Search

Introduction: Osteoporosis is a metabolic skeletal disease characterized by low bone mass and strength, and increased risk for fragility fractures. It is a major health issue in aging populations, due to fracture-associated increased disability and mortality. Antiresorptive treatments are first line choices in most of the cases. Areas covered: Bone homeostasis is complicated, and multiple factors can compromise skeletal health. Bone turnover is a continuous process regulated by the coupled activities of bone cells that preserves skeletal strength and integrity. Imbalance between bone resorption and formation leads to bone loss and increased susceptibility to fractures. Antiresorptives prevent bone loss and reduce fracture risk, by targeting osteoclastogenesis and osteoclast function and survival. Their major drawback is the coupling of osteoclast and osteoblast activity, due to which any reduction in bone resorption is followed by suppression of bone formation. Expert opinion: During the last couple of decades significant progress has been made in understanding of the genetic and molecular basis of osteoporosis. Critical pathways and key molecules that mediate regulation of bone resorption have been identified. These factors may underpin novel therapeutic avenues for osteoporosis, but their potential for translation into clinical applications is yet to be tested. [ABSTRACT FROM AUTHOR]

There is variability amongst clinicians in the management of medication-related osteonecrosis of the jaw (MRONJ) though numerous guidelines are available. The aim of this critical review is to appraise current international and national guidelines on MRONJ to evaluate areas of consensus or inconsistency, identify areas lacking evidence, and discuss recommendations with agreement and variability across guidelines. A literature search was performed to identify all national and international guidelines published until May 2022 on the prevention and treatment of MRONJ. Included guidelines were compared and critically appraised with Appraisal of Guidelines for Research and Evaluation II (AGREE II). The included sixteen guidelines were published from ten different countries, two of which had international collaborations. AGREE II assessment found four guidelines of high quality. There is consensus to optimise oral health prior to and during therapy, to conservatively manage established MRONJ in earlier stages and consider surgery at advanced stages. There is disparity on strategies to reduce the risk of osteonecrosis such as the avoidance of invasive dental procedures, therapy suspension, and techniques to reduce the impact of invasive surgery. The authors recommend an international lead in the development of dental guidelines to establish a global standardised management approach aiming for better health equality. [ABSTRACT FROM AUTHOR]

Antiresorptive drugs are commonly used to treat cancer and bone metastases. These drugs can impose the risk of osteonecrosis of the jaw (ONJ). ONJ is a serious complication that can lead to significant morbidity and mortality. This study aimed to investigate the incidence and preventive measures utilization of ONJ among cancer patients treated with antiresorptive agent. This retrospective cohort study investigated 210 adult patients with cancer on either zoledronic acid (ZA) or denosumab at a tertiary cancer center. The primary endpoint was to determine the incidence rate of Osteonecrosis of the Jaw. Secondary endpoints were to determine the utilization rate of antiresorptive agent related ONJ preventive measures and the exposure duration of antiresorptive agents to the ONJ incidence. Of 210 patients, 68 were on zoledronic acid (group 1) and 142 were maintained on denosumab (group 2). The median incidence rate of medication related ONJ (MRONJ) was 3.8 % (8 out of 210), with 4.4 % (3 out of 68) in the first group and 3.5 % (5 out of 142) in the second group. All ONJ cases were females with metastatic breast cancer to bone. The utilization rate of ONJ preventive measures was 5.2 %, including regular dental check-ups (3.3 %) and oral hygiene education (1.9 %). The median duration of exposure before ONJ was 1 year for zoledronic acid and 2 years for denosumab. Risk factors included female sex, diabetes mellitus, and hypertension. Duration of Denosumab exposure, but not ZA, was associated with incidence of ONJ. Higher incidence rate of ONJ among denosumab-treated group. The findings emphasize the importance of female sex, diabetes, and hypertension as significant risk factors. The use of preventive measures was found to be low, indicating a need for better education and awareness. [ABSTRACT FROM AUTHOR]

Aging of the general population has led to a substantial increase in the prevalence of osteoporosis over the past decades. While there are effective pharmacological agents that increase bone formation, decrease bone resorption, and decrease fracture risk, they do not uniformly cure osteoporosis. This has prompted investigations to examine whether combination therapy (COMBO) with these agents can result in an additive benefit. Since concomitant therapy with denosumab and teriparatide has shown promise in this respect, investigations were undertaken to explore whether the changes in osteogenic phenotype could provide insight into the cellular and molecular mechanism of this effect. Investigations were performed in postmenopausal women receiving denosumab, teriparatide, or both for 3 months. Histomorphometric parameters were the primary outcome, while exploratory studies examined RNA expression in bone biopsies as well as in sorted and cultured bone marrow stromal cells (BMSCs). Osteogenic colony forming units of BMSCs were also evaluated. The studies demonstrated that COMBO results in an increase in osteoprogenitors, evidenced by an increase in osteoblastic colony-forming units. This was associated with an increased in BMSC expression of LGR6 (leucine-rich repeat containing G protein–coupled receptor 6), a stem cell marker and activator of the canonical Wnt signaling pathway. These data suggest that enhancement of canonical Wnt signaling contributes to the increase in osteoprogenitors and consequently an increase in bone density in postmenopausal women receiving COMBO for osteoporosis. [ABSTRACT FROM AUTHOR]

Introduction: Antiresorptive drugs are commonly used to treat cancer and bone metastases. These drugs can impose the risk of osteonecrosis of the jaw (ONJ). ONJ is a serious complication that can lead to significant morbidity and mortality. This study aimed to investigate the incidence and preventive measures utilization of ONJ among cancer patients treated with antiresorptive agent. Materials and Methods: This retrospective cohort study investigated 210 adult patients with cancer on either zoledronic acid (ZA) or denosumab at a tertiary cancer center. The primary endpoint was to determine the incidence rate of Osteonecrosis of the Jaw. Secondary endpoints were to determine the utilization rate of antiresorptive agent related ONJ preventive measures and the exposure duration of antiresorptive agents to the ONJ incidence. Results: Of 210 patients, 68 were on zoledronic acid (group 1) and 142 were maintained on denosumab (group 2). The median incidence rate of medication related ONJ (MRONJ) was 3.8 % (8 out of 210), with 4.4 % (3 out of 68) in the first group and 3.5 % (5 out of 142) in the second group. All ONJ cases were females with metastatic breast cancer to bone. The utilization rate of ONJ preventive measures was 5.2 %, including regular dental check-ups (3.3 %) and oral hygiene education (1.9 %). The median duration of exposure before ONJ was 1 year for zoledronic acid and 2 years for denosumab. Risk factors included female sex, diabetes mellitus, and hypertension. Duration of Denosumab exposure, but not ZA, was associated with incidence of ONJ. Conclusion: Higher incidence rate of ONJ among denosumab-treated group. The findings emphasize the importance of female sex, diabetes, and hypertension as significant risk factors. The use of preventive measures was found to be low, indicating a need for better education and awareness.

Abstract Objective Medication-related osteonecrosis of the jaw bones (MRONJ) is a well-known complication of antiresorptive and antiangiogenic drugs. Since the first report, more occurrences of MRONJ have been described worldwide. Dental extraction has been described by many studies as one of the risk factors for MRONJ. Comprehensive dental care (CDC) is a preventive dental method provided to patients prior to drug commencement. This study aims to determine the association between CDC and MRONJ. Patients and methods. A retrospective analysis was performed on 75 medical records of patients on antiresorptive and/or antiangiogenic drugs between February 2018 and May 2021. Demographics and clinical and radiographic data were collected. Univariate and multivariate analyses were performed to determine the factors associated with MRONJ. Results Of the 75 patients who met the inclusion criteria, 11 (14.7%) developed MRONJ. Three out of 11 patients (27.2%) developed MRONJ spontaneously, while eight patients (72.8%) developed it after trauma from dentures or dental extractions. Following a binary logistic regression analysis, the lack of CDC was identified as a significant predictor of MRONJ. Patients who did not receive CDC had an odds ratio of 8.64 (95% confidence interval (CI): 1.27–58.62, p = 0.03). However, dental extraction did not show a statistically significant association with MRONJ in both the univariate and multivariate analyses. Conclusion CDC before treatment with antiresorptive and antiangiogenic drugs is a potentially effective preventive method for reducing MRONJ. Dental extraction was not a significant factor in relation to MRONJ.

Objective: Medication-related osteonecrosis of the jaw bones (MRONJ) is a well-known complication of antiresorptive and antiangiogenic drugs. Since the first report, more occurrences of MRONJ have been described worldwide. Dental extraction has been described by many studies as one of the risk factors for MRONJ. Comprehensive dental care (CDC) is a preventive dental method provided to patients prior to drug commencement. This study aims to determine the association between CDC and MRONJ. Patients and methods. A retrospective analysis was performed on 75 medical records of patients on antiresorptive and/or antiangiogenic drugs between February 2018 and May 2021. Demographics and clinical and radiographic data were collected. Univariate and multivariate analyses were performed to determine the factors associated with MRONJ. Results: Of the 75 patients who met the inclusion criteria, 11 (14.7%) developed MRONJ. Three out of 11 patients (27.2%) developed MRONJ spontaneously, while eight patients (72.8%) developed it after trauma from dentures or dental extractions. Following a binary logistic regression analysis, the lack of CDC was identified as a significant predictor of MRONJ. Patients who did not receive CDC had an odds ratio of 8.64 (95% confidence interval (CI): 1.27–58.62, p = 0.03). However, dental extraction did not show a statistically significant association with MRONJ in both the univariate and multivariate analyses. Conclusion: CDC before treatment with antiresorptive and antiangiogenic drugs is a potentially effective preventive method for reducing MRONJ. Dental extraction was not a significant factor in relation to MRONJ. [ABSTRACT FROM AUTHOR]

Summary: Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. Purpose: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. Methods: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. Results: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. Conclusion: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF. [ABSTRACT FROM AUTHOR]

Introduction: Medication‐related osteonecrosis of the jaw (MRONJ) is uncommon but can result in severe destruction of the jaw. This case–control study investigated the therapeutic effects of daily or weekly administration of teriparatide in the management of MRONJ using a cohort for osteonecrosis of the jaw. Methods: Patients who were diagnosed with MRONJ and consented to teriparatide administration were assigned either to a group of daily injection or of weekly injection and completed a 4‐week course of injection preoperatively and at least an 8‐week course postoperatively. The control group received either the intraoperative rhBMP treatment (CG_BMP) or no additional perioperative treatment (CG_noBMP). The state of MRONJ was evaluated 2 months (T1) and 6 months (T2) postoperatively for all participants. Results: Either group of daily injection (8.35 weeks ± 1.58; n = 17) or weekly injection (9.17 ± 3.79; n = 12) showed significantly faster healing than those of CG_BMP (14.40 ± 6.08; n = 25) or CG_noBMP (15.79 ± 9.79; n = 39). MRONJ was resolved completely in 24 out of 29 participants who completed the course of teriparatide injections, whereas 46.9% of CG showed delayed resolution. Multiple regression analysis indicated 7.50 times (95% CI, 1.77–31.82) more likelihood of complete resolution of MRONJ for participants with teriparatide injections. Conclusion: A course of daily or weekly administration of teriparatide injections may improve treatment outcomes for patients with MRONJ. [ABSTRACT FROM AUTHOR]

Study Design: Retrospective Cohort Objective: Antiresorptive drugs are often given to minimize fracture risk for bone metastases, but data regarding optimal time or ability to reduce stereotactic body radiotherapy (SBRT)-induced fracture risk is limited. This study examines the association between antiresorptive use surrounding spinal SBRT and vertebral compression fracture (VCF) incidence to provide information regarding effectiveness and optimal timing of use. Methods: Patients treated with SBRT for spinal metastases at a single institution between 2009-2020 were included. Kaplan-Meier analysis was used to compare cumulative incidence of VCF for those taking antiresorptive drugs pre-SBRT, post-SBRT only, and none at all. Cox proportional hazards and Fine-Gray competing risk models were used to identify additional factors associated with VCF. Results: Of the 234 patients (410 vertebrae) analyzed, 49 (20.9%) were taking bisphosphonates alone, 42 (17.9%) were taking denosumab alone, and 25 (10.7%) were taking both. Kaplan-Meier analysis revealed a statistically significant lower VCF incidence for patients initiating antiresorptive drugs before SBRT compared to those taking none at all (4% vs 12% at 1 year post-SBRT, P =.045; and 4% vs 23% at 2 years, P =.008). On multivariate analysis, denosumab duration (HR:.87, P =.378) or dose (HR: 1.00, P =.644) as well as bisphosphonate duration (HR:.98, P =.739) or dose (HR:.99, P =.741) did not have statistical significance on VCF incidence. Conclusion: Initiating antiresorptive agents before SBRT may reduce the risk of treatment-induced VCF. Antiresorptive drugs are underutilized in patients with spine metastases and may represent a useful intervention to minimize toxicity and improve long-term outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Osteoporosis is a chronic systemic skeletal disorder characterized by compromised bone strength and an increased risk of fracture, with a high prevalence worldwide. It is associated with a negative quality of life and an increased morbidity and mortality. Postmenopausal women are more prone to develop osteoporosis, and many of them will suffer at least one fragility fracture along their lifetime. Areas covered: This review starts by summarizing the pathogenesis of postmenopausal osteoporosis (PMO), with focus on the estrogen deficiency-associated bone loss. It continues with the current PMO diagnostic and fracture risk prediction tools, and it finally addresses management of PMO. All the efficacy and safety profiles of the current and future osteoporosis medications are reviewed. Furthermore, strategies to optimize the long-term disease management are discussed. For this review, only publications in English language were selected. References were extracted from PubMed, Embase, and Medline. Expert opinion: PMO disease management is far from being ideal. Educational and communication programs with the goal of improving disease knowledge and awareness, as well as reducing the health-care gap, should be implemented. In addition, most effective sequential prevention and treatment strategies should be initiated from the early menopause. [ABSTRACT FROM AUTHOR]

Summary: Bone strength estimates are important for fracture prevention. This study compared bone strength changes in postmenopausal women with low bone mass who were assigned to 12 months of exercise, a bone medication, or control. Exercise and bone medications benefited structure at the hip. Structure should be considered in fracture prevention research. Purpose: Exercise and bisphosphonates reduce fracture risk, but their impact on estimates of bone strength remains uncertain. This study compared changes in tibial bone strength using peripheral quantitative computed tomography (pQCT) and hip structure analysis (HSA) outcomes from dual-energy X-ray absorptiometry (DXA) scans in postmenopausal women with low bone mass assigned to 12 months of exercise, risedronate, or control. Methods: In this RCT, 276 postmenopausal women within 6 years of menopause were randomly assigned to three groups: exercise (92), risedronate (91), or control (93). Exercise included weighted jogging and progressive resistance exercises; risedronate treatment was 150 mg monthly; all groups received calcium and vitamin D. pQCT and DXA images were obtained at baseline and 6 and 12 months and compared between groups over time. Results: Participants had a mean (± SD) age of 54.5 (± 3.2) years with an average of 36.7 (± 40.7) months postmenopause. No significant differences were found between groups for the change in pQCT outcomes (volumetric bone mineral density, area, and strength estimates). At 12 months, mean percent differences (95% CI) in HSA measures between exercise and controls were as follows: intertrochanteric, cross-sectional area 2.25% (0.28, 4.12) (p =.03), cross-sectional moment of inertia (CSMI) 5.67% (1.47, 9.87) (p <.01), and section modulus (SM) 4.38% (1.02, 7.74) (p =.01), and narrow neck, average cortical thickness 2.37% (−0.08, 4.83) (p =.031). Mean percent differences (95% CI) in HSA measures between risedronate and control were as follows: intertrochanteric, CSMI 4.28% (−0.24, 8.81) (p =.03) and SM 3.35% (−0.21, 6.91) (p =.03), and shaft, subperiosteal width 0.82% (0.05, 1.58) (p =.047), CSMI 2.53% (0.88, 4.18) (p =.004), and SM 1.57% (0.34, 2.8) (p =.008). Exercise maintained neck-shaft angle compared to both control 1.27% (0.13, 2.41) (p =.04) and risedronate 1.31% (0.23, 2.39) (p =.03). All other differences for changes in HSA outcomes over time were not significantly different between the exercise and risedronate groups. Conclusion: Exercise and bisphosphonates may influence structural and strength estimates at the hip, but not at peripheral sites (tibia). Neither exercise nor bisphosphonates were found to be superior in improving estimates of hip bone strength. [ABSTRACT FROM AUTHOR]

Background: Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term strategy should be scheduled by considering the mechanisms of action in therapy and the estimated fracture risk. Objective: A systematic review was conducted to evaluate the sequential strategy in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines. Design: Systematic review and meta-analysis. Data sources and methods: PubMed, Embase, and the Cochrane Library were investigated up to February 2021 to update the search of a recent systematic review. Randomized clinical trials (RCTs) that analyzed the sequential therapy of antiresorptive, anabolic treatment, or placebo in patients with or at risk of a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using fixed-effects models. The primary outcome was the risk of refracture, while the secondary outcome was the bone mineral density (BMD) change. Results: In all, 17 RCTs, ranging from low to high quality, met our inclusion criteria. A significantly reduced risk of fracture was detected at (i) 12 or 24 months after the switch from romosozumab to denosumab versus placebo to denosumab; (ii) 30 months from teriparatide to bisphosphonates versus placebo to bisphosphonates; and (iii) 12 months from romosozumab to alendronate versus the only alendronate therapy (specifically for vertebral fractures). In general, at 2 years after the switch from anabolic to antiresorptive drugs, a weighted BMD was increased at the lumbar spine, total hip, and femoral neck site. Conclusion: The Task Force formulated recommendations on sequential therapy, which is the first treatment with anabolic drugs or 'bone builders' in patients with very high or imminent risk of fracture. Plain language summary: A systematic review to evaluate the sequential therapy of antiresorptive (denosumab and bisphosphonate, such as alendronate, minodronate, risedronate, and etidronate), anabolic treatment (such as romosozumab, teriparatide), or placebo in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines Subjects with previous fragility fractures should promptly receive effective strategies to prevent the risk of subsequent events. Indeed, patients with a fragility fracture have a doubled risk of a new fracture. For this reason, it is essential to provide adequate sequential therapy based on the mechanisms and the rapidity of action. A systematic review was performed to identify the sequential strategy in patients at high- or imminent-risk of (re)fracture and to support the Panel of the Italian Fragility Fracture Guideline in formulating recommendations. Our systematic review included seventeen studies mostly focused on women and enabled us to strongly recommend the anabolic drugs as first-line treatment. Specifically, for the sequential therapy from anabolic to antiresorptive treatment, there was a significant reduction in the risk of different types of fractures after the switch from romosozumab to denosumab versus placebo to denosumab. These findings were confirmed at 24 months after the switch. Considering the sequential treatment from antiresorptive to anabolic medications, there was a decreased risk of fracture 12 months after the switch from placebo to teriparatide versus bisphosphonate or antiresorptive to teriparatide. Moreover, a greater bone mineral density increase after the switch from anabolic to antiresorptive medications was shown in the lumbar spine, total hip, and femoral neck. The results of this systematic review and meta-analysis confirm that initial treatment with anabolic drugs produces substantial bone mineral density improvements, and the transition to antiresorptive drugs can preserve or even amplify the acquired benefit. These findings support the choice to treat very high-risk individuals with anabolic drugs first, followed by antiresorptive drugs. [ABSTRACT FROM AUTHOR]

Summary: We assessed the prevalence of hypocalcemia after denosumab injections in a real-world cohort routinely monitored for calcium during up to 7.5 years of treatment. Among 1096 injections in 242 patients, 6.3% resulted in hypocalcemia, and was independent of the injection number. Severe hypocalcemia was rare (1%). Purpose: To assess the prevalence of and risk factors for hypocalcemia after administration of denosumab in a patient cohort routinely monitored for ionized calcium after each dose. Methods: In this retrospective observational study, we analyzed denosumab-induced hypocalcemia in a real-world cohort who were routinely followed up with ionized calcium pre- and post-injection (within 31 days after injection) during the period 2011 to 2020. Results: In total, we included data from 1096 denosumab injections in 242 individuals (1–15 injections per patient). The mean age for the first injection was 74 ± 10 years, and 88% were female. Post-injection hypocalcemia occurred after 6.3% of all injections (4.6% mild, 0.6% moderate, and 1.1% severe) and was independent of the number of injections (rate of hypocalcemia varied from 3–8%). Risk factors for hypocalcemia were male sex, severe renal failure, pre-injection hypocalcemia, hypomagnesemia, hypophosphatemia, and vitamin D insufficiency. Furthermore, older age was not associated with an increased hypocalcemia risk. Conclusions: Denosumab-induced hypocalcemia is a prevalent adverse event, which occurs independently of the number of injections. However, severe hypocalcemia is a rare occurrence, and severe renal failure and nutritional status appear to be important predictive factors. Magnesium and phosphate might add value in the pre-injection risk assessment; however, this observation needs to be confirmed in larger cohorts. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is an age-related common bone disorder characterized by low bone mineral density and increased fragility fracture risk. Various Antiresorptive medications are being used to target osteoclast mediated bone resorption to prevent bone loss and reduce fracture risk. About Denosumab: Denosumab is a novel biological antiresorptive drug that belongs to the class of monoclonal antibodies. It binds to and inhibits the cytokine receptor activator of nuclear factor kappa-B ligand (RANKL), which is requisite for osteoclast differentiation, function and survival. Effectiveness: Denosumab has been shown to be a potent and effective therapy for osteoporosis, with clinical trial data demonstrating significant improvement in bone mineral density (BMD) and reductions in fracture risk at various skeletal sites for more than 10 years of treatment. Safety Profile: Denosumab has a favourable benefit/risk profile, with low rates of complications such as infection, atypical femoral fracture and osteonecrosis of the jawbone. Challenges: However, denosumab treatment requires continuous administration, as discontinuation leads to rapid bone mineral loss and increased risk of multiple vertebral fractures due to rebound of bone turnover. Therefore, modification to another anti-osteoporosis drug therapy after denosumab discontinuation is required to maintain bone health. Conclusion: Denosumab is a promising biological antiresorptive therapy for osteoporosis that offers high efficacy and safety, but also poses challenges for long-term management. [ABSTRACT FROM AUTHOR]

Background: Bisphosphonates, synthetic analogs of endogenous pyrophosphates, are pivotal in managing various bone disorders, primarily osteoporosis, which affects millions globally. While osteoporosis, especially postmenopausal osteoporosis, significantly benefits from bisphosphonate therapy, considerations arise regarding their administration and potential side effects. Clinical application of Bisphosphonates: Bisphosphonates, divided into nitrogen-containing and non-nitrogenous groups, exert their influence through distinct mechanisms, with the former being notably more potent. The role of bisphosphonates in other diseases, such as Paget's bone and skeletal metastasis disease is also discussed. Detailed information on the administration routes, dosage regimens, and considerations for drug holidays is provided. The article navigates through the chemical structure, generations, and mechanism of action of bisphosphonates. The article covers administration routes, dosage regimens, and drug holidays, in addition to discussing potential adverse effects and contraindications. Conclusions: Bisphosphonates hold an unrivaled legacy in the management of osteoporosis. The ubiquitous availability and the cost-effectiveness of these time-tested medications make them an invaluable asset in the osteoporosis treatment landscape, especially in developing nations like India. [ABSTRACT FROM AUTHOR]

Fibrous dysplasia (FD) is a rare skeletal disorder in which normal bone is replaced by a fibro-osseous tissue, resulting in possible deformities and fractures. The aim of this systematic review and meta-analysis was to synthesize the available evidence on the use of antiresorptive drugs in FD in terms of changes in bone turnover markers (BTMs), bone mineral density (BMD), and reducing pain. Three databases were searched in October 2022, with an update in July 2023. Of the 1037 studies identified, 21 were retained after eligibility assessment. A random-effects model was used to calculate global effect size and the corresponding standard error. Pamidronate and Denosumab were the most reported drugs in a total of 374 patients assessed. The initiation of treatments was accompanied by an average reduction of 40.5% [CI95% -51.6, -29.3] in the bone resorption parameters, and 22.0% [CI95% -31.9, -12.1] in the parameters of bone formation after 6–12 months. BMD was increased in both FD lesions and in the unaffected skeleton. Pain was reduced by 32.7% [CI95% -52.7, -12.6] after 6–12 months of treatment, and by 44.5% [CI95% -65.3, -23.6] after a mean 41.2 months of follow-up. The variation in pain was highly correlated to variation in bone resorption (R2 = 0.08, p < 0.0001) and formation parameters (R2 = 0.17, p < 0.0001). This study supports the overall efficacy of antiresorptive therapies in terms of reducing bone remodeling, improving bone density, and pain in FD. [ABSTRACT FROM AUTHOR]

Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease stage. HCM is associated with impaired quality of life, increased risk of hospitalisation and limited survival. Evidence-based guidelines for management of HCM have been lacking to date, despite its prevalence and detrimental impact. This concise guidance highlights key recommendations from the recent Endocrine Society Clinical Practice Guidelines on Treatment of Hypercalcaemia of Malignancy in Adults, published in December 2022. A systematic review and meta-analysis was commissioned to support the guideline development process. Key suggestions include the use of denosumab in preference to intravenous bisphosphonates as first-line treatment for HCM and the use of denosumab in cases of recurrent or refractory HCM in patients previously treated with intravenous bisphosphonates. The guideline also identifies priority areas for future research. [ABSTRACT FROM AUTHOR]

Abstract Background Despite robust weight loss and cardiometabolic benefit, lean mass loss following sleeve gastrectomy (SG) confers health risk. Bisphosphonates are a potential therapeutic agent for lean mass maintenance. Thus, our objective was to explore the effect of 6 months of risedronate (vs. placebo) on change in dual‐energy x‐ray absorptiometry (DXA)‐ and computed tomography (CT)‐derived lean mass metrics in the year following SG. Methods Twenty‐four SG patients were randomized to 6 months of 150‐mg oral risedronate or placebo capsules (NCT03411902). Body composition was assessed at baseline and 6 months with optional 12‐month follow‐up using whole‐body DXA and CT at the lumbar spine and mid‐thigh. Group treatment effects and 95% confidence intervals (CIs) were generated from a mixed model using contrast statements at 6 and 12 months, adjusted for baseline values. Results Of 24 participants enrolled [55.7 ± 6.7 years (mean ± SD), 79% Caucasian, 83% women, body mass index (BMI) 44.7 ± 6.3 kg/m2], 21 returned for 6‐month testing and 14 returned for 12‐month testing. Six‐month weight loss was −16.3 kg (−20.0, −12.5) and −20.9 kg (−23.7, −18.1) in the risedronate and placebo groups, respectively (P = 0.057). Primary analysis at 6 months revealed a non‐significant sparing of appendicular lean mass in the risedronate group compared with placebo [−1.2 kg (−2.3, −0.1) vs. −2.1 kg (−3.0, −1.2)]; P = 0.20. By 12 months, the risedronate group displayed no change in appendicular lean mass from baseline [−0.5 kg (−1.5, 0.6)]; however, the placebo group experienced significantly augmented loss [−2.9 kg (−3.6, −2.1)]. Conclusions Pilot data indicate that risedronate treatment may mitigate appendicular lean mass loss following SG. Further study is warranted.

ABSTRACT New anabolic medications (abaloparatide and romosozumab) were recently approved for osteoporosis, and data suggest that prescribing antiresorptive medications after a course of anabolic medications offers better outcomes. This study aimed to characterize prescription trends, demographics, geographical distributions, out‐of‐pocket costs, and treatment sequences for anabolic and antiresorptive osteoporosis medications. Using a commercial claims database (Clinformatics Data Mart), adult patients with osteoporosis from 2003 to 2021 were retrospectively reviewed and stratified based on osteoporosis medication class. Patient demographics and socioeconomic variables, provider types, and out‐of‐pocket costs were collected. Multivariable regression analyses were used to identify independent predictors of receiving osteoporosis treatment. A total of 2,988,826 patients with osteoporosis were identified; 616,635 (20.6%) received treatment. Patients who were female, Hispanic or Asian, in the Western US, had higher net worth, or had greater comorbidity burden were more likely to receive osteoporosis medications. Among patients who received medication, 31,112 (5.0%) received anabolic medication; these were more likely to be younger, White patients with higher education level, net worth, and greater comorbidity burden. Providers who prescribed the most anabolic medications were rheumatologists (18.5%), endocrinologists (16.8%), and general internists (15.3%). Osteoporosis medication prescriptions increased fourfold from 2003 to 2020, whereas anabolic medication prescriptions did not increase at this rate. Median out‐of‐pocket costs were $17 higher for anabolic than antiresorptive medications, though costs for anabolic medications decreased significantly from 2003 to 2020 (compound annual growth rate: −0.6%). A total of 8388 (1.4%) patients tried two or more osteoporosis medications, and 0.6% followed the optimal treatment sequence. Prescription of anabolic osteoporosis medications has not kept pace with overall osteoporosis treatment, and there are socioeconomic disparities in anabolic medication prescription, potentially driven by higher median out‐of‐pocket costs. Although prescribing antiresorptive medications after a course of anabolic medications offers better outcomes, this treatment sequence occurred in only 0.6% of the study cohort. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population‐based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one‐third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over‐the‐counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population‐based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2. Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Prolonged use of antiresorptives such as the bisphosphonate alendronate (ALN) and the RANKL inhibitor denosumab (DMAb) are associated with rare cases of atypical femoral fracture (AFF). The etiology of AFF is unclear, but it has been hypothesized that potent osteoclast inhibitors may reduce bone fatigue resistance. The purpose of this study was to quantify the relationship between antiresorptive treatment and fatigue life (cycles to failure) in bone fromovariectomized cynomolgusmonkeys. We analyzed humeral bone from30 animals across five treatment groups. Animals were treated for 12 months with subcutaneous (sc) vehicle (VEH), sc DMAb (25 mg/kg/month), or intravenous (iv) ALN (50 µg/kg/month). Another group received 6 months VEH followed by 6 months DMAb (VEH-DMAb), and the final group received 6 months ALN followed by 6 months DMAb (ALN-DMAb). A total of 240 cortical beam samples were cyclically tested in four-point bending at 80, 100, 120, or 140 MPa peak stress. High-resolution imaging and density measurements were performed to evaluate bone microstructure and composition. Samples from the ALN (p = 0.014), ALN-DMAb (p = 0.008), and DMAb (p < 0.001) groups illustrated higher fatigue-life measurements than VEH. For example, at 140 MPa the VEH group demonstrated a median ± interquartile range (IQR) fatigue life of 1987 ± 10593 cycles, while animals in the ALN, ALN-DMAb, andDMAb groups survived 9850 ± 13648 (+395% versus VEH), 10493 ± 16796 (+428%), and 14495 ± 49299 (+629%) cycles, respectively. All antiresorptive treatment groups demonstrated lower porosity, smaller pore size, greater pore spacing, and lower number of canals versus VEH (p < 0.001). Antiresorptive treatment was also associated with greater apparent density, dry density, and ash density (p = 0.03). We did not detect detrimental changes following antiresorptive treatments that would explain their association with AFF. In contrast, 12 months of treatment may have a protective effect against fatigue fractures. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Medication-related osteonecrosis is a well-documented yet rare complication of antiresorptive treatment. The risk of MRONJ is well established in the adult population but has yet to be established in the pediatric population. Additionally, the risk to this population in adulthood following many years of antiresorptive use is unknown. This case report describes a patient who received long-term antiresorptive medication as an adolescent and spontaneously developed MRONJ at age 23. To the authors’ knowledge, this is the youngest patient with MRONJ reported in the literature.

Medication-related osteonecrosis of the jaw (MRONJ) is defined by the American Association of Oral and Maxillofacial Surgeons (AAOMS) as the presence of an exposed bone area in the maxillofacial region, present for more than eight weeks in patients treated with the use of antiresorptive or antiangiogenic agents, with no history of radiation or metastatic disease. Bisphosphonates (BF) and denosumab (DS) are widely used in adults for the management of patients with cancer and osteoporosis, and recently there has been an increase in their use in child and young patients for the management of disorders such as osteogenesis imperfecta (OI), glucocorticoid-induced osteoporosis, McCune-Albright syndrome (MAS), malignant hypercalcemia, and others. There are differences between case reports in adults compared to child and young patients related to the use of antiresorptive/antiangiogenic drugs and the development of MRONJ. The aim was to analyze the presence of MRONJ in children and young patients, and the relation with oral surgery. A systematic review, following the PRISMA search matrix based on the PICO question, was conducted in PubMed, Embase, ScienceDirect, Cochrane, Google Scholar, and manual search in high-impact journals between 1960 and 2022, publications in English or Spanish, including randomized and non-randomized clinical trials, prospective and retrospective cohort studies, cases and controls studies, and series and case reports. A total of 2792 articles were identified and 29 were included; all of them published between 2007 and 2022, identifying 1192 patients, 39.68% male and 36.24% female, aged 11.56 years old on average, using these drugs mainly for OI (60.15%); 4.21 years on average was the therapy time and 10.18 drug doses administered on average; oral surgery was observed in 216 subjects, reporting 14 cases of MRONJ. We concluded that there is a low presence of MRONJ in the child and youth population treated with antiresorptive drugs. Data collection is weak, and details of therapy are not clear in some cases. Deficiencies in protocols and pharmacological characterization were observed in most of the included articles. [ABSTRACT FROM AUTHOR]

Bone mineral density (BMD) levels achieved on osteoporosis treatment are predictive of subsequent fracture risk, and T-score > -2.5 has been proposed as a minimum treatment target for women with osteoporosis. Knowing the likelihood of attaining target T-scores with different medications for different baseline BMD levels can help determine appropriate initial treatment for individual patients. In this post hoc analysis, we estimated the probability of achieving a non-osteoporotic T-score (> -2.5 or ≥ -2.0) at the total hip (TH) or lumbar spine (LS) in postmenopausal women >60 years old treated with denosumab for either 3 or 10 years in the FREEDOM trial and its long-term extension. In women with baseline TH T-scores of -2.7, -3.0, and -3.5, the probabilities of achieving target T-scores > -2.5 with 3 years of denosumab were 71%, 12%, and 0.1%, respectively. At LS, for baseline T-scores of -2.7, -3.0, and -3.5, the probabilities were 86%, 59%, and 11%, respectively. Longer treatment duration of up to 10 years increased the probability of achieving target T-scores. The baseline T-scores that permitted at least 50% of women to achieve a target T-score > -2.5 was -2.8 at TH and -3.1 at LS after 3 years and -3.0 at TH and -3.7 at LS after 10 years of treatment. To achieve higher treatment targets (T-scores ≥ -2.0), overall probabilities were lower at both skeletal sites, particularly for TH, even with longer treatment duration. Our results demonstrate that the probability of achieving T-score targets with denosumab is dependent on baseline BMD, skeletal site, and treatment duration. Knowing the probability of achieving treatment targets for different baseline TH and LS T-scores can help determine whether denosumab is an appropriate first choice of treatment in individual patients., (© The Author(s) 2025. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Introduction: Cases involving invasive cervical root resorption (ICRR) in oncological patients are rare, in addition, follow-up of these patients has not yet been reported in the literature., Objective: This study aims to present a literature review and report a case of denosumab as a possible cause of ICRR in a patient with breast cancer with 2 years of follow-up., Case Report: A 39-year-old female with a history of luminal breast cancer was treated with denosumab semiannually for osteopenia with discontinuation 1 year ago. Oral examination revealed areas of ICRR lesions on two mandibular teeth. The patient presented irreversible pulpitis on the lower left first molar (#19). The lower right first premolar (#28) was asymptomatic, and the resorption cavity was restricted to the tooth crown. Cone-beam computed tomography (CBCT) established the ICRR 2Bp and 2Ad diagnosis in teeth #19 and #28, respectively. Periodontal surgery and a nonsurgical root canal were performed in the molar and restorative treatment was performed in the premolar. Two years after treatment, both teeth were functional and asymptomatic, and probing was within normal limits (< 3 mm) without bleeding. Periapical radiographic examination revealed no progression of resorption nor new lesions., Conclusions: This article highlights a rare adverse effect of an antiresorptive therapy, unfamiliar to most clinicians and specialists. In addition, it emphasizes that the early diagnosis and follow-up of ICRR are relevant and can provide successful treatment, avoiding infections and extractions., (© 2024 Special Care Dentistry Association and Wiley Periodicals LLC.)

Summary: In this retrospective study, the effectiveness of short-term teriparatide with denosumab in reducing fragility fracture risk was determined in comparison with denosumab monotherapy. Administration of sequential teriparatide with denosumab showed excellent outcomes in suppressing the risk for fragility fractures compared with denosumab monotherapy. Introduction: To determine the effectiveness of short-term teriparatide with denosumab in reducing the risk of fragility fractures in comparison to denosumab monotherapy. Methods: The data of postmenopausal patients treated with denosumab for > 2 years between August 2015 and October 2020 were retrospectively analyzed. One hundred sixty four postmenopausal women of a total 615 were excluded, since they did not undergo > 2 bone mineral density (BMD) tests, were lost to follow-up, or received long-term teriparatide therapy. Total 320 patients received denosumab monotherapy and 131 patients received teriparatide for ≥ 3 months followed by denosumab. The number of osteoporotic fractures, presence of back pain before and after treatment, and annual BMD during treatment were comparatively assessed using t-test, Chi-square test, and linear mixed model analysis. Results: Before treatment, the denosumab monotherapy group had fewer osteoporotic fractures (mean ± standard deviation; 0.459 ± 0.689) than the sequential therapy group had (1.037 ± 0.871; p < 0.001). After treatment, the sequential therapy group had fewer osteoporotic fractures than the denosumab monotherapy group had (0.119 ± 0.348 versus 0.144 ± 0.385; p < 0.001). At 1 and 2 years after treatment, the increase in lumbar spine BMD was greater in the sequential therapy group than in the denosumab monotherapy group (p = 0.08, group × time). The difference between post and pre-treatment back pain visual analog scale score was significantly lower in the sequential therapy group than in the monotherapy group (3.246 ± 3.426 versus 1.734 ± 3.049; p < 0.001). Conclusion: Short-term teriparatide use before denosumab showed excellent outcomes in suppressing the risk of fragility fractures compared with denosumab monotherapy. [ABSTRACT FROM AUTHOR]

Copyright of Revista ADM is the property of Asociacion Dental Mexicana and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Despite well-defined criteria for radiographic diagnosis of atypical femur fractures (AFFs), missed and delayed diagnosis is common. An AFF diagnostic software could provide timely AFF detection to prevent progression of incomplete or development of contralateral AFFs. In this study, we investigated the ability for an artificial intelligence (AI)-based application, using deep learning models (DLMs), particularly convolutional neural networks (CNNs), to detect AFFs from femoral radiographs. A labelled Australian dataset of pre-operative complete AFF (cAFF), incomplete AFF (iAFF), typical femoral shaft fracture (TFF), and non-fractured femoral (NFF) X-ray images in anterior-posterior view were used for training (N = 213, 49, 394, 1359, respectively). An AFFnet model was developed using a pretrained (ImageNet dataset) ResNet-50 backbone, and a novel Box Attention Guide (BAG) module to guide the model's scanning patterns to enhance its learning. All images were used to train and internally test the model using a 5-fold cross validation approach, and further validated by an external dataset. External validation of the model's performance was conducted on a Sweden dataset comprising 733 TFF and 290 AFF images. Precision, sensitivity, specificity, F1-score and AUC were measured and compared between AFFnet and a global approach with ResNet-50. Excellent diagnostic performance was recorded in both models (all AUC >0.97), however AFFnet recorded lower number of prediction errors, and improved sensitivity, F1-score and precision compared to ResNet-50 in both internal and external testing. Sensitivity in the detection of iAFF was higher for AFFnet than ResNet-50 (82 % vs 56 %). In conclusion, AFFnet achieved excellent diagnostic performance on internal and external validation, which was superior to a pre-existing model. Accurate AI-based AFF diagnostic software has the potential to improve AFF diagnosis, reduce radiologist error, and allow urgent intervention, thus improving patient outcomes. • A deep learning model was developed to classify atypical femur fracture (AFF) from typical and non-fractured femur images. • The model achieved excellent diagnostic performance on internal and external validation testing (all AUC >0.97). • AFFnet outperformed a conventional training model in the detection of incomplete AFFs (accuracy rate 82% vs 55%). • An accurate AFF diagnostic software may improve AFF detection, reduce clinician error, and allow urgent intervention. [ABSTRACT FROM AUTHOR]

Summary : To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence. Introduction : Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively). Methods: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available). Results: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab). Conclusion: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence. [ABSTRACT FROM AUTHOR]

Background: Giant-cell tumor of bone (GCTB) is a relatively benign, but locally aggressive osteoclastogenic stromal tumour of the bone. Although denosumab has been approved as an monoclonal antibody against RANK ligand for the treatment of GCTB, few clinical trials of the benefit in tumor response have been conducted to prove the efficiency in Chinese population. Objectives: In this multicentric, random controlled, clinical trial, 160 patients were enrolled to compare the therapeutic efficacy and safety of denosumab and zoledronic acid treatment in patients with surgically unsalvageable GCTB. Methods: Between 2nd Jan 2015 and 1st Jan 2018, 160 adults (aged ≥ 18 years) with ①surgically unsalvageable GCTB, ②surgically salvageable GCTB with planned surgery expected to result in severe morbidity were included in this randomized clinical trial. Patients received either subcutaneous denosumab (DB group; 120 mg once every 4 weeks with loading doses of 120 mg subcutaneously admininstered on days 8 and 15; n = 80) or intravenous zoledronic acid (ZA group; 4 mg once every 4 weeks; n = 80) for six cycles. Disease status, clinical benefits, treatment-emergent adverse effects, overall survival, and cost of treatment were evaluated during the follow-up period. Statistical significance was determined using 95% confidence intervals. Results: Denosumab and zoledronic acid had similar tumor responses (p = 0.118) and clinical benefits (p = 0.574). Disease progression was observed in fewer patients in the DB group (12.5%) than ZA group (15.0%). Denosumab caused fatigue (p = 0.001) and back pain (p

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder, results in persistent synovitis with severe bone and cartilage destruction. Bisphosphonates (BPs) are often utilized in RA patients to reduce bone destruction and manage osteoporosis. However, BPs, especially at high doses, are associated with osteonecrosis of the jaw (ONJ). Here, utilizing previously published ONJ animal models, we are exploring interactions between RA and ONJ incidence and severity. DBA1/J mice were divided into four groups: control, zoledronic acid (ZA), collagen-induced arthritis (CIA), and CIA-ZA. Animals were pretreated with vehicle or ZA. Bovine collagen II emulsified in Freund's adjuvant was injected to induce arthritis (CIA) and the mandibular molar crowns were drilled to induce periapical disease. Vehicle or ZA treatment continued for 8 weeks. ONJ indices were measured by micro-CT (µCT) and histological examination of maxillae and mandibles. Arthritis development was assessed by visual scoring of paw swelling, and by µCT and histology of interphalangeal and knee joints. Maxillae and mandibles of control and CIA mice showed bone loss, periodontal ligament (PDL) space widening, lamina dura loss, and cortex thinning. ZA prevented these changes in both ZA and CIA-ZA groups. Epithelial to alveolar crest distance was increased in the control and CIA mice. This distance was preserved in ZA and CIA-ZA animals. Empty osteocytic lacunae and areas of osteonecrosis were present in ZA and CIA-ZA but more extensively in CIA-ZA animals, indicating more severe ONJ. CIA and CIA-ZA groups developed severe arthritis in the paws and knees. Interphalangeal and knee joints of CIA mice showed advanced bone destruction with cortical erosions and trabecular bone loss, and ZA treatment reduced these effects. Importantly, no osteonecrosis was noted adjacent to areas of articular inflammation in CIA-ZA mice. Our data suggest that ONJ burden was more pronounced in ZA treated CIA mice and that RA could be a risk factor for ONJ development. © 2016 American Society for Bone and Mineral Research.

Background: Because of poor clinical outcomes, rotator cuff healing in patients with osteoporosis has recently gained attention. Antiresorptive therapy for osteoporosis has been reported to improve healing after repair. However, the comparative effectiveness of anabolic and antiresorptive agents has not been investigated. Hypothesis: Anabolic therapy with abaloparatide (ABL) would outperform antiresorptive therapy with denosumab (Dmab) to improve rotator cuff healing in the osteoporotic status. Study Design: Controlled laboratory study. Methods: A chronic rotator cuff tear model was established in ovariectomy-induced postmenopausal osteoporotic rats. Then, bilateral rotator cuff repairs were conducted in all experimental rats, which were randomly divided into control (CON), Dmab, and ABL groups to receive the corresponding subcutaneous injections. The rats sacrificed at 2 weeks (the early healing period) were used to detect osteoblast and osteoclast activities, related gene expression (osteoclastogenesis, osteogenesis, and chondrogenesis), new bone formation, and mineralization. In the rats sacrificed at 4 and 8 weeks, the bone mineral density and bone architecture at the repaired site were assessed by micro–computed tomography, and rotator cuff healing was evaluated using histological and biomechanical analyses. Results: At 8 weeks, significantly higher failure load and stiffness were observed in the ABL (25.13 ± 3.54 N, P <.001; 21.65 ± 3.08 N/mm, P <.001; respectively), and Dmab (21.21 ± 2.55 N, P <.001; 16.15 ± 2.07 N/mm, P =.008; respectively) groups than in the CON group (13.36 ± 1.70 N; 11.20 ± 2.59 N/mm; respectively), whereas the ABL treatment provided better failure load and stiffness than Dmab (P =.019; P =.003). Although tendon-to-bone healing was improved by Dmab, the most mature tendon insertion at the interface was observed in the ABL group, including a more organized collagen and fibrocartilage and higher bone quality. ABL significantly promoted bone remodeling via coupling between osteoclasts and osteoblasts (osteoblast to osteoclast ratio: 4.80 ± 0.39; P =.022), thereby stimulating more new bone formation and mineralization at the tendon-to-bone healing interface than Dmab (osteoblast to osteoclast ratio: 3.21 ± 0.75) at 2 weeks. Moreover, ABL had significant effects on gene expression [Runt-realted transcription factor 2 (Runx2, collagen type I-alpha 1 (Col1A1 ]), and sclerostin for osteogenesis; aggrecan and collagen type II (Col2) for chondrogenesis] in mineralized tissues, indicative of enhanced bone and fibrocartilage formation when compared with the CON and Dmab groups. Conclusion: ABL promoted rotator cuff healing in osteoporotic rats by significantly increasing the mineralized tissue quality and collagen maturity at the reattachment site, leading to improved biomechanical properties, and was superior to Dmab in both biomechanical and histological analyses. Clinical Relevance: Anabolic therapy with ABL may outperform antiresorptive therapy with Dmab in improving outcomes after rotator cuff repair in osteoporotic patients. [ABSTRACT FROM AUTHOR]

Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon. [ABSTRACT FROM AUTHOR]

This update incorporates the most relevant information that has emerged during the seven years since the publication of the previous version, with a particular focus on diagnostic procedures and therapeutic options. Among the diagnostic procedures, we highlight the use of the Trabecular Bone Score (TBS) and densitometry for identifying the risk of vertebral fractures. Novel therapeutic modalities include the use of anabolic drugs with comparative studies focused on their efficacy for the treatment of severe osteoporosis. Guidelines for actions to be taken after discontinuation of antiresorptive agents, sequential therapy and current recommended treatment schemes are included. [ABSTRACT FROM AUTHOR]

Antiresorptive medications, such as bisphosphonates and denosumab, are an important class of medication used to treat a wide range of diseases from osteoporosis to multiple myeloma. Unfortunately, they are also associated with a rare but devastating side effect – medication-related osteonecrosis of the jaw (MRONJ). First reported in 2003, much research has been done into the area; however, the exact pathophysiology continues to elude clinicians and researchers. What has been ascertained is that intravenous treatment, duration of treatment, and tooth extraction are major risk factors. Staging and treatment guidelines have been proposed; however, there has been no universal acceptance, and clinicians rely on various position papers. Over the next 30 years, the aging population is set to double, and with it, the prescription of antiresorptive medication and incidence of MRONJ will undoubtedly increase. In 2013, Gupta et al. published a paper on bisphosphonate-related osteonecrosis of the jaw; however, there have many changes since then. This paper aims to provide a succinct update on those changes. [ABSTRACT FROM AUTHOR]

Summary: The purpose of this study was to explore the efficacy of 150 mg once monthly oral risedronate use in the prevention of sleeve gastrectomy (SG) associated bone loss. Twenty‐four SG patients (56 ± 7 years, 83% female, 21% black) were randomized to risedronate or placebo for 6 months, with an optional 12‐month assessment. Outcome measures included 6 (n = 21) and 12 (n = 14) month change in dual energy x‐ray absorptiometry‐acquired regional areal bone mineral density (aBMD). Six‐month treatment effect estimates [mean (95% CI)] revealed significant between group aBMD differences at the femoral neck [risedronate: +0.013 g/cm2 (−0.021, 0.046) vs. placebo: −0.041 g/cm2 (−0.067, −0.015)] and lumbar spine [risedronate: +0.028 g/cm2 (−0.006, 0.063) vs. placebo: −0.029 g/cm2 (−0.054, −0.004)]; both p ≤ 0.02. When followed postoperatively to 12 months, differential aBMD treatment effects were observed at the total hip [risedronate: −0.035 g/cm2 (−0.061, −0.009) vs. placebo: −0.072 g/cm2 (−0.091, −0.052)] and lumbar spine [risedronate: +0.012 g/cm2 (−0.038, 0.063) vs. placebo: −0.052 g/cm2 (−0.087, −0.017)]; both p < 0.05. Preliminary treatment effect estimates signal 6 months of risedronate use may be efficacious in reducing aBMD loss at the axial skeleton post‐SG, with benefit largely maintained throughout the 1‐year postoperative period. Confirmatory data from an adequately powered trial are needed. [ABSTRACT FROM AUTHOR]

Sequential and combined therapy for osteoporosis is challenging because of the many options, and difficult because robust fracture data are not available, especially for combination therapies, mostly because the studies are too small. The principle of sequential and combined therapy for osteoporosis is that osteoanabolic therapy (teriparatide [TPTD]), whether sequential or combined, leads to an increase in bone mineral density (BMD), especially in the lumbar spine. The only exception is the sequence of TPTD after denosumab (Dmab), which leads to a loss (transient) of BMD in both the lumbar spine and the hip; for this reason, this sequence should be avoided at all costs. A second principle is that the stronger and longer the antiresorptive pretreatment was, the more delayed and reduced the effect of osteoanabolic therapy (TPTD). A third principle is the need for antiresorptive retreatment after therapies with TPTD and Dmab or their combination to prevent vertebral fractures (Dmab) and maintain bone density (TPTD). An effect of osteoanabolic therapy with TPTD on BMD of the hip is expected only in combination with antiresorptive therapy (bisphosphonates, Dmab). If the antiresorptive therapy is not continued, there is a transient loss in the first months of osteoanabolic monotherapy, the more so the stronger the antiresorptive pretreatment was. [ABSTRACT FROM AUTHOR]