Antiresorptive Therapy Research Articles

Treatment options for postmenopausal osteoporosis

Osteoporosis is a systemic skeletal disease, characterized by a decrease of bone mass and bone quality, with a subsequent reduction of bone strenght and an increased risk of fracture. Hormone Therapy for menopausal women can significantly prevent osteopenia and osteoporosis, thus reducing the fracture risk. The use of HT, according to guidelines, is for postmenopausal women within 10 years since last menstruation or under the age of 60 years. Only HT at standard dose is able to reduce the fracture risk, while low-dose HT can prevent bone loss. Estrogens (with and without the addition of a progestin) and tibolone showed a fracture risk reduction effect. Also Tissue Selective Estrogen Complex (TSEC) can reduce the bone loss in postmenopause. For women without climacteric symptoms (as hot flushes and/or night sweats) the use of Selective Estrogen Receptor Modulators (SERMs) can be indicated, with a reduction of risk of vertebral fracture (for raloxifene and bazedoxifene), and non-vertebral fracture in high-risk women (for bazedoxifene). In more advence ages, antiresoptive agents as Bisphosphonates (Alendronate, Risedronate, Ibandronate and Zoledronate) can reduce the risk of vertebral, non-vertebral and hip fracture risk. Denosumab (DMAB), monoclonal antibobody against Rank-ligand (RANKL), providing an increased bone mass, significantly decreases risk of vertebral, non-vertebral and hip fracture. A drug holiday or treatment interruption is not recommended with DMAB, and DMAB dosing should not stopped without subsequent antiresorptive or other therapy to prevent a "rebound effect" with a possible increased risk of multiple vertebral fracture. Teriparatide (fraction 1-34 of recombinant PTH, administered daily 20 mcg sc) can stimulate osteoblast activity, with an important increase of bone mass and a significant reduction of risk of vertebral fracture, and of multiple vertebral fractures, but also of non-vertebral fragility fracture. Romosozumab (RMZ, adimnistered monlty 210 mg sc), is a bone-forming monoclonal antibody that binds to and inhibits sclerostin, with a dual effect of increasing bone formation and decreasing bone resorption. RMZ has showed to give marked increases in spine and hip bone density after 1 year of administration, also reducing fracture risk. The differences among the various treatments is the basis for the individualization of osteoporosis treatment, according to combination and/or sequential regimens of administration.

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

A Study of Oral Health Parameters and the Properties and Composition of Saliva in Oncological Patients with and without Medication-Related Osteonecrosis of the Jaw Who Take Bisphosphonates.

Background and Objectives: The aim of this study was to examine how the status of the oral cavity, composition and properties of saliva change in oncological patients with and without Medication-Related Osteonecrosis of the Jaw (MRONJ) undergoing bisphosphonate therapy. Materials and Methods: A retrospective case-control study of 49 oncological patients using bisphosphonates (BPs) was conducted. The study population was divided into two groups-Group I consisted of 29 patients with MRONJ and Group II of 20 patients without MRONJ. The control group consisted of 32 persons without oncological history and without antiresorptive therapy. Standard dental examination included the assessment of the number of teeth remaining, teeth with caries and fillings, Approximal Plaque Index (API) and Bleeding on Probing (BOP). In terms of MRONJ, localization and stage were assessed. Laboratory tests of saliva included determination of pH and concentrations of Ca and PO4 ions, total protein, lactoferrin, lysozyme, sIgA, IgA, cortisol, neopterin, activity of amylase at rest, and stimulated saliva. The buffering capacity and microbiological tests (Streptococcus mutans, Lactobacillus spp. load) of stimulated saliva were also determined. Results: There were no statistically significant differences between the selected oral parameters and saliva of Group I and Group II. Significant differences were found between Group I and the control group. BOP, lysozyme and cortisol concentration were higher, while the number of teeth with fillings, Ca and neopterin concentrations were lower in comparison to the control group. In Group I, a significantly higher percentage of patients with a high colony count (>105) of Streptococcus mutans and Lactobacillus spp. was also found. The significant differences between Group II and the control group concerned the concentrations of lysozyme, Ca ions, sIgA, neopterin and the colony count of Lactobacillus spp. In the Group I patients who received a significantly higher cumulative dose of BP compared to the Group II, a significant positive correlation was found between the received BP dose and the BOP. Most MRONJ foci were stage 2 and were mainly located in the mandible. Conclusions: Among oncological patients with and without MRONJ undergoing BP therapy compared to the control group, there are statistically significant differences in the dental, periodontal and microbiological status and in the composition of the saliva. Particularly noteworthy are the statistically significant differences in the decreased level of Ca ions, the increased level of cortisol and the elements of saliva related to the immune response (lysozyme, sIgA, neopterin). Additionally, a higher cumulative dose of BPs may affect the susceptibility to the development of osteonecrosis of the jaws. Patients undergoing antiresorptive therapy should receive multidisciplinary medical care, including dental care.

Retrospective analysis of the relationship between time to anti-resorptive therapy and incidence of skeletal related events in patients with multiple myeloma.

8048 Background: Patients with multiple myeloma (MM) often have bone disease at diagnosis and are at risk of developing skeletal related events (SRE) (pathological fractures, spinal cord compression, and/or need for radiotherapy or surgery to bone). It is well established that for patients with lytic bone lesions at diagnosis, the use of anti-resorptive agents lead to a lower incidence of SREs. However, it is common for initiation of anti-resorptive therapy to be delayed. Recent studies have demonstrated that anti-resorptive therapy is underutilized in patients with MM. However, the effect of time to initiation of anti-resorptive agent after diagnosis of MM on SREs has not been well studied. Herein, we conducted a multi-center retrospective analysis to determine if time to anti-resorptive agent has an adverse impact on the risk of SREs. Methods: We performed a retrospective cohort study using our Electronic Health Record system to identify patients with newly diagnosed MM between July 1st, 2016 and June 30th, 2019 at two large academic centers. Patients previously treated or patients not treated with anti-resorptive therapy were excluded. The study’s primary endpoint was hazard ratio of developing a SRE based on time to anti-resorptive therapy. The relationship between incidence of SREs and time to anti-resorptive therapy, gender, age, International Staging System (ISS) stage at diagnosis, and prior SRE present at diagnosis was analyzed by using a multivariable Cox proportional hazards model. The cutoff point of anti-resorptive therapy delay was based on the recursive partitioning of univariable Cox model. Results: 759 patients were included in the study (Thomas Jefferson University: n = 232; The Ohio State University: n = 527). Median age at diagnosis is 60.2 years (IQR: 12.4 years). 57% of patients were male. 77.9% and 20.3% of patients identified as white and black respectively. 210 patients (27.7%) were noted to have osteopenia, 45 (5.9%) had osteoporosis, 229 (30.2%) were vitamin D deficient, and 319 (42%) were obese at diagnosis. A skeletal related event was present at diagnosis in 338 (45.1%) of patients. 180 (34%) patients received anti-resorptive agents within 31 days. A delay in initiating anti-resorptive agents of greater than 31 days from diagnosis had an increased risk for SRE with a hazard ratio 1.654 (1.054~2.598; p-value: 0.029). Conclusions: This large multicenter retrospective study demonstrated that time to anti-resorptive therapy MM patients has a significant impact on the risk of SRE. Given many of the challenges in starting anti-resorptive therapy in a timely manner, this study emphasizes the need for inter-professional, multi-disciplinary collaborations to streamline the workflow and start therapy within the first month of diagnosis. Ongoing efforts are underway to develop quality improvement processes to achieve this goal.

Associations of estrogen therapy and non-estrogen anti-resorptive therapy with diabetes mellitus risk: A classical and Bayesian meta-analysis.

Anti-resorptive therapy (AT) increases insulin resistance and decrease insulin secretion through reduced undercarboxylated osteocalcin in mice. However, there are inconsistent findings regarding the impact of AT use on the risk of diabetes mellitus in humans. We examined the association between AT and incident diabetes mellitus using classical and Bayesian meta-analysis. We searched Pubmed, Medline, Embase, Web of Science, Cochrane, and Google Scholar for studies listed from database inception to 25 February 2022. Randomized controlled trials (RCTs) and cohort studies reporting associations of estrogen therapy (ET) and non-estrogen anti-resorptive therapy (NEAT) with incident diabetes mellitus were included. Two reviewers independently extracted research data such as ET and NEAT, diabetes mellitus, risk ratios (RRs), and 95% confidence intervals (CIs) for incident diabetes mellitus associated with ET and NEAT from individual studies. This meta-analysis included data from nineteen original studies, consisting of fourteen ET and five NEAT studies. ET was associated with reduced risk of diabetes mellitus in the classical meta-analysis (RR: 0.90; 95% CI: 0.81-0.99). Slightly stronger results were found in the meta-analysis of RCTs (RR: 0.83; 95% CI: 0.77-0.89). The probability that RR<1.0 was 95% in the overall analysis and 99% in RCTs under weakly informative prior. Although NEAT was associated with reduced risk of diabetes mellitus overall (RR: 0.80; 95% CI: 0.67-0.97), this was not found in the RCT meta-analysis (RR: 0.90; 95% CI: 0.75-1.10). Under weakly informative prior, the probabilities that NEAT reduces diabetes mellitus by >0% were 99%, and 73% in the overall and RCT meta-analysis, respectively. In conclusion, meta-analysis provided consistent evidence against the hypothesis that AT increases diabetes risk. ET may reduce the risk of diabetes mellitus. Whether NEAT reduces the risk of diabetes mellitus is uncertain and requires additional evidence from RCTs.

External validation of biomechanical computed tomography for fracture risk classification in metastatic hormone sensitive prostate cancer.

e24077 Background: For men with metastatic hormone-sensitive prostate cancer (mHSPC) on androgen deprivation therapy (ADT), guidelines recommend dual-energy X-ray absorptiometry (DXA) screening to identify fracture risk and benefit from antiresorptive therapy. However, only 8% of men with mHSPC receive routine DXA screening. Biomechanical computed tomography (BCT) is a radiomic technique that measures bone mineral density (BMD) and bone strength from routine staging and surveillance CT scans but has not been validated in mHSPC. Methods: This retrospective cohort study included 99 patients with incident mHSPC beginning ADT (2013-2020) at one academic (n = 70) and one tertiary VA medical center (n = 29) with CT abdomen/pelvis or PET/CT imaging at baseline (within 1 year prior to ADT initiation) and follow-up (1-2 years after ADT initiation). BCT-assessed BMD T-score and femoral strength were calculated from baseline and follow-up CT scans. We evaluated the association between BCT measures and subsequent pathologic and non-pathologic fractures within 3 years following mHSPC diagnosis. Results: Among 99 patients, mean age was 68 years, 48 (48.5%) were White, and 45 (45.4%) were Black. During median follow-up of 19 months, 23 (24%) developed a pathologic and 15 (15%) a non-pathologic fracture. BCT and DXA-assessed femoral-neck BMD T-score were strongly correlated (R2= 0.94, N = 23). Higher BCT-assessed baseline BMD (Odds Ratio [OR] 0.5, p = 0.03) and bone strength (OR 0.57, p = 0.02) were each associated with decreased pathologic fracture (Table). Neither BMD nor bone strength were significantly associated with non-pathologic fracture. BCT identified 10 (10%) men eligible for antiresorptive therapy by established BMD, strength, or FRAX criteria at ADT initiation, 4 (40%) of whom never received it by the end of follow-up. Between baseline and follow-up, both BMD (-0.27) and bone strength (-0.34) decreased among patients who did not receive antiresorptive therapy (n = 76), with no difference in longitudinal change between ADT alone vs with androgen receptor signaling inhibitors. Conclusions: In this diverse, multicenter cohort of men with mHSPC beginning ADT, BCT BMD assessed from routine CT scans strongly correlated with DXA-assessed BMD. BCT measurements predicted subsequent pathologic fracture and identified additional men who would benefit from antiresorptive therapy. BCT may provide a practical method to assess the role for anti-resorptive therapy in patients with mHSPC. [Table: see text]

Multicenter, retrospective population-based study on the incidence of medication-related osteonecrosis of the jaw in patients with breast cancer with bone metastases.

6588 Background: Antiresorptive therapy with bisphosphonates or denosumab is standard care for patients with primary or secondary osseous metastasized breast cancer. The most important toxicity of this class of drugs is medication-related osteonecrosis of the jaw (MRONJ). MRONJ represents a major medical burden and impairs quality of life. Based on recent studies, the risk of MRONJ occurrence ranges from 1% to 3%. The objective of this study was to assess the population-based incidence of MRONJ in breast cancer patients with bone metastases in Tyrol, Austria. Methods: This retrospective multicenter study was conducted between 2000 and 2020 at nine centers across Tyrol, Austria, including 8,860 patients with breast cancer. Depending on whether patients with bone metastases received denosumab, bisphosphonates or denosumab following bisphosphonates they were allocated to one of three groups. Data was collected using an electronic case report form (e-CRF) and managed via the web-based database AskiMed. MRONJ incidences with 95% confidence intervals and the differences between the median of cumulative incidences were calculated in patients treated with bisphosphonates and/or denosumab. Results: A total of 639 patients had bone metastasis and received antiresorptive therapy. MRONJ was diagnosed in 56 (8.8%) patients. Regarding the 292 (45.7%) patients treated with denosumab alone, the MRONJ incidence was 11.6% (95%CI 8.2%-15.9%). The group of patients treated with only bisphosphonates included 255 (39.9%) patients; their MRONJ incidence was 2.7% (95%CI 1.1%-5.6%). Of the 92 (14.4%) patients receiving both antiresorptive therapies consecutively, the MRONJ incidence was 16.3% (95%CI 9.4%-25.5%). Thus, a total of 49 (12.8%) MRONJ cases were detected in patients using denosumab alone as well as using the combination of denosumab following bisphosphonates. Patients treated with denosumab developed a MRONJ in median 60 months earlier than with bisphosphonates alone or followed by denosumab. The hazard ratio for MRONJ from start of therapy of denosumab compared to bisphosphonates alone or followed by denosumab was 7.9 (3.8-16.2; p-value &lt; 0.0001). Conclusions: This study showed a substantially higher MRONJ incidence for denosumab alone or bisphosphonates followed by denosumab in the tyrolean cohort when compared to other recent studies. Future comparative real-world-evidence research provide explicit benefit-harm tradeoffs to inform treatment decision making.

Comparison of Different Antibiotic Regimes for Preventive Tooth Extractions in Patients with Antiresorptive Intake-A Retrospective Cohort Study.

In the present study, the impacts on success rates between three different antibiotic regimes in patients receiving preventive tooth extraction during/after antiresorptive treatment were compared. For the retrospective analysis, we enrolled patients who had undergone tooth extraction from 2009 to 2019 according to the specified preventive conditions under antiresorptive therapy. Three antibiotic regimens were distinguished: (Group 1) intravenous for 7 days, (Group 2) oral for 14 days, and (Group 3) oral for 7 days of application. The primary endpoint was the occurrence of medication-related osteonecrosis of the jaw at 12 weeks after surgery. A total of 760 patients and 1143 extraction regions were evaluated (Group 1 n = 719; Group 2 n = 126; Group 3 n = 298). The primary endpoint showed no significant difference in the development of medication-related osteonecrosis of the jaw between the groups studied (Group 1 n = 50/669 (7%); Group 2 n = 9/117 (7%); Group 3 n = 17/281 (6%); p = 0.746). Overall, the success rate was 93% after intervention when preventive measures were followed. With the same success rate, a reduced, oral administration of antibiotics seems to be sufficient regarding the possible spectrum of side effects, the development of resistance and the health economic point of view.

The impact of CHOP versus bendamustine on bone mineral density in patients with follicular lymphoma enrolled in the GALLIUM study

Introduction: A standard treatment with CHOP or CVP includes a cumulative dose of 3,000–4,000 mg prednisone. Observational studies have shown increased risk of fractures in patients treated with R-CHOP/R-CVP. However, it is not clear whether reductions in bone mineral density (BMD) are mainly caused by glucocorticoids or the combined impact of chemotherapy and glucocorticoids. The objective of this study was to investigate the impact of G/R-bendamustine versus G/R-CHOP on BMD in patients with follicular lymphoma (FL) enrolled in the GALLIUM study. Methods: Patients enrolled in the GALLIUM study, an international randomized phase 3 trial of first-line treatment for FL, were included if they were ≥60 years at inclusion and in complete remission following treatment with G/R-bendamustine or G/R-CHOP. Exclusion criteria were treatment with anabolic or antiresorptive therapies prior to baseline, co-existing medical conditions associated with low BMD, and new anti-lymphoma treatment during the initial 5 years of follow-up. CT scans were performed at baseline, induction treatment completion (ITC), and annually in five years after inclusion. Hounsfield units (HU) measured in an ovoid region in the anterior of L1 were used as surrogate for BMD, which has been shown to correlate with BMD measurements from conventional dual-energy X-ray absorptiometry (DXA). Low HU values represent lower bone density while high values represent more dense bone. Vertebral compression fractures were defined as vertebral height loss of ≥20%. Results: At ITC, 244 patients ≥60 years old were in CR. Of those, 155 fulfilled the inclusion criteria, 55 (35%) received G/R-CHOP and 100 (65%) received G/R-bendamustine. CT scans with contrast were performed at baseline and ITC in 143 patients. Baseline characteristics, including age and gender, were balanced between groups. The mean baseline HU was 143.8 in the CHOP group and 141.5 in the bendamustine group (P = 0.74). The mean HU decrease from baseline to ITC was 27.8 after CHOP versus 17.1 after bendamustine, corresponding to a difference of 12.5 (95% CI: 5.5–19.5) after adjusting for age, sex, B-symptoms, and baseline HU. BMD remained at the ITC level, and thus below baseline, during the first 3 years of follow-up. During treatment and 5 years follow up, a total of nine new compression fractures were recorded in five patients. One patient in the bendamustine group and four patients in the CHOP group developed new vertebral fractures. Keywords: Indolent non-Hodgkin lymphoma, Late Effects in Lymphoma Survivors No conflicts of interests pertinent to the abstract.

An Update on Medication-Related Osteonecrosis of the Jaw in Patients with Osteoporosis

Medication-related osteonecrosis of the jaw (MRONJ) is a feared complication of anti-resorptive or anti-angiogenic therapy, presenting with non-healing areas of bone, which may form de novo or after dental intervention. The condition primarily affects patients under the care of oncologists and rheumatologists. Patients using these medications under the care of rheumatologists are predominantly being treated for osteoporosis, a highly prevalent condition causing considerable morbidity and mortality in the European population. In the two decades since the condition was first described, there has been considerable progress in the understanding of the pathophysiology of the condition, although this remains incomplete. Additionally, clinicians may now benefit from long-term follow-up data to give a more evidence-based approach to MRONJ risk stratification. At present, there is considerable variation between guidelines produced by advisory groups. This paper focuses exclusively on the osteoporotic cohort, and aims to review recent findings to explore the differences in risk profiles between osteoporotic and oncological cohorts, as well as between different anti-resorptive medications. Further sections discuss prevention and management of MRONJ in osteoporosis, including the timing of tooth extraction, and consider the direction of future research. The findings suggest that patients with osteoporosis treated with bisphosphonates carry an extremely low risk of MRONJ, although denosumab presents a higher risk. Nevertheless, the reduced fracture rate from prompt treatment with anti-resorptives likely outweighs the risk of MRONJ. Dental hygiene should be optimised to reduce risk, and tooth extraction should take place in a timely fashion, with no convincing evidence to support the use of drug holidays. Treatment at present favours a surgical approach, with potential roles for antibiotics, but at present there is insufficient evidence for other medical adjuncts.

Is it possible to stop the osteolysis of the periprosthetic bone during re-endoprosthetics of the hip joint against the background of osteoporosis?

Revision interventions due to aseptic instability show a marked upward trend, and one of the reasons is an increase in the number of people with osteoporosis in the population. The impaired bone metabolism in these cases persist even after re-endoprosthetics. The authors aim to draw attention of trauma orthopaedists to the need to treat osteoporosis either before or immediately after the re-endoprosthetic surgery. A clinical case is presented. A 65-year-old patient T., 5 months after surgery, complained of persistent pain in the left hip joint radiating to the left knee joint, which intensified when walking, lameness, inability to move without additional support (two crutches), limited range of motion within the left hip joint that had undergone surgery (endoprosthesis). The patient had a history of femoral neck fracture associated with a low energy fall. The left hip joint re-endoprosthetics was performed due to aseptic instability of the femoral and acetabular components of the prosthetic implant. The diagnosed diseases included secondary osteoporosis, D-deficiency, hypocalcemia, and periprosthetic osteolysis. Given the increased intensity of resorption and the fact that the femoral neck fracture occurred with underlying secondary osteoporosis, it was decided to prescribe antiresorptive therapy with denosumab 60 mg once every 6 months combined with alfacalcidol and calcium supplement. Despite an objective 3-month delay in antiresorptive therapy initiation, the treatment result was achieved in the observed patient. In summary, denosumab 60 mg increases the effectiveness of re-endoprosthetics with underlying osteoporosis by reducing activity of the periprosthetic bone osteolysis.

Abstract #1403811: Rapidly Progressive Aortic Stenosis After Teriparatide Initiation: A Rare Case

Recombinant Parathyroid Hormone (rPTH) or Teriparatide is frequently used to manage severe osteoporosis due to its anabolic mode of action particularly in patients who are at a high risk of vertebral and non-vertebral fractures. Aortic valve stenosis is a common valve condition seen in the older population. There are multiple etiologies for aortic stenosis, but drug induced aortic stenosis is rare. Moreover, its natural history includes gradual progression towards severity. We present an interesting case of rapidly progressive aortic stenosis after teriparatide initiation. An 84-year-old female with history of hypertension, hyperlipidemia, atrial fibrillation presented to the endocrine clinic for management of osteoporosis. She was diagnosed with osteoporosis in 2000 at age 62. Initial etiology was assumed to be post-menopausal and was treated with oral bisphosphonates. As she had compression fractures of her spine while on treatment, secondary causes of osteoporosis were explored, and she was found to have primary hyperparathyroidism. Her labs were significant for PTH-84 pg/ml, Ca-10.8 mg/dl. She underwent parathyroidectomy in 2016 with normalization of PTH and calcium. After her surgery, she was treated with denosumab infusions every 6 months. She did well till June 2021. Her bone mineral density scores were stable throughout this period. At this point, she suffered bilateral atypical femoral fractures and was thought to be due to chronic anti-resorptive therapy. We stopped denosumab and transitioned her to teriparatide daily injections. She did well for 1 year but then presented to us for management in Aug 2022 prior to valve replacement for severe aortic stenosis. Her labs were significant for normal calcium, 25-hydroxy vitamin D and phosphorus levels. On reviewing her echocardiograms prior to and after initiation of teriparatide we found a rapid progression of her aortic stenosis from moderate to severe, based on mean gradients and peak velocities, over a span of 7 months. Natural progression of aortic stenosis from mild to severe happens over several years (mean duration-5 years), not just a few months. One possible explanation for this rapid progression seen in our patient is due to the presence of osteoblast like cells (arising from vascular endothelial cell precursor cells) in the aortic valve which appear to be stimulated by PTH and hence valve calcification/stenosis. On a thorough review of literature there were no clinical studies that have reported aortic stenosis progression from teriparatide use. To our knowledge, there was a single case report that reported the same phenomenon in Israel. As a result, we wanted to educate the community about the possible association between teriparatide use and worsening aortic stenosis in certain cases. Performing serial echocardiograms in high-risk patients and involving cardiology for early diagnosis and management is essential.

Medication-related osteonecrosis of the jaw and the role of the doctor of dental surgery: a literature review

Introduction: Medication-related Osteonecrosis of the Jaw (MRONJ) is a condition that may affect patients undergoing oral surgery procedures that use antiresorptive drugs. It is essential that the Doctor of Dental Surgery (DDS) is familiar with the pathology and how to diagnose, prevent and approach it. Objectives: To perform a literature review on MRONJ and to guide the DDS on how to manage the affected patients. Methodology: a systematized search was conducted on the PubMed virtual database using the terms: "diphosphonates", "dentist's practice pattern", "dentists", "dentist's role" and "Bisphosphonate-Associated Osteonecrosis of the Jaw". 29 articles in English, published in the last 5 years, were included. Results and discussion: MRONJ is characterized by exposed and necrotic bone that persists for more than 8 weeks and happens in patients taking antiresorptive agents. It is multifactorial and its severity depends on the dosage, route of administration, and treatment duration. Its management must be multidisciplinary to improve the patient's quality of life. The DDS must focus on prevention. Every patient should have their oral health evaluated before starting antiresorptive therapy and be informed of its risks and benefits. Most DDSs do not feel confident to adequately manage these cases, even though information on MRONJ is more widespread among younger DDSs and recent graduates. Conclusion: MRONJ is a harmful condition for the patient and it is the DDS's responsibility to know how to treat and prevent it, by having adequate knowledge of this pathology and making decisions based on the latest scientific evidence.

Surgical treatments for medication-related osteonecrosis of the jaws: advantages and limitations

Objective: The purpose of this paper is to discuss the surgical methods available for the treatment of MRONJ, pointing out their advantages and limitations. Methodology: An integrative review of the literature was performed by searching the PubMed virtual database using the MeSH term "bisphosphonate associated osteonecrosis of the jaw/surgery" and including 26 publications. Results: Surgical intervention is presented as a treatment option in an attempt to reduce disease progression with the recognition that this early intervention may predict beneficial outcomes for the patient. Surgical approaches confer superior treatment outcomes over conservative treatments, with success rates of 80-90% and 10-62%, respectively. To establish treatment, consideration should be given to therapy for removing nonhealing exposed bone, which can be accomplished through curettage, sequestrectomy, and surgical resection. When approaching soft tissue, different flaps can be performed, according to their indications. Conclusion: Surgical treatment has shown maintenance of mucosal coverage, improved quality of life, and quick resumption of antiresorptive therapy for all stages of the disease, with high rates of therapeutic success. However, continued efforts should be encouraged to investigate the best treatment for this pathology.

Adverse Effects of Denosumab in Kidney Transplant Recipients: A 20-Year Retrospective Single-Center Observation Study in Central Taiwan

Bone loss can be noted in kidney transplantation recipients (KTRs) and can be related to fracture events. Denosumab, a potent monoclonal antibody to RANK ligand, increases lumbar bone mineral density. However, safety data for denosumab remain limited regarding transplant recipients. Hypocalcemia and increased genital tract infections have been mentioned as adverse effects in KTRs after being prescribed denosumab. We retrospectively analyzed the electronic medical records of KTRs during the recent 20 years who had been prescribed antiresorptive therapy and were >18 years old. Medical records and their clinical data were reviewed and analyzed. We compared the frequency of adverse effects between denosumab with other antiresorptive therapies. A total of 70 KTRs were enrolled, with 46 patients being given denosumab and the first injection being noted on October 31, 2014. No significant differences were seen in mortality rate, opportunistic infection, pneumonia, or genitourinary tract infection. One diagnosis of osteonecrosis of the jaw was noted in the denosumab group (2.2%). A higher incidence of hypocalcemia (<8.4 mg/dL) was noted in the denosumab group (34.8%), and a higher but nonsignificant difference in the incidence of severe hypocalcemia was also noted in the group. Denosumab may be considered as safe as other antiresorptive therapies for KTRs. However, more hypocalcemia events have been noted, so medical personnel may need to be cautious when prescribing its use.

Skin and bones: systemic mastocytosis and bone.

We report the case of a 69-year-old female with systemic mastocytosis, diagnosed based on widespread pigmented papules and macules, elevated serum tryptase levels and confirmatory skin and bone marrow biopsy, on a background of osteoporosis. A CT demonstrated multiple sclerotic lesions within lumbar vertebral bodies, sacrum and ileum, with surrounding osteolysis but no obvious compression fractures. She was treated with the RANK-L inhibitor denosumab, resulting in significant bone mineral density gain over the following 5 years. However, her serum tryptase levels gradually increased during this period despite treatment with the multikinase inhibitor, midostaurin. It is thus conceivable that her rapid increase in bone mineral density may be partly contributed by a predominance of pro-osteoblastic mediators released by abnormal mast cells, suggestive of more advanced disease. This case highlights the complexities of systemic mastocytosis-related bone disease and the interplay of numerous mediators contributing to a phenotype of both increased bone resorption and formation. Systemic mastocytosis is a neoplastic disease of mast cells characterized by abnormal proliferation and accumulation in the skin and other organs. It is most frequently associated with the somatic gain-of-function KIT D816V mutation. Systemic mastocytosis should be suspected in patients presenting with not only cutaneous symptoms suggestive of mast cell degranulation such as anaphylaxis, flushing or urticaria but also unexplained osteoporosis and gastrointestinal and constitutional symptoms. The prevalence of osteoporosis in systemic mastocytosis is high. Mast cell activation leads to the secretion of numerous chemical mediators which either promote or inhibit osteoclastic and/or osteoblastic activity, with the balance usually in favour of increased bone resorption. However, in advanced diseases with high mast cell burden, mast-cell-derived cytokines and mediators may promote osteoblastic activity, leading to osteosclerosis and apparent increases in bone mineral density. Treatment of osteoporosis in systemic mastocytosis involves antiresorptive therapy with bisphosphonates and more recently, denosumab. There are limited data on the role of osteoanabolic agents.

Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. Astellas Pharma.

The effect of denosumab on disseminated tumor cells (DTCs) of breast cancer patients with neoadjuvant treatment: a GeparX translational substudy

BackgroundDisseminated tumor cells (DTCs) in the bone marrow are observed in about 40% at primary diagnosis of breast cancer and predict poor survival. While anti-resorptive therapy with bisphosphonates was shown to eradicate minimal residue disease in the bone marrow, the effect of denosumab on DTCs, particularly in the neoadjuvant setting, is largely unknown. The recent GeparX clinical trial reported that denosumab, applied as an add-on treatment to nab-paclitaxel based neoadjuvant chemotherapy (NACT), did not improve the patient’s pathologic complete response (pCR) rate. Herein, we analyzed the predictive value of DTCs for the response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow.MethodsA total of 167 patients from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive patients were re-analyzed for DTCs after NACT ± denosumab.ResultsAt baseline, DTCs were observed in 43/167 patients (25.7%) in the total cohort, however their presence did not predict response to nab-paclitaxel based NACT (pCR rates: 37.1% in DTC-negative vs. 32.6% DTC-positive; p = 0.713). Regarding breast cancer subtypes, the presence of DTCs at baseline was numerically associated with response to NACT in TNBC patients (pCR rates: 40.0% in DTC-positive vs. 66.7% in DTC-negative patients; p = 0.16). Overall, denosumab treatment did not significantly increase the given DTC-eradication rate of NACT (NACT: 69.6% DTC-eradication vs. NACT + denosumab: 77.8% DTC-eradication; p = 0.726). In TNBC patients with pCR, a numerical but statistically non-significant increase of DTC-eradication after NACT + denosumab was observed (NACT: 75% DTC-eradication vs. NACT + denosumab: 100% DTC-eradication; p = 1.00).ConclusionThis is the first study worldwide, demonstrating that neoadjuvant add-on denosumab over a short-term period of 24 months does not increase the DTC-eradication rate in breast cancer patients treated with NACT.

Genistein and coumestrol reduce MCF-7 breast cancer cell viability and inhibit markers of preferential metastasis, bone matrix attachment and tumor-induced osteoclastogenesis

The propensity of breast cancer to preferentially metastasize to the skeleton is well known. Once established in bone metastatic breast cancers have a poor prognosis due to their ability to promote extensive bone loss which augments tumor burden. Unfortunately, current anti-resorptive therapies for skeletal metastasis are typically prescribed after secondary tumors have formed and are palliative in nature. One group of compounds with the potential to reduce both tumor burden and osteolysis are phytoestrogens (PE), but the mechanisms mediating a beneficial effect are unclear. Therefore, the current study examined the effect of genistein and coumestrol alone or in combination on breast cancer cell number, expression of mediators of preferential skeletal metastasis, bone matrix attachment and tumor-induced osteoclast formation. Results showed that genistein and coumestrol significantly reduced viable cell number in an estrogen receptor dependent manner (p < 0.05), whereas combinations of PE had no effect. In addition, genistein and coumestrol significantly reduced expression of genes driving epithelial to mesenchymal transition (snail), bone attachment (CXCR4 and integrin αV) and osteolysis (PTHrP and TNF-α). In keeping with this genistein and coumestrol significantly suppressed attachment of breast cancer cells to bone matrix and inhibited tumor and RANKL-induced osteoclast formation. Our data suggests that phytoestrogens not only decrease breast cancer cell viability but also antagonize essential tumor bone interactions that establish and drive the progression of skeletal metastasis.

Mitigating the Denosumab-Induced Rebound Phenomenon with Alternating Short- and Long-Acting Anti-resorptive Therapy in a Young Boy with Severe OI Type VI.

Osteogenesis imperfecta (OI) type VI, a recessively inherited form of OI caused by mutations in SERPINF1, is a severe form distinguished by osteomalacia on bone histomorphometry. We describe a boy with severe OI type VI who was initially treated with intravenous (IV) zoledronic acid (ZA) at 1.4years of age; however, a year later he transitioned to denosumab 1mg/kg sub-cutaneously every three months in an effort to decrease fracture rates. After two years on denosumab, he presented with symptomatic hypercalcemia due to the denosumab-induced, hyper-resorptive rebound phenomenon. Laboratory parameters at the time of the rebound were as follows: elevated serum ionized calcium (1.62mmol/L, N 1.16-1.36), elevated serum creatinine due to hypercalcemia-induced muscle catabolism (83µmol/L, N 9-55), and suppressed parathyroid hormone (PTH) (< 0.7pmol/L, N 1.3-5.8). The hypercalcemia was responsive to low-dose IV pamidronate, with a rapid decline in serum ionized calcium, and otherwise normalization of the aforementioned parameters within 10days. To benefit from the powerful, albeit short-term, anti-resorptive effect of denosumab without further rebound episodes, he was treated thereafter with denosumab 1mg/kg alternating every three months with IV ZA 0.025mg/kg. Five years later, he remained on dual alternating anti-resorptive therapy without further rebound episodes, and an overall improvement in his clinical status. This novel pharmacological approach of alternating short- and long-term anti-resorptive therapy every three months has not previously been described. Our report suggests this strategy may be an effective method for prevention of the rebound phenomenon in select children for whom denosumab may be beneficial.