting formula for predicting mandibular density is Y = 5.9 X1 + 49 HU. CONCLUSION: The model has limitations due to the study design but still can be used by oncologists and dentists to assess mandibular density in patients taking zolendronic acid.

Minodronate for severe multiple vertebral fractures due to pregnancy- and lactation-associated osteoporosis: a case report and literature review.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare type of premenopausal osteoporosis, typically occurring during the third trimester of pregnancy and the early postpartum lactation period. This report presents a case involving severe multiple vertebral fractures due to PLO with low bone mineral density (BMD) and heightened bone turnover. A 39-year-old primiparous Japanese woman reported low back pain (LBP) starting at 28 weeks of pregnancy. The pain temporarily improved after delivery, although the LBP recurred and worsened 2 months into breastfeeding. Thereafter, the patient visited the Obstetrics and Orthopedic departments. Plain radiographs of the thoracic and lumbar spine showed loss of vertebral body height at the T4-12 and L1-3,5 vertebrae, leading to a diagnosis of 13 fractured vertebrae. BMD and serum bone turnover markers revealed low bone density and heightened bone turnover. In the absence of any identified alternative cause of secondary osteoporosis, the diagnosis was severe PLO with 13 vertebral fractures related to pregnancy and lactation. After treatment with bisphosphonates and an active vitamin D analog, the patient exhibited an increased BMD and normalization of bone turnover and resumed regular daily activities. Although the optimal PLO treatment strategy remains uncertain, bisphosphonates are an option; however, bisphosphonates can potentially affect the fetus through placental transfer. Therefore, careful consideration is required for patients planning pregnancy. Despite bisphosphonates' widespread use and cost-effectiveness, selecting PLO medications involves multiple factors, necessitating further research.

Incidence and prevention of skeletal-related events in multiple myeloma patients: A population-based real-world experience.

Novel treatments in multiple myeloma (MM) could influence the incidence of skeletal-related events (SREs). We aimed to examine the incidence of SRE and the preventive use of osteoclast inhibitors (OIs) in a cohort of MM patients in the era of modern treatment. In this real-world retrospective study, we included 199 patients with a diagnosis of MM between January 1, 2010, and December 31, 2019, with follow-up at St. Olavs University Hospital. Data was extracted from The Myeloma Registry of Central Norway. SREs occurred in 46% of patients at baseline and 55.8% during follow-up. Excluding baseline SREs, the incidence rate was 29 (95% confidence interval: 26-33) per 100 person years. 48% experienced > 1 SRE. The incidence of SREs was highest at baseline followed by a gradual increase in each subsequent line of treatment. The first two years after diagnosis 80% received bisphosphonates (BPs). The proportion of recommended dosage was 46%. Only two cases (1.2%) of symptomatic hypocalcemia and one case (0.6%) of osteonecrosis of the jaw were identified. SREs are still a common problem in an era of novel treatment. Cumulative dosage of BPs was lower than recommended, and treatment with BPs was safe in this population.

Use of an emulated trial to investigate the association between use of nitrogen-based bisphosphonates and risk of epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. METHODS: Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004-12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. RESULTS: Of the 313 383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. CONCLUSIONS: Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.

Shoring Up Osteoporosis Management: A Fresh Start?

Anabolic bone agents, such as parathyroid hormone receptor agonists (teriparatide and abaloparatide) and sclerostin-inhibiting monoclonal antibody (romosozumab), are superior at preventing clinically significant fractures and/or vertebral fractures in women with and without severe osteoporosis compared with bisphosphonates.

Efficacy of Bisphosphonates in Total Hip Arthroplasty Patients: Systematic Review and Meta-Analysis.

The scientific literature suggests that, if periprosthetic osteolysis (PPO) is not treated, it may have a negative impact on the results of a total hip replacement and possibly result in failure. This systematic review aimed to determine the efficacy of using bisphosphonates preventatively to limit PPO after a total hip arthroplasty (THA). METHODS: A systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PICOS template was developed to ensure a structured approach. A search for relevant studies was performed across four databases, including Pubmed, Scopus, Embase, and Cochrane. They were all last searched on March 1st and were assessed using the Cochrane risk of bias tool for randomised studies. RESULTS: The final analysis included seven studies with a total of 126 study group participants and 144 control group participants. The studies looked at Bony Mass Density in terms of bone loss on Gruen's femoral zones after THA in a bisphosphonate (treatment) and control group (placebo/no treatment). The analysis revealed a statistically significant difference (p < 0.05) in favour of the bisphosphonate group in many of the included studies at 6, 12, and 24 postoperative months. CONCLUSIONS: This systematic review and meta-analysis, using the most recent applicable studies, showed the efficacy of bisphosphonates in limiting periprosthetic osteolysis after THA in a period between 6 and 24 postoperative months. Future studies should focus increasing group sizes and collecting results beyond the 2-year mark.

Risk of Subsequent Hip Fractures across Varying Treatment Patterns for Index Vertebral Compression Fractures.

Introduction: Vertebral compression fractures (VCFs) pose a considerable healthcare burden and are linked to elevated morbidity and mortality. Despite available anti-osteoporotic treatments (AOTs), guideline adherence is lacking. This study aims to evaluate subsequent hip fracture incidence after index VCF and to elucidate AOT prescribing patterns in VCF patients, further assessing the impact of surgical interventions on these patterns. Materials and Methods: Patients with index VCFs between 2010 and 2021 were identified using the PearlDiver database. Diagnostic and procedural data were recorded using International Classification of Diseases (ICD-9, ICD-10) and Current Procedural Terminology (CPT) codes. Patients under age 50 and follow-up

Osteoporosis and Bone Fragility in Children: Diagnostic and Treatment Strategies.

The incidence of osteoporosis in children is increasing because of the increased survival rate of children with chronic diseases and the increased use of bone-damaging drugs. As childhood bone fragility has several etiologies, its management requires a thorough evaluation of all potentially contributing pathogenetic mechanisms. This review focuses on the main causes of primary and secondary osteoporosis and on the benefits and limits of the different radiological methods currently used in clinical practice for the study of bone quality. The therapeutic and preventive strategies currently available and the most novel diagnostic and treatment strategies are also presented. Optimal management of underlying systemic conditions is key for the treatment of bone fragility in childhood. DXA still represents the gold standard for the radiologic evaluation of bone health in children, although other imaging techniques such as computed tomography and ultrasound evaluations, as well as REMS, are increasingly studied and used. Bisphosphonate therapy is the gold standard for pharmacological treatment in both primary and secondary pediatric osteoporosis. Evidence and experience are building up relative to the use of monoclonal antibodies such as denosumab in cases of poor response to bisphosphonates in specific conditions such as osteogenesis imperfecta, juvenile Paget's disease and in some cases of secondary osteoporosis. Lifestyle interventions including adequate nutrition with adequate calcium and vitamin D intake, as well as physical activity, are recommended for prevention.

Effect of bisphosphonate and denosumab treatment on TBS in Japanese breast cancer patients with AIBL.

INTRODUCTION: Bisphosphonates and denosumab increase bone mineral density (BMD) for osteoporosis treatment in patients with aromatase inhibitor-associated bone loss (AIBL). This study aimed to directly compare bisphosphonates with denosumab in treating patients with AIBL and to determine the effect of denosumab on the trabecular bone score (TBS). MATERIALS AND METHODS: Thirty-nine patients with AIBL receiving osteoporosis treatment (21 in the bisphosphonates group and 18 in the denosumab group) were retrospectively evaluated for changes in lumbar spine and femoral BMD, lumbar spine bone quality (assessed by TBS), and blood bone metabolic markers. The Mann-Whitney and Wilcoxon tests were used for statistical evaluation. RESULTS: After 24 months of treatment, the lumbar spine BMD change rate was 5.82 ± 1.10% with bisphosphonates and 10.49 ± 1.20% with denosumab, with the change rate of denosumab significantly increasing over that of bisphosphonates. The change rate in femoral BMD was 2.69 ± 1.16% with bisphosphonates and 2.95 ± 1.26% with denosumab, with no significant difference between the two groups. The rate of decrease in tartrate-resistant acid phosphatase isoform 5b was significantly higher in the denosumab group. The change rate in TBS at 24 months of treatment was 0.53 ± 1.26% in the bisphosphonates group and 1.08 ± 1.33% in the denosumab group, with no significant difference between the two groups. After 24 months, TBS remained stable. CONCLUSION: Both bisphosphonates and denosumab may increase BMD, improve bone metabolism, and inhibit bone quality loss in patients with AIBL.

Aromatase inhibitor-induced bone loss osteosarcopenia in older patients with breast cancer: effects of the RANK/RANKL system's inhibitor denosumab vs. bisphosphonates.

The raising number of older patients who are diagnosed with breast cancer represents a significant medical and societal challenge. Aromatase inhibitors (AI), which are commonly utilized to treat this condition in these patients have significant adverse events on bone and muscle health. Falling estrogen production leads to an increase in RANKL secretion by osteoblasts with accelerated bone remodeling due to osteoclast activity. Furthermore, estrogen deficiency reduces skeletal muscle strength and mass. The humanized monoclonal antibody, denosumab, neutralizes RANKL, thereby inhibiting osteoclast formation, function and survival and ultimately exerting powerful anti-resorptive effects.. In this study, we report on the efficacy of denosumab in mitigating aromatase inhibitor-induced bone loss (AIBL) and sarcopenia in older women with breast cancer. From January 2022 to January 2023, we enrolled 30 patients (female sex, ≥ 65 years) diagnosed with non-metastatic breast cancer undergoing adjuvant endocrine therapy; patients received, as per clinical practice, primary bone prophylaxis with denosumab (60 mg via subcutaneous injection every 6 months) according to oncologic guidelines. This group was matched with 30 patients with non-metastatic breast cancer, who were treated with biphosphonates (BF) therapy (oral alendronate 70 mg/week). For each patient bone mineral density (BMD) and bone quality in terms of trabecular bone score (TBS) in addition to body composition and Relative Skeletal Muscle Index (RSMI) was assessed by bone densitometry at baseline and after one year of treatment. Significant improvements in TBS at the lumbar spine, RSMI and whole-body composition (arms, legs, and trunk) were observed in the denosumab group compared with the BF group. These findings underscore the role of denosumab as an effective strategy in managing AIBL and osteosarcopenia in older women with breast cancer and undergoing adjuvant endocrine therapy, which is crucial for improving quality of life, preventing functional decline, and optimizing treatment outcomes.

A Case of Bilateral Transient Pregnancy-Related Osteoporosis of the Hip Diagnosed Late During the Lactation Period: A Rare Clinical Presentation and a Mini Review of the Literature.

Transient pregnancy-related osteoporosis of the hip is a rare, idiopathic, benign, and usually self-limiting condition caused by edema of the bone marrow, which can be visualized on magnetic resonance imaging. Bilateral localization of the disease is even less common. Our case concerns a 31-year-old primigravida who, during the 35th week of pregnancy, was hospitalized at the Obstetrics and Gynecology Clinic of the General Hospital of Trikala with lumbar and hip pain. The pain gradually increased in intensity and was accompanied by severe movement limitation. No history of falls or injury was reported. Her personal history was unremarkable, and the course of the pregnancy was uneventful. A clinical examination by a team of orthopedic surgeons established a diagnosis of acute hip and back pain. Rest and administration of paracetamol did not improve her clinical condition. During the postpartum and lactation period, the lack of symptom relief led to the decision to further evaluate the patient. The diagnosis of pregnancy-related transient osteoporosis of both hips was established by magnetic resonance imaging. Immediate treatment with bisphosphonate medication after the discontinuation of breastfeeding led to a definitive remission of the symptoms three months later. In this study, after the case description, a brief literature review of this rare clinical entity is presented. Proper knowledge of this condition helps to provide the best possible short- and long-term prognostic outcomes for the mother, fetus, and newborn.

A multifaceted role of bisphosphonates from palliative care to anti-cancer therapy in solid tumors.

INTRODUCTION: Bisphosphonates (P-C-Ps) also called diphosphonates are the structural analogs of naturally occurring pyrophosphates. Bisphosphonates are traditionally used and shown to provide long-term success in the treatment and prevention of osteoporosis and other bone loss pathologies. Furthermore, bisphosphonates are gaining popularity in the present era of cancer therapeutics and prevention. The usage of bisphosphonates as adjuvant or neoadjuvant therapy, either as a single agent or combined with other chemotherapy, has been studied in different solid tumors. This review aims to present the various roles of bisphosphonates in solid tumors. DATA SOURCES: Articles in MEDLINE/PubMed and the National Institutes of Health Clinical Trials Registry (http://www. Clinicaltrials.gov) between 1 January 2011 and 1 February 2022 were extracted using MeSH terms "bisphosphonates/diphosphosphonates and mechanism," "bisphosphonates and breast cancer," "bisphosphonates and prostate cancer," "bisphosphonates and lung cancer," "bisphosphonates and cancer risk," and "bisphosphonates and adverse events." Manual searches of some major oncology journals were also conducted. DISCUSSION: This review article focuses on the antitumor activity of bisphosphonates, safety profile, and the role of bisphosphonates as preventive, neoadjuvant, and adjuvant chemotherapy. A significant improvement in overall survival and cancer-specific survival and recurrence-free survival with the usage of bisphosphonates is noted in breast cancer patients, particularly in post-menopausal women. Though great progress has been achieved in over 20 years, further research is needed to identify the subgroup of patients that are most likely to benefit from adjuvant bisphosphonate therapy and to determine regimens with greater efficacy and better safety profile.