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Background: The Radiotherapy IBandronate (RIB) trial compared single dose radiotherapy and a single infusion of ibandronate in 470 bisphosphonate naïve patients with metastatic bone pain from prostate cancer randomised into a non-inferiority two arm study. Results for the primary endpoint of pain score response at 4 weeks showed that the ibandronate arm was non-inferior to single dose radiotherapy. Patients and method: In addition to pain assessments including analgesic use made at baseline, 4, 8, 12, 26 and 52 weeks, urine was collected at baseline, 4 and 12 weeks. It was subsequently analysed for urinary N-telopeptide (NTx) and cystatin C. Linear regression models were used to compare the continuous outcome measures for urinary markers within treatment arms and baseline measurements were included as covariates. Interaction terms were fitted to allow for cross-treatment group comparisons. Results: The primary endpoint of the RIB trial was worst pain response at 4 weeks and there was no treatment difference seen. Urine samples and paired pain scores at 4 weeks were available for 273 patients (radiotherapy 168; ibandronate 159)The baseline samples measured for the RIB trial had an average concentration of 193 nM BCE/mM creatinine (range of 7.3–1871) compared to the quoted normal range of 33 nM BCE/mM creatinine (3 to 63). In contrast the average value of Cystatin C was 66 ng/ml (ranges ND – 1120 ng/ml) compared to the quoted normal range of 62.9 ng/ml (ranges 12.6–188 ng/ml). A statistically significant reduction in NTx concentrations between baseline and 4 weeks was seen in the ibandronate arm but not in the radiotherapy arm. No correlation between pain response and urinary marker concentration was seen in either the ibandronate or radiotherapy cohort at any time point. Conclusion: NTx was significantly raised compared to the normal range consistent with a role as a biomarker for bone metastases from prostate cancer. A significant reduction in NTx 4 weeks after ibandronate is consistent with its action in osteoclast inhibition which was not seen after radiotherapy implying a different mode of action for radiation. There was no correlation between bone biomarker levels and pain response.

Osteoporosis (OP) constitutes a significant health concern that profoundly affects individuals’ quality of life. Bisphosphonates, conventional pharmaceuticals widely employed in OP treatment, encounter limitations related to inadequate drug targeting and a short effective duration, thereby compromising their clinical efficacy. The burgeoning field of nanotechnology has witnessed the development and application of diverse functional nanosystems designed for OP treatment. Owing to the bone tissue affinity of bisphosphonates, these nanosystems are modified to address shortcomings associated with traditional drug delivery. In this review, we explore the potential of bisphosphonate-modified nanosystems as a promising strategy for addressing osteoporotic conditions. With functional modification, these nanosystems exhibit a targeted and reversible effect on osteoporotic remodeling, presenting a promising solution to enhance precision in drug delivery. The synthesis methods, physicochemical properties, and in vitro/in vivo performance of bisphosphonate-modified nanosystems are comprehensively examined in this review. Through a thorough analysis of recent advances and accomplishments in this field, we aim to provide insights into the potential applications and future directions of bisphosphonate-modified nanosystems for targeted and reversible osteoporotic remodeling.

Bisphosphonates (BP) are anti-resorptive drugs that are widely used to prevent bone loss in osteoporosis. Since inhibition of bone resorption will cause a decrease in bone formation through a process called coupling, it is hypothesized that extended treatment protocols may impair bone healing. In this study, β-tri‑calcium-phosphate (βTCP) ceramics were inserted into critical-size long bone defects in estrogen-deficient mice under BP therapy. The study assessed the benefits of coating the ceramics with Bone Morphogenetic Protein-2 (BMP2) and an engineered BMP2 analogue (L51P) that inactivates BMP antagonists on the healing process, implant resorption, and bone formation.Female NMRI mice (11–12 weeks of age) were ovariectomized (OVX) or sham operated. Eight weeks later, after the manifestation of ovariectomy-induced osteoporotic bone changes, BP therapy with Alendronate (ALN) was commenced. After another five weeks, a femoral critical-size defect was generated, rigidly fixed, and βTCP-cylinders loaded with 0.25 μg or 2.5 μg BMP2, 2.5 μg L51P, and 0.25 μg BMP2/2.5 μg L51P, respectively, were inserted. Unloaded βTCP-cylinders were used as controls. Femora were collected six and twelve weeks post-implantation.Histological and micro-computer tomography (MicroCT) evaluation revealed that insertion of cylinders coated with 2.5 μg BMP2 accelerated fracture repair and induced significant bone formation compared to controls (unloaded cylinders or coated with 2.5 μg L51P, 0.25 μg BMP2) already six weeks post-implantation, independent of estrogen-deficiency and BP therapy. The simultaneous administration of BMP2 and L51P (0.25 μg BMP2/2.5 μg L51P) did not promote fracture healing six and twelve weeks post-implantation. Moreover, new bone formation within the critical-size defect was directly linked to the removal of the βTCP-implant in all experimental groups. No evidence was found that long-term therapy with ALN impaired the resorption of the implanted graft. However, osteoclast transcriptome signature was elevated in sham and OVX animals upon treatment with BP, with transcript levels being higher at six weeks than at twelve weeks post-surgery. Furthermore, the transcriptome profile of the developing repair tissue confirmed an accelerated repair process in animals treated with 2.5 μg BMP2 implants. L51P did not increase the bioefficacy of BMP2 in the applied defect model.The present study provides evidence that continuous administration of BP does not inhibit implant resorption and does not alter the kinetics of the healing process of critical-size long bone defects. Furthermore, the BMP2 variant L51P did not enhance the bioefficacy of BMP2 when applied simultaneously to the femoral critical-size defect in sham and OVX mice.

Introduction: Bisphosphonates are commonly used to prevent osteoporotic fractures. Many randomized controlled trials have proved the efficacy of bisphosphonates, showing their ability to increase bone mineral density and decrease the risk of hip and vertebral fractures. Atypical, bisphosphonate-related fractures concerning the femur have been widely described and a list of primary and secondary clinical and radiographic criteria are used in order to achieve diagnosis. Research question: To identify clinical and radiographic findings for a possible association of vertebral fractures to prolonged bisphosphonate therapy. Material and methods: In this paper we present a case of an atraumatic bilateral pedicle lumbar fracture, assuming the hypothesis of an insufficiency atypical fracture due to prolonged Alendronate therapy for osteoporosis. We highlight the various aspects for diagnosis, treatment and a review of the existing literature was carried out. Discussion and conclusion: Atypical fractures in the spine are rarely reported in the literature. Pedicle anatomy is partially similar to a long bone, described as a strong bridge between the posterior arch and the vertebral body composed of a cortical bone and a cancellous core. Stress fractures are reported as a result of an underlying bone disease, trauma, post-surgery and stress fractures. In our opinion, the criteria described for atypical femoral fractures are a useful tool to also classify these rare pedicle lesions as insufficiency, bisphosphonate-correlated fractures.

Background/purpose: The incidence of medication-related osteonecrosis of the jaw is increasing worldwide, mostly due to the use of antiresorptive agents (ARAs) such as bisphosphonate (BP) and denosumab (Dmab). However, the proportion of BP-related osteonecrosis of the jaw (BRONJ) and Dmab-related osteonecrosis of the jaw (DRONJ) among all ARA-related osteonecrosis of the jaw (ARONJ) cases is not clear; this hinders appropriate treatment, recurrence-prevention planning, and avoidance of unnecessary Dmab withdrawal. Moreover, the causative drug administered at each disease stage remains unknown. Therefore, we conducted a retrospective study of patients with ARONJ who visited oral and maxillofacial surgery departments at hospitals in Hyogo Prefecture, Japan, over 3 years to classify and compare patient characteristics with those having BRONJ and DRONJ. We sought to identify the proportion of DRONJ in ARONJ. Materials and methods: After excluding stage 0 patients, 1021 patients were included (471 high-dose; 560 low-dose). ARA treatment for bone metastases of malignant tumors and multiple myeloma was considered high dose, while that for cancer treatment-induced bone loss and osteoporosis was low dose. Results: Low doses of BP and Dmab accounted for >50% patients; the results differed from those in other countries. DRONJ accounted for 58% and 35% of high-dose and low-dose cases, respectively. Stage 3 ARONJ cases comprised 92 (19.5%) low-dose BRONJ, 39 (20.1%) high-dose BRONJ, 24 (30%) low-dose DRONJ, and 68 (24.5%) high-dose DRONJ. Eighty-nine patients who received switch therapy were divided into BRONJ or DRONJ, but there was no difference in the ratio of each stage compared to the non-switch therapy. Conclusion: To the best of our knowledge, this is the first study to clarify the proportion of BRONJ and DRONJ cases, causative drug, and its doses by disease stages. DRONJ accounted for approximately 30% of the ARONJ, approximately 60% of which was due to high doses.

Background: Atypical femur fractures (AFFs) are stress or insufficiency fractures often associated to long term use of bisphosphonates (BPs). AFFs are usually not comminuted, sometimes bilateral involving the subtrochanteric region or the diaphysis. Prodromal symptoms may have been present for weeks or months before AFFs. The aim of this case report is to highlight that the correlation between the duration of BPs therapy and the risk of AFFs may be not so strong as reported in the literature, and to evaluate the tools available to the physician for preventing this complication. Case report: A 54 years old woman was transported by ambulance to our emergency department following an accidental fall in the street. She experienced bilateral thigh collapse accelerating her step while crossing the street and was unable to get up complaining severe pain in both lower limbs. X-rays showed bilateral complete transverse fracture of the femoral diaphysis. Early treatment in emergency department has been application of trans-tibial traction; on the same day the patient was admitted to orthopaedic department. Investigating patient's medical history, it emerged that the only medication she had been taking was Risedronate, for only 18 months, for a diagnosis of osteoporosis 6 years earlier. As prodromal symptom, about 6 months before hospitalization, she started experiencing bilateral thigh pain, without investigating it. Subsequently she underwent fixation with anterograde long intramedullary nails. Both femurs were treated in the same operating session. From the day after surgery, she began passive mobilization and strengthening of postural muscles; on the fourth day after surgery she began the protocol of re-education to standing and walking with progressive load over time. Conclusion: This case report highlights the possible limitations of the current management of BPs therapy. The occurrence of AFFs may not be solely dependent on the duration of BPs therapy and the age of patients, as widely acknowledged in the current literature. The management of BPs therapy may require a redefinition, with the need, according to the authors, to evaluate the introduction of therapeutic windows, especially in patients with clinical signs of high risk of AFFs.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication associated with antiresorptive medications managing osteoporosis, such as bisphosphonates (BPs). To date, there is very limited evidence from prospective, controlled studies to support or refute the controversial prevention regimen that if a discontinuation of BPs before dentoalveolar surgery, so called “drug holiday”, is effective in reducing the risk of MRONJ development in patients with osteoporosis. We proposed an experimental animal study, aiming to investigate the prevention of MRONJ following tooth extractions in osteoporotic condition, with the implementation of a BP drug holiday. Methods: Twenty rats were subjected to bilateral ovariectomy. After establishing the osteoporotic condition, all rats were exposed to weekly injections of zoledronate acid (ZA) for 8 weeks. After ZA treatment, 10 rats were subjected to dental extraction and defined as control group, and the rest 10 rats assigned to the DH group had a drug holiday of 8 weeks prior to dental extraction. Eight weeks after the dentoalveolar surgery, bone turnover biomarker in serum, occurrence of MRONJ-like lesion and histomorphometric assessment of osteonecrosis in mandible, and bone microarchitecture indices in femur, were examined. Results: Eight weeks after dental extraction, the DH group showed a recovered osteoclastic activity, indicated by significantly increased number of osteoclasts in the mandibles and serum level of C-terminal telopeptides of type I collagen, as compared to the control group. No significant differences were observed in the gross-view and histological occurrences of MRONJ-like lesions between the two groups.There was no significant difference in bone microarchitecture in the femur between the control and DH groups before ZA therapy and 8 weeks after dental extraction. Conclusion: Our data provided the first experimental evidence in the osteoporotic animal model that the implementation of a BP holiday in prior to dental extractions could partially recover osteoclastic activity, but could not alleviate the development of MRONJ-like lesion or exacerbate the osteoporotic condition in the femur. Longer-term drug holiday, or combination of drug holiday and other prophylaxes to prevent MRONJ in patients with osteoporosis could be worth exploring in future studies, to pave the way for clinical managements. The translational potential of this article: This in vivo prospective study reported that a recovery of osteoclastic activity by a BP drug holiday for 8 weeks in osteoporosis rats did not alleviate the development of MRONJ-like lesion followed by dental extractions. It contributes to the understanding of regimens to prevent MRONJ.

Background: Despite recognized improvements in obesity-related comorbidities, mounting evidence implicates surgical weight loss in the onset of skeletal fragility. Sleeve gastrectomy (SG) is the most commonly performed bariatric procedure and is associated with 3–7% axial bone loss in the year following surgery. Bisphosphonates are FDA-approved medications for the prevention and treatment of age-related bone loss and may represent a strategy to reduce bone loss following SG surgery. Methods: The Strategies to Reduce the Onset of Sleeve Gastrectomy Associated Bone Loss (STRONG BONES) trial (NCT04922333) is designed to definitively test whether monthly administration of the bisphosphonate, risedronate, for six months can effectively counter SG-associated bone loss. Approximately 120 middle-aged and older (≥40 years) SG patients will be randomized to six months of risedronate or placebo treatment, with skeletal outcomes assessed at baseline, six, and 12-months post-surgery. The primary outcome of the trial is 12-month change in total hip areal bone mineral density (aBMD), measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and quantitative computed tomography (QCT) derived changes in bone quality. Change in muscle mass and function will also be assessed, as well as biomarkers of bone health, turnover, and crosstalk, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Discussion: Results from the STRONG BONES trial have the potential to influence current clinical practice by determining the ability of bisphosphonate use to mitigate bone loss and concomitant fracture risk in middle-aged and older SG patients.

Since most of the reports of BRONJ onset are adults, in order to clarify the current situation of BRONJ onset in children, it is necessary to search for articles and report on the current status and actual conditions of surgical treatment of children with BP preparations who are being followed up in our clinic.In previous reports both inside and outside Japan, there was no mention of jaw bone necrosis during tooth extraction or surgery in children who were receiving or had a history of BP administration.There were 15 children with a history of BP administration who manage the oral cavity in our clinic. No unpleasant events in the extraction of deciduous teeth were confirmed in medical records. It is necessary to intervene early on oral management of pediatric BP-administered children, especially BP-and steroid-administered children, obtain plaque control to keep the oral cavity cleaner, respond early to infectious diseases, and manage to prevent inflammation from spreading to the jawbone. When surgical treatment is unavoidable, it is important to consider reducing the invasion as much as possible and to cooperate with the medical department such as administration of antibiotics to prevent infection.

Background/purpose: Bone resorption inhibitors, such as bisphosphonates (BPs) and anti-receptor activator of nuclear factor kappa B ligand antibodies (denosumab; Dmab), are used to treat osteoporosis and effectively reduce the risk of fracture. However, medication-related osteonecrosis of the jaw (MRONJ) has been reported as a rare adverse effect. Invasive tooth extraction procedures are reportedly a factor in the development of MRONJ. In this study, we aimed to retrospectively observe and clinically examine the effect of medication status on MRONJ development after tooth extraction in patients receiving drug treatment for osteoporosis. Materials and methods: This study was conducted among patients who visited our hospital between December 2015 and December 2021. We collected and analyzed the medical information of patients who underwent dental extractions while using osteoporosis medications, including oral and injectable BPs and Dmab. Results: Among antiresorptive medication users, 40 patients (70 teeth) underwent extraction. The mean duration of BP/Dmab use was 40.4 months, and the mean duration of drug holiday was 6.9 months. MRONJ after tooth extraction was not seen in BP users, but we observed two cases in Dmab users. A significant difference in MRONJ development was confirmed with the use of injectable compared with oral medication administration (odds ratio＝5.01). Conclusion: The use of injectable bone resorption inhibitors was associated with a higher risk of developing MRONJ. The route of administration, duration of medication, and withdrawal period should be carefully considered to prevent MRONJ after tooth extraction.

Background/Objective: Adrenal crisis is a medical emergency and an acute complication of adrenal insufficiency (AI). It can be triggered by stressors such as infection, dehydration, trauma, or surgery. Case Report: We present a case of a 70-year-old woman with a history of Addison’s disease, who presented in adrenal crisis within 24 hours after receiving her first infusion of zoledronic acid. No trigger was identified after extensive evaluation, making infusion with zoledronic acid the most likely cause of adrenal crisis. Discussion: Adverse reactions to medications can potentially trigger adrenal crisis. The present case report demonstrates that intravenous bisphosphonates can cause an acute phase reaction that may lead to adrenal crisis. Given the increased risk of osteoporosis in patients with AI there is an increased likelihood of prescription of intravenous bisphosphonates in this patient population. Conclusion: Patients with AI undergoing infusion with zoledronic acid may require an increased dose of glucocorticoid prior to infusion and may need to undergo monitoring post infusion for possible adrenal crisis.

Over the past few decades, the clinical outcomes of patients with cancer have significantly improved mostly owing to the development of effective chemotherapeutic treatments. However, chronic health conditions such as bone mass loss and risk of fragility fractures caused by chemotherapy have also emerged as crucial issues in patients treated for cancer. In this study, we aimed to understand the effect of eribulin mesylate (ERI), a microtubule-targeting agent currently used to treat metastatic breast cancer and certain subtypes of advanced sarcomas, on bone metabolism in mice. The administration of ERI reduced bone mass in mice, mainly by promoting osteoclast activity. Gene expression analysis of skeletal tissues revealed no change in the expression levels of the transcripts for RANK ligand, one of the master regulators of osteoclastogenesis; however, the transcript levels of osteoprotegerin, which neutralizes RANK ligand, were significantly reduced in ERI-treated mice compared with those in vehicle-treated controls, indicating a relative increase in RANK ligand availability after ERI treatment. In line with the increased bone resorption in ERI-treated mice, we found that zoledronate administration effectively suppressed bone loss in these mice. These results reveal a previously unrecognized effect of ERI on bone metabolism and suggest the application of bisphosphonates for patients with cancer undergoing treatment with ERI.

Bone-modifying agents (BMAs), with bone-resorptive inhibitory effects, such as zoledronic acid and denosumab, are widely used at higher doses for bone-related events caused by bone metastasis of malignant tumors. These drugs have been suggested to be associated with atypical femoral fractures (AFFs), and the relationship between BMAs and AFFs has attracted attention. To investigate the clinical features including bone union time of AFFs in patients administered BMA for bone metastasis, we conducted a retrospective multicenter study. Thirty AFFs from 19 patients were enrolled in this study. Thirteen patients had bilateral AFFs, and nineteen AFFs had prodromal symptoms. Eighteen AFFs underwent surgery after complete fracture, three failed to achieve bone union and required nonunion surgery, and 11 AFFs that achieved bone union had an average period until bone union of 16.2 months, which was much longer than that previously reported for ordinary AFFs. Seven patients discontinued the BMAs, but not due to AFFs. Stopping BMAs in patients with bone metastasis would make it difficult to secure their performance of activities of daily living, and AFF with BMA administration might require a longer time for union. Therefore, it would be important to prevent incomplete AFF from becoming complete AFF via prophylactic internal fixation.

Osteochondritis dissecans (OCD) is a disease of the joints characterized by idiopathic focal subchondral lesions. Aggrecan, a proteoglycan encoded by the ACAN gene, is important for cartilage structure and function. We describe the clinical evolution of a patient with short stature, multi-focal OCD, and subchondral osteopenia that appeared linked to a novel pathogenic ACAN variant. A multi-disciplinary approach including medical (bisphosphonate) therapy, surgical intervention and rehabilitation were successful in restoring wellness and physical function.

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 a major problem that can occur in people taking certain medications such bisphosphonates and denosumab. It can be used to treat osteoporosis or cancer. Bisphosphonate exposure, dental diseases and procedures, age, sex, anatomical factors, medical issues, and hereditary factors are all variables that enhance the risk of MRONJ. Even though MRONJ and antiresorptive medications have a close association, the pathophysiology of MRONJ is unknown. Careful dental preparation and oral hygiene instructions significantly minimize the risk of osteonecrosis of the jaw (ONJ). It is ideal to start antiresorptive treatment after the completion of required dental treatment; it is not contraindicated and carries low risk in patients who are on oral antiresorptive medications for less than three years. Drug holidays are one proposed solution to address MRONJ. However, there is still inadequate evidence to support their effectiveness. The objectives of this literature review are to recognize the main diagnostic principles and risk factors and to review the pathophysiology, protective procedures and treatment modalities related to MRONJ.The following topics are covered in the review: epidemiology, diagnostic criteria, risk factors, pathogenesis and mechanism, MRONJ staging and symptoms, clinical and radiographic findings, treatment strategies, prevention and drug holiday.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a serious complication associated with antiresorptive and antiangiogenic medications, of which impaired angiogenesis is a key pathological alteration. Since Magnesium (Mg)-based implants possess proangiogenic effects, we hypothesized that the biodegradable Mg implant could alleviate the development of MRONJ via enhancing angiogenesis. Methods: MRONJ model was established and divided into the Veh ​+ ​Ti group (Vehicle-treated rat, with Titanium (Ti) implant), BP ​+ ​Ti group (Bisphosphonate (BP)-treated rat, with Ti implant), BP ​+ ​Mg group (BP-treated rat, with Mg implant), BP ​+ ​Mg ​+ ​SU5416 group (BP-treated rat, with Mg implant and vascular endothelial growth factor (VEGF) receptor-2 inhibitor), BP ​+ ​Mg ​+ ​BIBN group (BP-treated rat, with Mg implant and calcitonin gene-related peptide (CGRP) receptor antagonist), and BP ​+ ​Mg ​+ ​SU5416+BIBN group (BP-treated rat, with Mg implant and VEGF receptor-2 inhibitor and CGRP receptor antagonist). The occurrence of MRONJ, alveolar bone necrosis, new bone formation and vessel formation were assessed by histomorphometry, immunohistochemistry, and micro-CT analysis. Results: Eight weeks after surgery, the BP ​+ ​Mg group had significantly reduced occurrence of MRONJ-like lesion and histological osteonecrosis, increased bone microstructural parameters, and increased expressions of VEGFA and CGRP, than the BP ​+ ​Ti group. By simultaneously blocking VEGF receptor-2 and CGRP receptor, the vessel volume and new bone formation in the BP ​+ ​Mg group were significantly decreased, meanwhile the occurrence of MRONJ-like lesion and histological bone necrosis were significantly increased. Conclusion: Biodegradable Mg implant could alleviate the development of MRONJ-like lesion, possibly via upregulating VEGF- and CGRP-mediated angiogenesis. Mg-based implants have the translational potential to be developed as a novel internal fixation device for patients with the risk of MRONJ. The Translational potential of this article: This work reports a biodegradable Mg implant which ameliorates the development of MRONJ-like lesions possibly due to its angiogenic property. Mg-based implants have the potential to be developed as a novel internal fixation device for patients at the risk of MRONJ.

Background/Purpose: Bisphosphonates (BPs) impact on the survival and cardiovascular safety of osteoporosis patients after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) was evaluated. Methods: A nationwide epidemiological study was conducted using the Taiwan National Health Insurance Research Database from 2000 to 2010. From the 1456 osteoporosis patients with previous ACS or AIS, mortality and cardiovascular safety was compared between 464 patients who used BPs and 464 patients who did not. Primary outcomes included all-cause mortality, and major adverse cardiovascular events. Results: The BPs group had a lower risk of all-cause mortality than the control group after the 8-year follow-up (HR, 0.64; 95% CI, 0.46–0.88; P = 0.006). The risks of myocardial infarction, ischemic stroke, cardiovascular death, hospitalization for heart failure or other causes of mortality were similar across groups. However, there was a higher risk of hospitalization for atrial fibrillation in the BPs group than the control group (HR, 1.76; 95% CI, 1.26–2.46; P = 0.001). Conclusion: Among osteoporosis patients after ACS or AIS, BPs use was associated with a reduced risk of all-cause mortality. However, patients with previous cardiovascular disease who received BP treatment should be careful about the risk of atrial fibrillation.

Background: The Radiotherapy IBandronate (RIB) trial compared single dose radiotherapy and a single infusion of ibandronate in 470 bisphosphonate naïve patients with metastatic bone pain from prostate cancer randomised into a non-inferiority two arm study. Results for the primary endpoint of pain score response at 4 weeks showed that the ibandronate arm was non-inferior to single dose radiotherapy., Patients and Method: In addition to pain assessments including analgesic use made at baseline, 4, 8, 12, 26 and 52 weeks, urine was collected at baseline, 4 and 12 weeks. It was subsequently analysed for urinary N-telopeptide (NTx) and cystatin C. Linear regression models were used to compare the continuous outcome measures for urinary markers within treatment arms and baseline measurements were included as covariates. Interaction terms were fitted to allow for cross-treatment group comparisons., Results: The primary endpoint of the RIB trial was worst pain response at 4 weeks and there was no treatment difference seen. Urine samples and paired pain scores at 4 weeks were available for 273 patients (radiotherapy 168; ibandronate 159)The baseline samples measured for the RIB trial had an average concentration of 193 nM BCE/mM creatinine (range of 7.3-1871) compared to the quoted normal range of 33 nM BCE/mM creatinine (3 to 63). In contrast the average value of Cystatin C was 66 ng/ml (ranges ND - 1120 ng/ml) compared to the quoted normal range of 62.9 ng/ml (ranges 12.6-188 ng/ml). A statistically significant reduction in NTx concentrations between baseline and 4 weeks was seen in the ibandronate arm but not in the radiotherapy arm. No correlation between pain response and urinary marker concentration was seen in either the ibandronate or radiotherapy cohort at any time point., Conclusion: NTx was significantly raised compared to the normal range consistent with a role as a biomarker for bone metastases from prostate cancer. A significant reduction in NTx 4 weeks after ibandronate is consistent with its action in osteoclast inhibition which was not seen after radiotherapy implying a different mode of action for radiation. There was no correlation between bone biomarker levels and pain response., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Proton pump inhibitors (PPIs) are among the most commonly prescribed medicines for the management of acid-related gastrointestinal diseases. Osteonecrosis of the jaw (ONJ) is a serious adverse event that is associated with the use of antiresorptive and antiangiogenic agents. According to previous clinical reports, the use of PPIs contributes to the pathogenesis of severe ONJ that requires surgery. Here, we investigated the effects of lansoprazole (LP) or LP in combination with zoledronate (ZOL) on ONJ development in mice. C57BL/6J mice were administered ZOL (125 μg/kg intravenously, twice weekly) and/or LP (10 mg/kg intraperitoneally; 3 weeks of 3 consecutive days followed by 1 day off). One week after initiation of the study, the first molar was atraumatically extracted. Concurrently with ZOL administration, dexamethasone (Dex) was administered (5 mg/kg intraperitoneally, twice weekly). Micro-computed tomography and histological evaluation were performed to characterize femoral structures, tooth extraction sockets, and osteonecrosis areas. The results showed that ZOL/Dex significantly increased bone mass compared to saline/Dex, while the simultaneous administration of LP and ZOL/Dex diminished the ZOL-induced enhancement of bone mass. In the alveolar bone around the tooth extraction socket, necrotic bone was significantly increased in the LP/Dex group compared to the saline/Dex group. However, no signs of more severe ONJ-like lesions were observed following combined administration of LP and ZOL/Dex, other than an increase in the number of non-attached TRAP-positive cells. Our findings in a mouse model suggest that LP use can be a risk factor for the development of ONJ.

Objectives: Osteoporosis medications are widely available in South Korea, and well reimbursed by the Government Health Insurance; however, some expensive drugs are not reimbursed. The prescription of anti-osteoporosis drugs (AODs) are increasing for the elderly and for postmenopausal women. We investigate the secular trends of AODs in South Korea. Methods: We used the Intercontinental Medical Statistics Health Sales Audit between January 1, 2006 and December 31, 2018. We analyzed the total sales costs and market share of AODs including bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone (PTH), calcitonins, and denosumab using the number of days of therapy (DOT). Changes of prescription patterns including original versus generic drugs, vitamin D combination, and types of medical institutions were also analyzed. Results: Bisphosphonates were the most frequently used drug during the study period although its DOT declined from 92.5% in 2008 to 80.0% in 2018. SERMs were the second-most used medication, and has maintained around 13% since 2015. The proportion of calcitonins has decreased since 2011, mainly due to malignancy risk. In contrast, the DOT of PTH and denosumab increased to 0.8% and 4.7% in 2018, respectively. The use of generics, vitamin D combination, and intravenous bisphosphonates has been increasing throughout the study period. Conclusions: Prescription patterns using DOT are changing probably due to the increase in older adult patients and severely osteoporotic patients. There are other issues including safety and the launching of new drugs.

Background: It may seem incredible, even unimaginable, that some issues have not been properly studied and explained in the literature. One of these issues is the non-surgical treatment of osteolytic tumors of the jaws, especially ameloblastoma. Main text: This tumour invades the jaw through a mechanism of resorption of the surrounding bone. Osteoclasts are known to initiate physiological bone remodelling during bone growth, tooth eruption and fracture healing. They are also able to mediate bone loss in pathological conditions such as ameloblastoma. Therefore, inhibition of osteoclasts would be a potential target for the treatment of ameloblastoma.To date, the mechanisms of bone resorption in ameloblastoma are associated with the expression of receptor activator of nuclear factor kappa B ligand (RANKL) and matrix metalloproteinases 2 and 9.However, in terms of therapeutic applications of this approach, bisphosphonates have been shown to inhibit the proliferation and differentiation of osteoclast precursors through the inactivation of molecular signalling pathways involving M-CSF and RANKL. The same is true for doxycycline, which inhibits the activity of mammalian collagenases and gelatinases, an activity unrelated to its antimicrobial efficacy. Conclusion: this review, we report on the current state of knowledge on the involvement of osteoclastogenesis in the pathogenesis of ameloblastoma. We also present possible clinical applications of a calcium phosphate cement-based local delivery device for bisphosphonates and doxycycline as a potential treatment for ameloblastoma of the jaws.

The quality of life, in itself, in cancer patients or in osteoporotic individuals, without even considering the side effects of the medication in the first place, has a considerable negative impact on the clinical outcome. The Medication Related Osteonecrosis of the Jaw (MRONJ), in the maxillofacial region, although rare, needs to be addressed with the prime importance. One of the key components of any given preventive treatment strategy is to, create awareness about the medication related unwanted effects, among health care professionals and patients. Objective: This study is aimed to explore and assess the awareness level among dental patients about MRONJ, the risk factors, and the high-risk category (who are prone to develop MRONJ). Material and methods: This is a prospective interviewer administered research electronic data capture (REDCap) survey. The sample included 68 patients, who are currently taking or will be taking Bisphosphonate (BP), and/or Denosumab, and anti-Angiogenic agent. Data have been analyzed using IBM SPSS software, Results: Sixty-eight patients (18 males and 50 females), participated in this study. Only 23 subjects (33.82%) were aware about the MRONJ. Females were more aware about the complications than males. The awareness among the subjects with education at college level appears to be higher than the subjects having education less than high school level. Even though, a dental check- up, is mandatory, prior to starting these medications, to see if any dental treatment is required, only slightly more than half of the patients (54.72%) had a dental checkup. Conclusion: This is a novel study in the Middle- East, used to assess awareness about the MRONJ including three type of related medications. Low awareness of MRONJ is alarming. The results of the study will help to initiate the process of providing the education materials, about the side effects and importance of oral hygiene maintenance, giving priority to improve the quality of life in such patients. Awareness of patients regarding the complications must be an important part of health care practice guidelines.

Subchondral insufficiency fractures of the knee are commonly misdiagnosed fractures that are both very painful and difficult to treat. A conservative treatment modality to control symptoms during rehabilitation has not previously been described. This case report presents the alternate use of cooled radiofrequency ablation technique of the genicular nerves for pain relief and bisphosphonate infusion to address the underlying poor bone mineralization/density with imaging follow-up before and after instituted treatments. A middle-aged female patient presenting with atraumatic pain in the medial aspect of the left knee diagnosed on an original magnetic resonance imaging as an insufficiency fracture and debilitating pain. Multiple-surgeon opinions of total knee arthroplasty were not a consideration the patient wanted or could consider given her lifestyle. Cooled radiofrequency ablation of the genicular nerve branches was performed with significant-complete pain relief achieved that lasted at least 6 months. Bisphosphonate infusions were instituted to address the underlying osteoporosis detected by a dual energy X-ray absorptiometry (DEXA) scan. Clinical performance after the radiofrequency ablations was followed with clinically validated surveys (The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)/Knee Injury and Osteoarthritis Outcome Score (KOOS)) at 2 weeks, 1, 3, and 6 months. Patient was also asked to follow a restricted-modified weight-bearing plan for 3 months followed by physical therapy. Eight weeks apart of bisphosphonate infusions were delivered after proper administration of vitamin D. There was resolution of the insufficiency fracture at the medial femoral condyle between the magnetic resonance imaging exams within 4.5 months apart treated with restricted weight-bearing regimen. Pain resolution, significant improved function, and range of motion were the end results of our instituted treatment plan. This case reports presents an alternate pathway for the treatment of this condition especially when there is lack of consensus among physicians in how to best address this condition.

Objective: The objective of this study was to assess the efficacy and safety of denosumab therapy in osteoporotic postmenopausal women who were previously treated with bisphosphonates. Methods: Meta-analyses of four available randomised controlled trials that compared osteoporotic patients who switched to denosumab from bisphosphonates (n ​= ​1416) and those who continued bisphosphonates therapy (n ​= ​1411) were included. Results: The increase in bone mineral density (BMD) of both the spine and hip was significantly higher in patients who shifted to denosumab than in those who continued bisphosphonates. Despite the incidence of adverse events (AEs) and fractures being comparable, treatment withdrawal owing to AEs was significantly less frequent in the denosumab group. Conclusion: The outcomes and treatment compliance were improved in postmenopausal osteoporotic women who shifted to denosumab from bisphosphonates. The translational potential of this article: The replacement of bisphosphonates with denosumab may lead to better therapeutic efficacy and fewer adherence barriers ​than those with continued usage of bisphosphonates, which in the future may guide the choice of drug therapy in clinics.

Purpose: To provide a summarized state of the art of the relative efficacy and rapidity of action of pharmacological treatments to prevent imminent osteoporotic fractures. Methods: We reviewed metanalyses (MA) and network metaanalyses (NMA) published during the last 10 years concerning the pharmacological treatment of osteoporosis. We compared the anti-fracture efficacy and the rapidity of action of various agents versus placebo and versus risedronate. Results: All bisphosphonates decrease the incidence of vertebral fractures compared with placebo. Ibandronate is the only one without demonstrated efficacy against non-vertebral and hip fractures. Zoledronate, denosumab and anabolic therapy are associated with a higher fracture risk reduction than oral bisphosphonates. Compared with risedronate, which significantly reduces the rate of hip fractures, zoledronate, denosumab, teriparatide, abaloparatide and romosozumab are more efficient for vertebral fractures but not for non-vertebral or hip fractures reduction. No studies have compared bone anabolic treatments with zoledronate or denosumab. Oral bisphosphonates significantly reduce fracture risk only after more than one year of therapy. A faster reduction of fracture risk is observed with zoledronate and denosumab, or with anabolic agents. For denosumab and anabolic agents, a sequential treatment is required to keep gains after treatment withdrawal. Conclusions: In patients at high risk of imminent fracture, starting therapy with potent antiresorptive agents or with an anabolic agent seems most appropriate to promptly reduce the fracture risk. Available NMA/MA suggest that, compared to zoledronate and denosumab, anabolic agents have a higher efficacy for vertebral fractures but head-to-head studies are lacking.

Renal cell carcinoma (RCC) is the most common malignancy of the kidney, representing 80–90% of renal neoplasms, and is associated with a five-year overall survival rate of approximately 74%. The second most common site of metastasis is bone. As patients are living longer due to new RCC targeting agents and immunotherapy, RCC bone metastases (RCCBM) treatment failure is more prevalent. Bone metastasis formation in RCC is indicative of a more aggressive disease and worse prognosis. Osteolysis is a prominent feature and causes SRE, including pathologic fractures. Bone metastasis from other tumors such as lung, breast, and prostate cancer, are more effectively treated with bisphosphonates and denosumab, thereby decreasing the need for palliative surgical intervention. Resistance to these antiresportives in RCCBM reflects unique cellular and molecular mechanisms in the bone microenvironment that promote progression via inhibition of the anabolic reparative response. Identification of critical mechanisms underlying RCCBM induced anabolic impairment could provide needed insight into how to improve treatment outcomes for patients with RCCBM, with the goals of minimizing progression that necessitates palliative surgery and improving survival.

Fracture fixation in an ageing population is challenging and fixation failure increases mortality and societal costs. We report a novel fracture fixation treatment by applying a hydroxyapatite (HA) based biomaterial at the bone-implant interface and biologically activating the biomaterial by systemic administration of a bisphosphonate (zoledronic acid, ZA). We first used an animal model of implant integration and applied a calcium sulphate (CaS)/HA biomaterial around a metallic screw in the tibia of osteoporotic rats. Using systemic ZA administration at 2-weeks post-surgery, we demonstrated that the implant surrounded by HA particles showed significantly higher peri‑implant bone formation compared to the unaugmented implants at 6-weeks. We then evaluated the optimal timing (day 1, 3, 7 and 14) of ZA administration to achieve a robust effect on peri‑implant bone formation. Using fluorescent ZA, we demonstrated that the uptake of ZA in the CaS/HA material was the highest at 3- and 7-days post-implantation and the uptake kinetics had a profound effect on the eventual peri‑implant bone formation. We furthered our concept in a feasibility study on trochanteric fracture patients randomized to either CaS/HA augmentation or no augmentation followed by systemic ZA treatment. Radiographically, the CaS/HA group showed signs of increased peri‑implant bone formation compared with the controls. Finally, apart from HA, we demonstrated that the concept of biologically activating a ceramic material by ZA could also be applied to β-tricalcium phosphate. This novel approach for fracture treatment that enhances immediate and long-term fracture fixation in osteoporotic bone could potentially reduce reoperations, morbidity and mortality. STATEMENT OF SIGNIFICANCE: • Fracture fixation in an ageing population is challenging. Biomaterial-based augmentation of fracture fixation devices has been attempted but lack of satisfactory biological response limits their widespread use. • We report the biological activation of locally implanted microparticulate hydroxyapatite (HA) particles placed around an implant by systemic administration of the bisphosphonate zoledronic acid (ZA). The biological activation of HA by ZA enhances peri‑implant bone formation. •Timing of ZA administration after HA implantation is critical for optimal ZA uptake and consequently determines the extent of peri‑implant bone formation. • We translate the developed concept from small animal models of implant integration to a proof-of-concept clinical study on osteoporotic trochanteric fracture patients. • ZA based biological activation can also be applied to other calcium phosphate biomaterials., Competing Interests: Declaration of competing interest D.B.R., L.L., M.T. and Y.L. are shareholders in Moroxite AB and Moroxite F AB, Lund, Sweden. All other authors have nothing to disclose. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lars Lidgren, Deepak Bushan Raina, and Magnus Tägil have received funding from the Olav-Thon Foundation. Deepak Bushan Raina has received funding from the Crafoord Foundation, the Maggie-Stephens Foundation, the Royal Physiographic Society Lund, the Sten K Johnson Foundation. Magnus Tägil, Hanna Isaksson and Yang Liu received funding from VINNOVA to conduct neutron tomography experiments. Deepak Bushan Raina, Lars Lidgren, Magnus Tägil and Yang Liu are shareholders in Moroxite AB and Moroxite F AB, Lund, Sweden. All other authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A 33-year-old primiparous woman with progressive idiopathic juvenile osteoporosis (IJO) who had had multiple vertebral compressions and bilateral femoral neck fractures since the age of 15 years presented for perinatal management at 11 weeks of gestation. Her vertebral bone mass was 0.634 g/cm2 before pregnancy. The target calcium intake was set at 800 mg/day. Cephalopelvic disproportion led to the patient having an elective cesarean section at 39 weeks 3 days of gestation and she delivered a female infant weighing 2785 g. After the delivery, her vertebral bone mass had increased to 0.700 g/cm2. At 34 years of age, she conceived her second child. With similar perinatal management, she delivered a female infant weighing 2580 g at 38 weeks of gestation by elective cesarean section. Her vertebral bone mass had increased again after the second pregnancy. Few cases of pregnancy complicated by progressive IJO have been reported. However, an uneventful pregnancy course can be expected with proper management, and pregnancy can be a good opportunity to increase bone mass.

This retrospective study aimed to examine the course and prognosis of medication-related osteonecrosis of the jaw (MRONJ) initially treated conservatively and the effects of various factors affecting treatment outcomes. We evaluated 129 patients with MRONJ between January 2008 and December 2018 at a university hospital. The factors examined included sex, age, stage of MRONJ (1–3), type of bone modifying agents (bisphosphonate or denosumab), primary disease (osteoporosis or malignant tumor), medical history (diabetes and rheumatoid arthritis), use of corticosteroids, the trigger of MRONJ (teeth extraction or others), and separation of sequestrum, using logistic regression analysis. Patients with MRONJ were treated conservatively as the initial treatment in accordance with the position paper of the American Association of Oral and Maxillofacial Surgeons. Of the 129 patients, 59 (45.7%) were cured, and the condition of 70 (54.3%) remained unchanged or worsened. The overall cure rates at 12, 36, and 60 months were 25.8%, 50.8%, and 72.4% respectively. The cure rate of stage 1 was lower than that of stages 2 and 3 at 80 months. In multivariate analysis, it was found that 37 (64.9%) of 57 patients with osteoporosis as a primary disease were cured (odds ratio [OR], 7.7; 95% confidence interval [CI], 2.4–24.4). In addition, 40 (69.0%) of 58 patients with separation of sequestrum were cured (OR, 8.9; 95% CI, 3.4–23.5). The cure rate was significantly higher in patients with osteoporosis than in those with cancer when the treatment outcomes of primary disease were compared using the Kaplan-Meier method (p

Objective: Osteoarthritis (OA) is a painful degenerative disease of the whole joint structure, including articular cartilage, synovial fluid, and subchondral bone. Hyaluronic acid (HA), an anionic non-sulfated glycosaminoglycan, is commonly used for intra-articular (IA) treatment in OA, while bisphosphonates (BPs) are anti-resorptive drugs that act on the bone. Here, a novel conjugate with a covalent and hydrolysable linker between HA and alendronate (ALD) was designed as an attractive therapeutic strategy for IA drug delivery. Design: The HA-ALD derivative was synthesized and tested in comparison with a simple mixture of HA and ALD for in vitro ALD release, rheological properties, cytotoxicity towards osteoblasts and chondrocytes and in an in vitro efficacy assay of OA inflammatory model on bovine cartilage explants. Results: The structure of HA-ALD was elucidated exhibiting no depolymerization and efficient drug incorporation. The controlled ALD release in vitro was slower compared to the simple mixture of HA and ALD; moreover, the derivative showed calcium-tuned rheological properties. The absence of cytotoxicity towards osteoblasts and chondrocytes was shown for up to 7 days, and the viability of chondrocytes was confirmed by fluorescence microscopy. Finally, a reduction in collagen release and MMP-13 expression was measured in the OA inflammatory model. Conclusion: This new HA-ALD derivative opens the door to a new approach for OA treatment, as it combines viscosupplementation and biological effects of HA with the pharmacological activity of BPs. Prolonged ALD release increased rheological properties and beneficial effect against cartilage degradation make it a promising IA therapy for OA.

Background: The optimal management of calciphylaxis in kidney transplant recipients (KTRs) is uncertain. Case presentation: We report 2 cases of refractory calciphylaxis in KTRs who suffered from persistent secondary hyperparathyroidism. They failed initial therapy with sodium thiosulphate but responded to treatment with bisphosphonates. No adverse events were noted with bisphosphonate therapy. Conclusion: Bisphosphonates appear to be an effective therapy for KTRs with calciphylaxis who cannot tolerate or respond poorly to STS, particularly if they have persistent hyperparathyroidism post-transplantation.

Bisphosphonates and the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab are effective anti-resorptive drugs commonly prescribed for osteoporosis. Both drugs may, however, have intolerable side effects; so, it is critical to examine their residual efficacy such as maintenance of bone mass following cessation. Therefore, we compared the changes in bone histology following discontinuation of the aminobisphosphonate risedronate and anti-RANKL antibody in ovariectomized (OVX) mice. Twelve-week-old female C57BL/6 N mice were OVX or sham operated. Four weeks after surgery, mice were treated with vehicle, a single injection of anti-RANKL antibody (5 mg/kg), or risedronate (5 μg/kg/day, s.c.) for 4 weeks (the treatment period), followed by vehicle treatment for an additional 4 weeks (discontinuation period). The lumbar spine and proximal tibia were evaluated by micro-computed tomography. In addition, the lumbar spine, proximal tibia, and the femoral shaft were examined by bone histomorphometry. After 4 weeks of discontinuation, OVX mice initially treated with the anti-RANKL antibody exhibited a trend of bone loss associated with increased turnover in both trabecular and cortical bones, although the difference was not significant. By contrast, OVX mice treated with risedronate exhibited maintained or even increased bone mass and suppressed bone turnover. Patients discontinuing denosumab should be carefully monitored for recurrent osteoporosis symptoms, and a replacement drug should be considered.

Introduction: Osteoporosis is one of the serious adverse effects associated with glucocorticoid therapy. Although bisphosphonates have been used for glucocorticoid-induced osteoporosis (GIO), some patients have shown an inadequate response. In such cases, denosumab or teriparatide are used. However, there is no consensus on which of these two drugs is superior. We prospectively compared denosumab's and teriparatide's effects on the bone mineral density (BMD) in GIO patients with prior bisphosphonate treatment. Materials and methods: After receiving oral bisphosphonates for ≥2 years, GIO patients with low T-score BMD (

Prostate cancer (PC) has a high propensity to develop bone metastases, causing severe pain and pathological fractures that profoundly impact a patients' normal functions. Current clinical intervention is mainly palliative focused on pain management, and tumor progression is refractory to standard therapeutic regimens. This limited treatment efficacy is at least partially due to a lack of comprehensive understanding of the molecular landscape of the disease pathology, along with the intensive overlapping of physiological and pathological molecular signaling. The niche is overwhelmed with diverse cell types with inter- and intra-heterogeneity, along with growth factor-enriched cells that are supportive of invading cell proliferation, providing an additional layer of complexity. This review seeks to provide molecular insights into mechanisms underlying PC bone metastasis development and progression., (Copyright © 2024. Published by Elsevier Inc.)

Background: As the life expectancy of cancer-bearing patients has increased, more patients with bone metastasis are receiving long-term treatment with bone-modifying agents (BMAs; e.g., zoledronate and denosumab), which are a risk factor for developing atypical femoral fracture (AFF). In this study, we surveyed the risk of iatrogenic AFF using a clinical database on treatment of bone metastasis in the past 10 years. Methods: From April 2011 through October 2019, 721 patients with bone metastasis (436 men, 285 women; mean age, 65.7 ± 12.4 years) were registered under the bone metastasis consultation system, which has been run by orthopaedic surgeons since 2011, at a university hospital in Japan. We retrospectively reviewed the database to identify patients who had received BMAs for treatment of bone metastasis, and we investigated the incidence of critical skeletal-related events (including AFF) which required surgical interventions by orthopaedic surgeons. Results: BMAs were administered to 529 patients (73.4%). Orthopaedic surgery for the treatment of skeletal-related events was performed in 36 patients (5.0%): femur, 13 (1.8%); others, 23 (3.2%). Eight AFFs in 5 patients (breast cancer, n = 4; prostate cancer, n = 1), who all had prior exposure to zoledronate or denosumab before onset of AFF, were treated with internal fixation using intramedullary nailing. In 192 patients with no BMA exposure, critical (surgically treated) AFF was not detected. In summary, the incidence of critical AFF was 0.9% among 529 patients who received BMAs for treatment of bone metastasis, and the incidence was 6.6% when limited to breast cancer patients (4 of 61). Conclusion: In treatment of bone metastasis using BMAs, especially for breast cancer patients, attention should be paid to the risk of developing AFFs. Routine radiographic screening for AFF might be necessary in patients with prolonged BMA use for bone metastasis, even if asymptomatic. This report alerts all physicians and surgeons involved in the management of cancer patients, especially those with bone metastasis, regarding the risk of AFF following BMA use.

Introduction: In October 2010, the US Food and Drug Administration (FDA) issued a safety communication regarding the risks of atypical fractures of the femur, with bisphosphonates drugs. This study evaluated the impact of the bisphosphonates FDA safety communication on the utilization of osteoporosis medications in Medicaid programs. Methods: Osteoporosis drugs utilization data from the July 2006 to June 2014 were extracted from the national Summary Files from the Medicaid State Drug Utilization Data maintained by the Centers for Medicare & Medicaid Services (CMS). We performed an interrupted time series analyses to evaluate trends in utilization of osteoporosis drugs before and after the 2010 FDA safety commination. Results: Time-series analyses of osteoporosis drug utilization in Medicaid program revealed a significant downward trend associated with the 2010 FDA bisphosphonates safety communication. Before the FDA safety communication was issued, the utilization rate was slightly decreased between 2006 and 2010. In the year following the FDA safety communication the bisphosphonate DDDs per 1000 beneficiaries of fell 22% yearly until the end of study period. Conclusions: The 2010 FDA bisphosphonates safety communication appeared to have influenced Osteoporosis utilization in Medicaid recipients. The 2010 FDA bisphosphonates safety communication was associated with a significant reduction in the utilization of bisphosphonates in the Medicaid program.

Objectives: Glucocorticoid (GC) treatment inhibits activation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation from stem cells. As a result, GC treatment results in bone loss, GC-induced osteoporosis (GIO), elevated fracture risk, and delayed bone healing. Bisphosphonates such as alendronate (ALN) are recommended for treating or preventing GIO, and low-intensity pulsed ultrasound (LIPUS) facilitates fracture healing and maturation of regenerated bone. Combined therapy with ALN and LIPUS may stimulate cancellous bone healing in GIO rats. Here, we examined the effect of ALN and LIPUS on cancellous bone osteotomy repair in the proximal tibia of GIO rats. Methods: Prednisolone (10 mg/kg body weight/day) was administered for 4 weeks to induce GIO in 6-month-old female Sprague-Dawley rats. Tibial osteotomy was then performed and daily subcutaneous injection of ALN (1-μg/kg body weight) was subsequently administered alone or in combination with LIPUS (20 min/day) for 2 or 4 weeks. Results: ALN significantly increased bone mineral density (BMD) at 2 and 4 weeks, and ALN + LIPUS significantly increased BMD at 4 weeks. Bone union rates were significantly increased after 2 and 4 weeks ALN and ALN + LIPUS treatment. Lastly, ALN and ALN + LIPUS significantly increased the proportion of Runx2 positive cells at 4 weeks. Conclusions: ALN monotherapy and combined ALN and LUPUS treatment augmented BMD and stimulated cancellous bone repair with increased Runx2 expression at the osteotomy site in GIO rats. However, the combined treatment had no additional effect on cancellous bone healing compared to ALN monotherapy.

Osteogenesis imperfecta is a hereditary bone dysplasia characterized by bone fragility, deformity, and short stature. Treatment focuses on preventing bone fractures and symptom relief. Pamidronate, a second-generation bisphosphonate drug that minimizes bone loss, is the chosen treatment in osteogenesis imperfecta. Radiologically, each cycle of pamidronate treatment is depicted as a line of sclerosed nondecalcified cartilage at the metaphysis, termed a pamidronate line. In this case report, we demonstrate that a treatment timeline can be visualized on plain radiographs as the number and spacing of pamidronate lines reflects the number and timing of treatment cycles. The educational value of this is to reassure physicians of the benign nature of “zebra lines,” to demonstrate that the pamidronate lines migrate and fade with bone growth, and alert physicians that the lack of expected pamidronate lines during treatment may reflect a change in the patient's condition that reduces the effectiveness of bisphosphonate infusions.

Objectives: Bisphosphonates (BPs) are a class of drugs that are used to treat osteoporosis. It has been suggested that BP coatings on dental implants have a positive effect on new bone formation. The purpose of this review is to analyse the currently available data concerning the clinical and experimental efficacy of BP-releasing titanium implants such that their potential in clinical oral implant dentistry may be ascertained. Methods: Based on a literature review, a focused research question was constructed: what is the effect of a BP-releasing coating on the osseointegration of titanium dental implant? The databases of PubMED/MEDLINE; ISI Web of Knowledge; Embase and Google Scholar were searched electronically using the keywords ‘dental implant’; ‘bisphosphonate’ and ‘titanium.’ The quality; general characteristics and outcomes of each study were summarized and analysed systematically. Results: A total of eleven articles fulfilled the criteria to be included in this review. Eight studies were experimental; two studies were clinical; and one study was experimental and clinical. In nine studies (82%), BP-coated implants resulted in higher osseointegration, as indicated by higher resonance frequency values, removal torque, bone-implant contact and new bone formation. In two studies (18%), there was no difference between the osseointegration of BP-coated implants and controls. Conclusions: Bisphosphonates-loaded implants may have a positive effect on osseointegration. However, more well-designed clinical studies are required to demonstrate their osseoconductive effects.

Background: Several guidelines have been reported for bone-directed treatment in women with early breast cancer (EBC) for averting fractures, particularly during aromatase inhibitor (AI) therapy. Recently, a number of studies on additional fracture related risk factors, new treatment options as well as real world studies demonstrating a much higher fracture rate than suggested by randomized clinical controlled trials (RCTs). Therefore, this updated algorithm was developed to better assess fracture risk and direct treatment as a position statement of several interdisciplinary cancer and bone societies involved in the management of AI-associated bone loss (AIBL). Patients and methods: A systematic literature review identified recent advances in the management of AIBL. Results with individual agents were assessed based on trial design, size, follow-up, and safety. Results: Several fracture related risk factors in patients with EBC were identified. Although, the FRAX algorithm includes fracture risk factors (RF) in addition to BMD, it does not seem to adequately address the effects of AIBL. Several antiresorptive agents can prevent and treat AIBL. However, concerns regarding compliance and long-term safety remain. Overall, the evidence for fracture prevention is strongest for denosumab 60 mg s.c. every 6 months. Additionally, recent studies as well as an individual patient data meta-analysis of all available randomized trial data support additional anticancer benefits from adjuvant bisphosphonate treatment in postmenopausal women with a 34% relative risk reduction in bone metastasis and 17% relative risk decrease in breast cancer mortality that needs to be taken into account when advising on management of AIBL. Conclusions: In all patients initiating AI treatment, fracture risk should be assessed and recommendation with regard to exercise and calcium/vitamin D supplementation given. Bone-directed therapy should be given to all patients with a T-score−1.5 SD and no risk factors should be managed based on BMD loss during the first year and the local guidelines for postmenopausal osteoporosis. Compliance should be regularly assessed as well as BMD on treatment after 12 - 24 months. Furthermore, because of the decreased incidence of bone recurrence and breast cancer specific mortality, adjuvant bisphosphonates are recommended for all postmenopausal women at significant risk of disease recurrence.

Objectives: We aim to elucidate the clinical outcomes of bisphosphonate-associated atypical femoral fracture and the clinical results depending on the bisphosphonate therapy period. Methods: Twenty cases involving 15 patients who had been diagnosed with atypical femoral facture between 2004 and 2014 and who had been followed up for at least 12 months were retrospectively analyzed. The control group was composed of 15 typical femoral facture patients. We used plain radiography and physical examinations to determine the period of time required for fracture healing as well as complication occurrence. We investigated the bisphosphonate administration status and duration and the names of its components, bilateral fracture occurrence status, the period of time required for bone union, and reoperation or bone graft status due to nonunion. Results: Revision surgery involving a bone graft was performed due to nonunion in 1 out of 15 cases. Except in one revision case, the duration of the union was 11.9 months on average in 14 cases of atypical fracture patients, and 4.3 months on average in the control group. This difference was statistically significant (p 0.05). Conclusions: Atypical femoral fractures required more time for bone union than typical ones and prolonged bisphosphonate administration led to a longer period of time required for bone union.

We present a case of a bisphosphonate-related femur fracture in an elderly woman, who failed treatment with both cephalomedullary nail and proximal femoral locking plate, leading to successful treatment with total hip arthroplasty. Hardware failure should be included in the differential of patients with previous internal fixation of bisphosphonate-related femur fracture that present with hip or groin pain. Arthroplasty can be an acceptable salvage option in an active elderly patient with a bisphosphonate-related femur fracture.

Objectives: There is limited scientific evidence regarding the medication-related osteonecrosis of the jaw (MRONJ) induced by regenerative therapy (RT) associated with dental implant treatment. Thus, the current scoping review systematically maps the MRONJ research induced by RTs in implant dentistry and recognizes the existing gaps in knowledge., Data: Original studies and reviews investigating the impact of RT on the development of MRONJ were included., Sources: Two reviewers independently searched the MEDLINE-PubMed and Scopus databases according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) extension for Scoping Review and included articles published in English up to March 31, 2023., Study Selection: Eighteen articles that fulfilled the inclusion and exclusion criteria were included in this study. Ten mapping parameters for investigating the association of RTs with MRONJ development were examined and evaluated within the selected articles., Results: There was severely limited information regarding the procedures of RTs including; the grafting materials, surgical protocols, and success and failure rates. The RT associated with MRONJ cases was sinus floor augmentation in patients taking bisphosphonate and denosumab. Moreover, there were limited data on the implant treatment associated with RTs such as time of insertion, implant length and diameter, and loading protocol., Conclusion: The current scoping review revealed that some specific RTs associated with other factors hold a potential risk of MRONJ occurrence. However, the scientific evidence is limited with many gaps. Further investigations are needed to establish an evidence-based clinical guideline for treating high-risk patients., Clinical Significance: Clinicians should cautiously assess the risk of MRONJ development during implant treatment planning for patients undertaking antiresorptive medications. The adverse outcome of RT procedures should not be underestimated and a complete explanation of the possible risks should be given to the patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to estimate the rate of gastrointestinal (GI) events, and association between GI events and compliance with osteoporosis therapy among osteoporotic women. Methods: A retrospective cohort study using a large administrative claims database in the United States from 2001 through 2010 was conducted. We studied women ≥55 years old who were continuously enrolled in a health plan for at least 2 years, a baseline year before and a follow-up year after the date of the first prescription of oral bisphosphonate as the first oral osteoporosis treatment. Compliance with osteoporosis therapy was measured using the medication possession ratio (MPR), with compliance defined as MPR ≥0.8. Multivariate logistic regression was used to assess the association between occurrence of GI events and compliance with osteoporosis therapy after controlling for demographic and clinical characteristics. Results: A sample consisting of 75,593 women taking at least one oral bisphosphonate with mean (SD) age of 64 (8) years was identified. A total of 21,142 (28%) patients experienced at least one GI event during the follow-up period. Only 31,306 (41%) patients were compliant with osteoporosis therapy. Patients who experienced GI events after initiation of oral bisphosphonates were 29% less likely to adhere to osteoporosis therapy as compared to patients who did not experience GI events (odds ratio [95% CI], 0.71 [0.69–0.74]; P

Background/Aim: Severe bone pain is experienced by 60–80% of patients with metastatic bone disease, and has a profound impact on quality of life. Therefore, effective pain relief is an important goal in managing metastatic bone disease. Orthopedic surgeons are often challenged with patients presenting with newly diagnosed bone metastases and severe and disabling bone pain. It is important to provide fast and sufficient analgesia. Clinical trials have demonstrated that bisphosphonates reduce effectively and sustained bone pain by approved standard dosage over time. Open label prospective trials have shown that short time high dose i.v. Ibandronate is effective in rapid pain relief in different primary tumors. Patients and methods: In 33 patients with metastatic bone pain from newly diagnosed skeletal metastases we utilized the loading-dose concept for intravenous ibandronate (6 mg infused over 1 h on 3 consecutive days). Results: In 33 patients loading-dose ibandronate therapy significantly reduced bone pain within the first 5–7 days (VAS day 0: 6–8 vs. day 7: 3–4). Only 3 patients showed no response concerning a distinct pain reduction within the first days of therapy. There was no increase in pain medication. Conclusion: This clinical observational study in selected patients with severe metastatic bone pain undergoing an intensive high dosed ibandronate-therapy for a short period demonstrated that loading-dose ibandronate (6 mg i.v., 3 consecutive days) resulted in a reduction of pain within days.