Intravenous Bisphosphonates Research Articles

Antibiotic Prophylaxis Prior to Dental Procedures

Antibiotic prophylaxis in dentistry has been recommended for different groups of patients, such as patients with impaired immunologic function, patients at risk of developing infective endocarditis or prosthetic joint infection, patients previously exposed to high-dose irradiation of the head and neck regions, and patients receiving intravenous bisphosphonate and antiangiogenic treatment. The guidelines have been changed over the years, and the list of medical conditions requiring antibiotic prophylaxis has been shortened considerably in the context of antibiotic resistance and unnecessary antibiotic prescription.

Evaluation of the Awareness and Knowledge Levels of Dentists Regarding Bisphosphonates and Bisphosphonate-Related Jaw Necrosis

Bisphosphonates are used in the treatment of osteoporosis, bone metastases, and metabolic bone diseases. Long-term use of bisphosphonates increases the risk of osteonecrosis in patients undergoing dental surgery. This study aimed to evaluate dentists’ knowledge about bisphosphonates and bisphosphonate-related osteonecrosis of the jaw (BRONJ) and their treatment approaches in patients using oral and intravenous bisphosphonates. In this study, a 25-question questionnaire was applied to dentists working in different institutions regarding their knowledge and experience about bisphosphonates and BRONJ, and treatment approaches for different surgical procedures in patients using bisphosphonates. The obtained data were statistically analyzed and evaluated. In total, 90.5% of the dentists identified osteoporosis, 79.8% identified bone metastases, 52.4% identified osteitis deformans, and 39.3% identified multiple myeloma as conditions in which bisphosphonates are used, thus answering correctly in a significant proportion. When participants were asked about treatment options according to the stages of BRONJ, participation in the “I’m not sure” option increased as the stages progressed, indicating that dentists were not sufficiently familiar with the treatments for different stages of BRONJ. In total, 88.5% of the participants stated that when they see an exposed bone area in patients they examine, they consider bisphosphonate use as a possible cause. There was a statistically significant difference between dentists with and without prior BRONJ experience regarding their ages (P=0.039) and years of practice (P=0.001). There was a statistically significant difference between dentists with and without BRONJ experience regarding whether they inquired about bisphosphonate use (P=0.001). It was found that dentists have serious deficiencies in knowledge regarding bisphosphonates, their side effects, and treatment approaches for patients using bisphosphonates. Increasing dentists’ knowledge and awareness of this issue would help reduce the risk of developing BRONJ.

7253 Changes In Bone Density Observed After Transitioning From Denosumab To Alendronate Or Zoledronic Acid

Abstract Disclosure: A. Khan: None. B.P. Ramchandani: None. R.A. Zielinski: None. J. Liu: None. F.S. Mirza: None. Introduction: Discontinuation of denosumab (Dmab) results in rebound increase in bone turnover and increased risk of vertebral fracture. Guidelines recommend that discontinuation of denosumab should be followed by an oral or intravenous bisphosphonate (BP), hormone therapy or selective estrogen receptor modulator (SERM). Hypothesis: We hypothesize that patients who received weekly alendronate (ALEN) after discontinuation of Dmab will have less of a decline in bone mineral density (BMD) compared to patients who received once yearly zoledronic acid (ZA). Methods: We conducted a retrospective chart review to compare the change in BMD and factors affecting BMD loss in patients who received sequential therapy with ZA versus ALEN. IRB approval was obtained. Patients were selected using Epic SlicerDicer if they had taken Dmab therapy from 2018 (year of epic implementation) onwards and had been transitioned to a BP. A total of 251 patients were initially selected. 35 patients met the inclusion criteria of being transitioned off to ALEN or ZA at least 1 year prior to date of data acquisition; 21 transitioned to ZA and 14 to ALEN. The rest of the patients were continuing Dmab and excluded from the analysis. BMD gain after Dmab therapy was evaluated. BMD change after 1 year of receiving sequential therapy was compared between the two groups at the lumbar spine (LS), femoral neck (FN), and total hip (TH). Results: A total of 35 patients were included in data analysis with mean age of 73.7 + 9 years. The mean percentage gain in BMD achieved after Dmab therapy was 9.9 + 8.5%, 4.6 + 10.6%, and 6 + 5.2% at the LS, FN and TH respectively. The mean duration of Dmab therapy was 4.4 + 2.1 years. One year following sequential therapy, mean percentage BMD loss at the LS was 4.5% with ALEN and 3.0% with ZA (p-value: 0.59, 95% CI: -0.04 to 0.08). Following sequential therapy, mean percentage loss at FN was 2.2% with ALEN and 0.2% with ZA (p-value: 0.1895% CI: (-0.01 to 0.04), mean percentage loss at TH was 2.0 % with ALEN and 2.2% with ZA (p-value: 0.78, 95% CI: -0.03 to 0.02). Mean vitamin D level of all patients at time of starting sequential therapy was 45.9 + 12.9 ng/ml. Duration of prior bisphosphonate use before starting Dmab therapy did not have any significant effect on BMD loss after sequential therapy. All patients had vitamin D level in a good range at the beginning and end of the study period. Conclusion: There is invariably some decline in BMD when transitioning from Dmab to BPs. Although our data showed somewhat greater BMD loss at LS and FN with ALEN compared to ZA, this difference was not statistically significant and failed to reject the null hypothesis. These findings need to be evaluated further in larger prospective studies. Presentation: 6/3/2024

7219 Ocular Findings in Jansen Metaphyseal Chondrodysplasia

Abstract Disclosure: F. Obiezu: None. K. Pan: None. A. Ninan: None. K.L. Roszko: None. L.S. Weinstein: None. C.R. Ferreira: None. R.I. Gafni: None. T. Magone De Quadros Costa: None. M.T. Collins: None. S. Jha: None. Jansen Metaphyseal Chondrodysplasia (JMC) is an ultra-rare disorder, with only 30 patients estimated to have the disease globally. It is caused by heterozygous pathogenic variants in PTHR1 that result in constitutive activation of parathyroid hormone type 1 receptor (PTHR1) signaling. A detailed description of craniofacial manifestations of the disease is lacking. Here we characterize the ophthalmological manifestations in patients with JMC. Six patients (4 males, 67%) with genetically confirmed JMC underwent a detailed ophthalmological evaluation, spectral-domain optical coherence tomography (OCT), craniofacial CT and 18F-NaF PET/CT scans. Median age at the time of the visit was 27.5 [IQR: 29] years. On physical examination, all patients were noted to have widely spaced eyes; 5 of the 6 had down slanted palpebral fissures, proptosis, or ptosis. Two patients had incomplete or defective closure of the eyelids (lagophthalmos), of which one had a history of progressive right facial nerve palsy with profuse epiphora. The second patient had central visual field defects, bilateral moderate optic disc pallor and bilateral retinal nerve fiber layer (RNFL) atrophy on OCT exam with bilateral optic canal narrowing on CT. Notably, comparison of these findings with a prior scan performed 5 years earlier showed progressive decrease in RNFL bilaterally. This patient had a history of prolonged intravenous bisphosphonate therapy, initiated in infancy for hypercalcemia and continued for over a decade. A third patient had normal vision, subtle temporal pallor of the optic nerve heads on dilated fundus exam, normal average RNFL, but decreased retinal ganglion cell layer analysis (GCA) on OCT. GCA was decreased in 4 of the 6 patients compared to age-matched reference range indicating a chronic optic nerve atrophic process. These data represent the first comprehensive report of the ophthalmologic findings in a cohort of patients with JMC. They demonstrate that patients with JMC have significant eye findings that appear to be more prevalent and pronounced with age. This suggests age-related, progressive optic neuropathy, which can be assessed by demonstrating OCT retinal GCA and RNFL loss and, may be a feature of JMC. The benefit and effect of long-term bisphosphonate therapy in patients with JMC remains unclear. Patients with JMC should undergo regular ophthalmologic examination including optic nerve OCT, visual field testing, and craniofacial imaging. Presentation: 6/1/2024

7334 Changing Trends In Oral Bisphosphonate Therapy: A 25-Year Surveillance In A US Healthcare System

Abstract Disclosure: J.C. Lo: None. M. Chandra: None. M.M. Khan: None. L.D. Carbone: None. E.A. Garcia: None. G.H. Tabada: None. D. Low: None. R.L. Hui: None. Introduction: Bisphosphonate (BP) drugs remain one of the first line therapies for fracture prevention, but treatment patterns have changed since BPs were first approved for osteoporosis. This study examines trends among adults initiating oral BP in a large US healthcare system over a 25-year period (1988-2022) and in each successive 5-year period. Methods: The study cohort comprised adults aged 50-89y who initiated alendronate, risedronate or oral ibandronate during 1998-2022 in an integrated healthcare delivery system, excluding those with select bone disorders, multiple myeloma, secondary metastatic cancer, end stage renal disease, and receipt of intravenous BP. Covariates included age (proportion age <65y), sex, race and ethnicity, and prior fracture (diagnosed within 5 years) using electronic health record data. Demographic trends and fracture status were examined across time periods. The chi-squared test and Cochrane-Armitage test for trend were used to examine differences and trends. This report extends findings from an earlier report of women initiating oral BP during 2004-2012 in the same healthcare population. Results: Among 208,780 adults (86% women) who initiated BP, including 26,646 (1998-2002, 35% <65y), 44,726 (2003-2007, 35% <65y), 34,005 (2008-2012, 24% <65y), 35,248 (2013-2017, 19% <65y), and 38,743 (2018-2022, 17% <65y) women and 2348 (1998-2002, 28% <65y), 4895 (2003-2007, 26% <65y), 5172 (2008-2012, 17% <65y), 5331 (2013-2017, 13% <65y), and 11,666 (2018-2022, 5% <65y) men in each 5-year period. Over time, an increasing proportion were age ≥65y (p<0.001 for trend), with larger numbers of older adults in later years partly reflecting initiatives targeting secondary fracture prevention (since 2008 for women, 2015 for men) and BMD screening (since 2011 for women, 2017 for men). Among women initiating BP, the proportion with prior fracture increased from 24-30% (pre-2008) to 43-45% (post-2008), partly reflecting secondary fracture prevention initiatives for women. For men, this proportion increased from 33% (1998-2002) to 42% (2003-2007), 47% (2008-2012), and 54% (2013-2017), but fell to 36% (2018-2022) after BMD screening initiatives began in 2017 for older men (primary prevention efforts). Racial and ethnic diversity in treatment also increased, comparing 1988-2002 (75.2% White, 2.5% Black, 8.6% Hispanic, 12.7% Asian/Pacific Islander) to 2018-2022 (61.5% White, 2.9% Black, 12.2% Hispanic, 21.1% Asian/Pacific Islander, p<0.001 for overall differences and % non-White). Conclusions: In a primary care population of adults initiating oral BP, a larger proportion in later years were age >65y, including larger numbers both with and without fracture coinciding with initiatives for fracture prevention. Among those initiating BP, the relative proportions with prior fracture in each period were likely influenced by primary or secondary prevention efforts. Presentation: 6/2/2024

9212 Changing Trends In Oral Bisphosphonate Therapy: A 25-Year Surveillance In A US Healthcare System

Abstract Disclosure: J.C. Lo: None. M. Chandra: None. M.M. Khan: None. L.D. Carbone: None. E.A. Garcia: None. G.H. Tabada: None. D. Low: None. R.L. Hui: None. Introduction: Bisphosphonate (BP) drugs remain one of the first line therapies for fracture prevention, but treatment patterns have changed since BPs were first approved for osteoporosis. This study examines trends among adults initiating oral BP in a large US healthcare system over a 25-year period (1988-2022) and in each successive 5-year period. Methods: The study cohort comprised adults aged 50-89y who initiated alendronate, risedronate or oral ibandronate during 1998-2022 in an integrated healthcare delivery system, excluding those with select bone disorders, multiple myeloma, secondary metastatic cancer, end stage renal disease, and receipt of intravenous BP. Covariates included age (proportion age <65y), sex, race and ethnicity, and prior fracture (diagnosed within 5 years) using electronic health record data. Demographic trends and fracture status were examined across time periods. The chi-squared test and Cochrane-Armitage test for trend were used to examine differences and trends. This report extends findings from an earlier report of women initiating oral BP during 2004-2012 in the same healthcare population. Results: Among 208,780 adults (86% women) who initiated BP, including 26,646 (1998-2002, 35% <65y), 44,726 (2003-2007, 35% <65y), 34,005 (2008-2012, 24% <65y), 35,248 (2013-2017, 19% <65y), and 38,743 (2018-2022, 17% <65y) women and 2348 (1998-2002, 28% <65y), 4895 (2003-2007, 26% <65y), 5172 (2008-2012, 17% <65y), 5331 (2013-2017, 13% <65y), and 11,666 (2018-2022, 5% <65y) men in each 5-year period. Over time, an increasing proportion were age ≥65y (p<0.001 for trend), with larger numbers of older adults in later years partly reflecting initiatives targeting secondary fracture prevention (since 2008 for women, 2015 for men) and BMD screening (since 2011 for women, 2017 for men). Among women initiating BP, the proportion with prior fracture increased from 24-30% (pre-2008) to 43-45% (post-2008), partly reflecting secondary fracture prevention initiatives for women. For men, this proportion increased from 33% (1998-2002) to 42% (2003-2007), 47% (2008-2012), and 54% (2013-2017), but fell to 36% (2018-2022) after BMD screening initiatives began in 2017 for older men (primary prevention efforts). Racial and ethnic diversity in treatment also increased, comparing 1988-2002 (75.2% White, 2.5% Black, 8.6% Hispanic, 12.7% Asian/Pacific Islander) to 2018-2022 (61.5% White, 2.9% Black, 12.2% Hispanic, 21.1% Asian/Pacific Islander, p<0.001 for overall differences and % non-White). Conclusions: In a primary care population of adults initiating oral BP, a larger proportion in later years were age >65y, including larger numbers both with and without fracture coinciding with initiatives for fracture prevention. Among those initiating BP, the relative proportions with prior fracture in each period were likely influenced by primary or secondary prevention efforts. Presentation: 6/2/2024

Real-life effects of pharmacological osteoporosis treatments on bone mineral density by quantitative computed tomography.

Monitoring of bone mineral density (BMD) is used to assess pharmacological osteoporosis therapy. This study examined the real-life effects of antiresorptive and osteoanabolic treatments on volumetric BMD (vBMD) of the spine by quantitative computed tomography (QCT). Patients aged ≥ 50years with a vBMD < 120mg/ml had ≥ 2 QCT. For analysis of therapy effects, the pharmacological treatment and the duration of each therapy were considered. Identical vertebrae were evaluated in all vBMD measurements for each patient. A linear mixed model with random intercepts was used to estimate the effects of pharmacological treatments on vBMD. A total of 1145 vBMD measurements from 402 patients were analyzed. Considering potential confounders such as sex, age, and prior treatment, a reduction in trabecular vBMD was estimated for oral bisphosphonates (-1.01mg/ml per year; p < 0.001), intravenous bisphosphonates (-0.93mg/ml per year; p = 0.015) and drug holiday (-1.58mg/ml per year; p < 0.001). Teriparatide was estimated to increase trabecular vBMD by 4.27mg/ml per year (p = 0.018). Patients receiving denosumab showed a statistically non-significant decrease in trabecular vBMD (-0.44mg/ml per year; p = 0.099). Compared to non-treated patients, pharmacological therapy had positive effects on trabecular vBMD (1.35mg/ml; p = 0.001, 1.43mg/ml; p = 0.004, 1.91mg/ml; p < 0.001, and 6.63mg/ml; p < 0.001 per year for oral bisphosphonates, intravenous bisphosphonates, denosumab, and teriparatide, respectively). An increase in trabecular vBMD by QCT was not detected with antiresorptive agents. Patients treated with teriparatide showed increasing trabecular vBMD. Non-treatment led to a larger decrease in trabecular vBMD than pharmacological therapy.

Approach to the Pediatric Patient with Glucocorticoid-Induced Osteoporosis.

Glucocorticoid (GC) therapy remains the cornerstone of treatment for many conditions of childhood and an important cause of skeletal and endocrine morbidity. Here, we discuss cases that bring to life the most important concepts in the management of pediatric GC-induced osteoporosis (pGIO). Given the wide variety of underlying conditions linked to pGIO, we focus on the fundamental clinical-biological principles that provide a blueprint for management in any clinical context. In so doing, we underscore the importance of longitudinal vertebral fracture phenotyping, how knowledge about the timing and risk of fractures influences monitoring, the role of bone mineral density in pGIO assessments, and the impact of growth-mediated "vertebral body reshaping" after spine fractures on the therapeutic approach. Overall, pGIO management is predicated upon early identification of fractures (including vertebral) in those at risk, and timely intervention when there is limited potential for spontaneous recovery. Even a single, low-trauma long bone or vertebral fracture can signal an osteoporotic event in an at-risk child. The most widely used treatments for pediatric osteoporosis, intravenous bisphosphonates, are currently recommended first-line for the treatment of pGIO. It is recognized, however, that even early identification of bone fragility, combined with timely introduction of the most potent bisphosphonate therapies, may not completely prevent osteoporosis progression in all contexts. Therefore, prevention of first-ever fractures in the highest-risk settings is on the horizon, where there is also a need to move beyond anti-resorptives to the study of anabolic agents.

Disease Activity and Bone Microarchitectural Phenotype in Patients With Axial Spondyloarthritis

Background: Axial spondyloarthritis (AxSpA) is a chronic rheumatic disease characterized by spine inflammation, abnormal bone growth, and paradoxically osteoporosis and vertebral fractures. The pathogenesis of skeletal deficits in this disease is poorly understood. Purpose: We sought to evaluate volumetric bone mineral density (vBMD) and bone microarchitecture in patients with AxSpA and to identify disease-related factors associated with skeletal abnormalities. Methods: We enrolled patients between 2018 and 2021 as part of a 2-year prospective study at a single institution investigating skeletal health and the skeletal effects of interleukin-17 (IL-17) treatment. Patients with AxSpA who met Assessment in SpondyloArthritis International Society (ASAS) classification criteria by X-ray or had evidence of active inflammation on magnetic resonance imaging suggestive of sacroiliitis were referred to the study by their rheumatologists. We excluded those with a history of fragility fracture, multiple myeloma, Cushing’s disease, primary hyperparathyroidism, osteomalacia, untreated vitamin D deficiency, secondary osteoporosis, or other systemic rheumatic diseases, as well as use of oral steroids for 2 or more weeks in the 6 months prior or current use of hormone replacement therapy, current oral bisphosphonate, past or current intravenous bisphosphonate, teriparatide, or denosumab therapies. A total of 1606 patients were screened for eligibility. Of these, 30 participants were enrolled (mean age 43 years, 50% male). Patients with AxSpA had dual-energy X-ray absorptiometry (DXA) measurements of areal BMD (aBMD) and high-resolution peripheral quantitative computed tomography (HR-pQCT) measurements of vBMD microarchitecture and failure load by finite element analysis. Standardized disease assessment tools used included the Bath Ankylosing Spondylitis Disease Activity (BASDAI), Metrology Index (BASMI), and Functional Index (BASFI). Results: In the 30 included patients, mean DXA and HR-pQCT Z-scores were within 1 standard deviation (SD) of normal for all indices, except for total vBMD in males (–1.2 SD below mean). Mean symptom duration was 11.7 years and mean scores for BASDAI, BASFI, and BASMI were 4.6, 3.6, and 2.7, respectively (range 1–10, 10 = severe limitation). Longer disease duration was associated with more severe skeletal deficits at the hip and tibia—specifically, lower hip aBMD, lower meta- and inner-trabecular vBMD, lower trabecular number, and higher trabecular separation and heterogeneity. Conclusion: This study of 30 patients with AxSpA found that abnormalities in bone density and microarchitecture at weightbearing sites were associated with longer disease duration. Because of its small sample size, larger studies are needed to better characterize the pathogenic disease factors that govern skeletal damage in AxSpA.

Bone Disease among Children with Sickle Cell Disease: A Scoping Review of Incidence and Interventions.

Children with sickle cell disease (SCD) are more likely to have deficient serum levels of vitamin D for bone metabolism. However, appropriate interventions are essential to prevent its progression and alleviate symptoms. The aim of this study is to determine interventions for managing bone disease in children with SCD. This study uses a scoping review. A literature review was conducted using PubMed, CINAHL, ScienceDirect, Scopus, and Google Scholar search engines. The study was eligible for inclusion if it included articles published from 2013 to 2023, full-text, and original study design. Study quality was assessed using the Joanna Briggs Institute (JBI) appraisal tool. This review identified six studies and 114 children with SCD, including 57 boys (50%) and 57 girls (50%). The majority of SCD types experienced were HbSS (86.84%), HbS-B0 Thal (7.01%), HbSC (5.27%), and the HbSS Arab-Indian haplotype (0.88%). Bone disease problems that often arise in children with SCD include Avascular Necrosis (AVN) (78.08%), Osteonecrosis of the Femoral Head (ONFH) (18.42%), and other bone problems (3.50%). Meanwhile, four types of intervention findings were used in managing bone disease among children with SCD: 1). Surgical procedures 53 (41.09%) included total hip arthroplasty (THA), Osteotomy, and Multiple epiphyseal drilling with Autologous Bone Marrow Implantation (AMBI); 2). Invasive procedures 67 (51.93%) included intravenous bisphosphonates, hydroxyurea (HU), and core decompression (CD) with bone marrow aspirate concentrate injection: 3). Oral pharmacological or Vitamin D3 (cholecalciferol) 4 (3.10%); 4). Non-pharmacology or physical therapy 5 (3.88%). Our findings highlight that surgical, invasive, pharmacological, and physical therapy interventions positively impact increasing bone mineral density (BMD) and functional improvement of bone disease among children with SCD. The interventions provided excellent functional outcomes with minimal complications and no life-threatening side effects.

Changes in serum bone turnover markers and bone mineral density Z-score in children with osteogenesis imperfecta after zoledronic acid treatment.

The study aimed to investigate the changes in the levels of serum bone turnover markers (BTMs) and bone mineral density (BMD) Z-score in pediatric patients with osteogenesis imperfecta (OI) after intravenous bisphosphonate therapy and their association with age and estimated glomerular filtration rate (eGFR). This retrospective study analyzed data from 10 pediatric OI patients treated with intravenous zoledronic acid for over 1 year. Patients' clinical data were collected. The levels of BTMs and BMD Z-score before and after zoledronic acid treatment were analyzed. Significant improvement in BMD Z-score was observed after 6 and 12 months of treatment compared to baseline (all p < 0.05). The N-terminal propeptide of type I procollagen (PINP) levels decreased over time (all p < 0.05), indicating that zoledronic acid treatment decreased bone turnover. The levels of beta-C-terminal telopeptide of type I collagen remained stable after treatment. No correlation was found between PINP level and age, eGFR, or BMD (all p > 0.05). Bisphosphonate treatment can improve BMD and decrease bone turnover (indicated by decreased levels of PINP) in pediatric OI patients. PINP may serve as an independent indicator for monitoring the efficacy of bisphosphonate treatment in pediatric OI patients, particularly in those under the age of 6, where standardized BMD Z-score criteria are lacking.

The Risk of Medication-Related Osteonecrosis of the Jaw in Children: Guidance for Antiresorptive Use in Pediatric Patients

Antiresorptive targeted cancer therapies, such as denosumab and bisphosphonates, are used in adults, but their application in pediatric cancer is more recent. Side effects such as osteonecrosis of the jaw (ONJ) observed in adults have curtailed use of these medications in the pediatric population. This study assesses the frequency of ONJ, other side effects, and the indications for use of denosumab versus bisphosphonates in pediatric subjects. A retrospective cohort study of pediatric subjects who underwent bisphosphonate or denosumab therapy at our institution from 2007-2023 was conducted. Subjects aged ≥ 18years at therapy initiation were excluded. The independent variable was antiresorptive therapy divided into 2 groups, treatment with intravenous bisphosphonates or denosumab. Primary outcomes were development of bisphosphonate-related and denosumab-related ONJ. Secondary outcomes included additional side effects. ONJ risk factors, subject demographics, indications for use, timing, duration, and cumulative dose of antiresorptive therapy were abstracted. Univariate and bivariate statistics were computed to describe the sample and measure associations between antiresorptive therapy and outcomes. P values < .05 conferred statistical significance. The sample was composed of 178 subjects with a mean age of 11.7±6.1years. There were 14 (7.9%) and 164 (92.1%) subjects treated with denosumab and bisphosphonate therapies, respectively. There were 0 cases of ONJ across all subjects. The most common indication for treatment was adjuvant targeted therapy for aggressive tumors and malignancy (39.3%) followed by osteoporosis (14.6%). Subjects treated with denosumab had higher frequencies of hypercalcemia and severe bone pain than subjects treated with bisphosphonates, 28.6% versus 1.2% (P<.001) and 14.3% versus 0.00% (P<.001), respectively. While invasive dental procedures are ideally performed before antiresorptive treatment, our data suggest that bisphosphonates may be used safely in the pediatric population with low concern for ONJ. Our data also demonstrated bisphosphonates may have a more tolerable side effect profile than denosumab. If the perceived benefits are similar, we recommend using bisphosphonates as first-line therapy in children while reserving denosumab for refractory cases. Future studies will help determine long-term side effects and differences in efficacies of these medications.

Platelet-Rich Fibrin Treatment Evaluation in Patients with Medication-Related Osteonecrosis of the Jaw and Osteoradionecrosis.

Background. Medication-related osteonecrosis of the jaw (MRONJ) and osteoradionecrosis (ORN) are associated with severe disability and continuous pain, both of which are very difficult to control. This study aims to evaluate the outcome of platelet-rich fibrin (PRF) treatment compared to iodoform gauze packing and the primary suture of oral mucosa in patients with both MRONJ and ORN. Methods. Patients suffering from MRONJ and ORN who were treated in the Oral and Maxillofacial Surgery Clinic of Cluj-Napoca in the last 10 years were selected for this study from the hospital database. Results. PRF treatment proved to be a reliable method to help heal the necrotic bone sites. High-ASA risk patients and immunosuppressed patients are more prone to recurrence and persistent signs and symptoms. Intravenous bisphosphonates produce more intense symptomatology compared to oral administration. The posterior mandible is more difficult to treat compared to other sites. Conclusions. The quality of life of MRONJ and ORN patients may be improved by a protocol that reduces pain and hospitalization.

Application of Platelet-rich Fibrin as a Method of Treatment for Medication-related Osteonecrosis of the Jaws in Bulgaria

Lately, medication-related osteonecrosis of the jaw (MRONJ) has emerged as a common disease due to the increasing use of antiresorptive drugs (intravenous bisphosphonates) for the treatment of oncological and osteoporotic diseases, which at an advanced stage significantly affects the quality of life of patients. Therefore, new therapies that accelerate the recovery of musculoskeletal tissue have become preferred in the treatment of such diseases in recent years. An innovative approach, which supports the healing processes is the application of autologous platelet concentrates known as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF). Platelets are unique blood elements responsible for hemostasis. Activated platelets secrete a large amount of growth factors that initiate regeneration in soft tissues and bones. PRP is plasma with many more platelets than are usually found in the blood. The concentration of platelets and therefore the concentration of growth factors may be 5–10 times higher (or richer) than usual. PRF is a biological material, which has the ability to release growth factors over time. Growth factors stimulate stem cells, which improve collagen and elastin in the skin. Platelets in PRF are thought to survive better than those in PRP and thus contribute to faster recovery and formation of new tissue. Fibrin is a biological scaffold that forms when an injury occurs anywhere in the body. Platelets normally circulate in the blood and bind to the fibrin scaffold. Thus connected, they are activated and release growth factors, which are small “granules”. These growth factors begin the process of wound healing by creating new skin cells, collagen and blood vessels. The present study is related to the treatment of MRONJ with PRF. It is aimed at researching the attitudes of oral and maxillofacial surgeons in Bulgaria regarding the application of innovative medical technology such as PRF in the treatment of MRONJ. An author's questionnaire was developed with the help of which the survey was carried out. The analysis of the data shows that the interest in PRF in Bulgaria is great, but unfortunately it is rarely applied. However, respondents believe that this is a promising and innovative method in various aspects of surgery.

Endophenotypes of Primary Osteoarthritis of the Hip Joint in the Bulgarian Population over 60 Years Old.

Aim. To identify subgroups of patients with primary osteoarthritis of the hip joint (pHOA) with similar imaging and laboratory findings, disease evolution, and response to conventional therapies. Methods. We performed further statistical analyses on patient data from two published, double-blind, randomized, and placebo-controlled studies (DB-RCTs), which examined the effects of intra-articular corticosteroids (ia-CSs), hyaluronic acid (ia-HA)-KИ-109-3-0008/14.01.2014, and intravenous bisphosphonates (iv-BPs) -KИ- 109-3-0009/14.01.2014 compared to the country's standard pHOA therapy. The data span an 8-year follow-up of 700 patients with pHOA, including: 1. Clinical parameters (WOMAC-A, B, C, and T; PtGA). 2. Laboratory markers (serum calcium and phosphate levels; 25-OH-D and PTH, markers for bone sCTX-I and cartilage uCTX-II turnover). 3. Radiological indicators: X-ray stage (Kellgren-Lawrence (K/L) and model (Bombelli/OOARSI), width (mJSW), speed (JSN mm/year), and zone of maximum narrowing of the joint space (max-JSN)-determining the type of femoral head migration (FHM). 4. DXA indicators: bone geometry (HAL; NSA; and MNW); changes in regional and total bone mineral density (TH-BMD, LS-BMD, and TB-BMD). 5. Therapeutic responses (OARSI/MCII; mJSW; JSNmm/yearly) to different drug regimens (iv-BP -zoledronic acid (ZA/-5 mg/yearly for 3 years)); ia-CS 40 mg methylprednisolone acetate, twice every 6 months; and ia-HA with intermediate molecular weight (20 mg/2 mL × 3 weekly applications, two courses every 6 months) were compared to standard of care therapy (Standard of Care/SC/), namely D3-supplementation according to serum levels (20-120 ng/mL; target level of 60 ng/mL), simple analgesics (paracetamol, up to 2.0 g/24 h), and physical exercises. The abovementioned data were integrated into a non-supervised hierarchical agglomerative clustering analysis (NHACA) using Ward's linkage method and the squared Euclidean distance to identify different endophenotypes (EFs). Univariate and multivariate multinomial logistic regression analyses were performed to determine the impact of sex and FHM on clinical and radiographic regression of pHOA. Results. A baseline cluster analysis using incoming (M0) patient data identified three EFs: hypertrophic H-HOA, atrophic A-HOA, and intermediate I-HOA. These EFs had characteristics that were similar to those of patients grouped by radiographic stage and pattern ('H'-RPs, 'I'-RPs, and 'A'-RPs), p < 0.05). The repeated cluster analysis of M36 data identified four EF pHOAs: 1. Hypertrophic (slow progressors, the influence of the type of femoral head migration (FHM) outweighing the influence of sex on progression), progressing to planned total hip replacement (THR) within 5 (K/LIII) to 10 (K/LII) years. 2. Intermediate (sex is more important than the FHM type for progression) with two subgroups: 2#: male-associated (slow progressors), THR within 4 (K/LIII) to 8 years. (K/LII). 2* Female-associated (rapid progressors), THR within 3 (K/LIII) to 5 (K/LII) years. 3. Atrophic (rapid progressors; the influence of FHM type outweighs that of sex), THR within 2 (K/LIII) to 4 (K/LII) years. Each EF, in addition to the patient's individual progression rate, was also associated with a different response to the aforementioned therapies. Conclusions. Clinical endophenotyping provides guidance for a personalized approach in patients with pHOA, simultaneously assisting the creation of homogeneous patient groups necessary for conducting modern genetic and therapeutic scientific studies.

Three-year effect of bisphosphonates on bone mineral density after denosumab withdrawal: observations from a real-world study.

Data on long-term treatment regimens for preventing bone mineral density (BMD) loss that occurs after denosumab (Dmab) withdrawal are scarce. Our aim was to evaluate the long-term changes (12-36months) in BMD and bone turnover markers in a group of postmenopausal women who had been treated with Dmab and received subsequent treatment with bisphosphonates. Secondary objectives were to evaluate factors associated with BMD loss, to compare the BMD change in patients who received oral vs intravenous bisphosphonates, and to assess the frequency of fragility fractures after Dmab discontinuation. The clinical data of 54 patients, 26 of whom had clinical and DXA assessments at 36months, were analyzed. After 12months, the mean LS BMD had decreased by 2.8% (±5.0), FN BMD by 1.9% (±5.8), and TH BMD by 1.9% (±3.7). After 36months, LS BMD had decreased by 3.7% (±6.7), FN BMD by 2.5% (±7.1), and TH BMD by 3.6% (±5.2). C-terminal cross-linked telopeptide of type I collagen significantly increased during the first 12months after Dmab withdrawal but then decreased at 36months. BMD loss at 12months was higher in patients with more than 30months of Dmab treatment, but this difference was only statistically significant at FN (-3.3% vs -0.3%, P = .252 at LS, -3.3% vs 0.3%, P = .033 at FN, and -2.1% vs 0.9, P = .091 at TH). There were no statistically significant differences regarding the change in BMD at 12 and 36months between oral and intravenous treatment. Seven patients suffered incidental vertebral fractures (clinical vertebral fractures: n = 6, morphometric fractures: n = 1) three of which were multiple. None of these patients were treated following international or institutional guidelines or recommendations. In summary, our study suggests that bisphosphonates can help maintain BMD for 36months after Dmab discontinuation.

The cost-effectiveness of osteoporosis medications for preventing periprosthetic fractures following femoral neck fracture indicated hip arthroplasty: a break-even analysis.

Osteoporosis treatment following arthroplasty for femoral neck fracture (FNF) is associated with lower rates of periprosthetic fracture (PPF). Although cost-effective in reducing the rate of secondary fragility fracture, the economic viability of osteoporosis treatment in preventing PPF has not been evaluated. Therefore, the purpose of this study is to use a break-even analysis to determine whether and which current osteoporosis medications are cost-effective in preventing PPF following arthroplasty for FNFs. Three-year average cost of osteoporosis medication (oral bisphosphonates, estrogen hormonal therapy, intravenous (IV) bisphosphonates, denosumab, teriparatide, and abaloparatide), costs of PPF care, and PPF rates in patients who underwent hip arthroplasty for FNFs without osteoporosis treatment were used to perform a break-even analysis. The absolute risk reduction (ARR) related to osteoporosis treatment and sensitivity analyses were used to evaluate the cost-effectiveness of this intervention and break-even PPF rates. Oral bisphosphonate therapy following arthroplasty for hip fractures would be economically justified if it prevents one out of 56 PPFs (ARR, 1.8%). Given the current cost and incidence of PPF, overall treatment can only be economically viable for PPF prophylaxis if the 3-year costs of these agents are less than $1500. The utilization of lower cost osteoporosis medications such as oral bisphosphonates and estrogen hormonal therapy as PPF prophylaxis in this patient population would be economically viable if they reduce the PPF rate by 1.8% and 1.5%, respectively. For IV bisphosphonates and newer agents to be economically viable as PPF prophylaxis in the USA, their costs need to be significantly reduced.

Impact of Osteoporosis on Autogenous Bone Graft Resorption

BackgroundOsteoporosis is a common disorder that is characterized by decreased bone density and increased bone resorption. This bone resorption may affect the grafted bone during the maxillofacial reconstruction. PurposeThis study aimed to measure the association between osteoporosis and resorption of anterior iliac crest bone grafts (AICBGs) used to reconstruct the atrophic anterior maxillae. Study design, setting, and sampleThis prospective cohort study included female patients requiring bone augmentation of the anterior maxilla. Patients with a ridge width of < 4 mm and ridge height of > 7 mm were enrolled in the study. Exclusion criteria were chronic use of corticosteroids or intravenous bisphosphonates, history of maxillofacial radiation therapy, current smoking, and underlying conditions contributing to bone metabolism (e.g., hyperparathyroidism, chronic renal failure, and hypophosphatemia). Predictor/exposure/independent variableOsteoporosis status was a predictor variable. Patients were allocated to the osteoporosis or control group based on T-scores obtained by dual-energy X-ray absorptiometry (DEXA). Mean T-scores ≤ -2.5 were assigned to the osteoporosis group. Main outcome variable(s)The outcome variable was graft resorption, defined as the difference in ridge width between measurements made immediately (T1) and six months postoperatively (T2) using cone-beam computed tomography (CBCT). CovariatesPatient age, pre-operative (T0) bone width, and the amount of bone augmentation, defined as the differences in ridge width between measurements made preoperatively (T0) and immediately after grafting (T1), were covariates of this study. ResultsThirty-two patients were included in the study (15 in the osteoporosis group and 17 in the control group). The amount of graft resorption at six-months after grafting was 2.57 ±0.59 mm in the osteoporosis group and 0.97±0.59 mm in the control group (p<0.001). A significant correlation was found between the mean T-score and graft resorption six months after grafting (p<0.001). ConclusionA significant correlation was observed between osteoporosis and graft resorption in the anterior maxilla after six months.

Diagnosis and treatment of Paget’s disease of bone: position paper from the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS)

IntroductionPaget’s disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget’s disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management.MethodsThrough selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice.Results and conclusionDescription of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Influence of zoledronic acid and pamidronate on tooth eruption in children with osteogenesis imperfecta

IntroductionOsteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children. MethodsAn ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption. ResultsThe age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration. ConclusionPatients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac.