Use Of Bisphosphonates Research Articles

Prevalence, outcomes, and complications of vitamin D deficiency among patients with multiple myeloma: Nationwide burden of disease.

Multiple myeloma (MM), constituting 10% of hematological malignancies, poses significant morbidity and mortality, especially with skeletal involvement. Bisphosphonate use in MM may lead to severe hypocalcemia due to vitamin D deficiency (VDD), exacerbating bone-marrow plasma cell burden. We aimed to assess VDD prevalence and its impact on outcomes in MM patients. A retrospective cross-sectional analysis (2008-2018) of nationwide inpatient data identified adult MM hospitalizations with VDD using ICD-10-CM codes. Univariate and multivariate analyses were conducted to evaluate prevalence, demographics, and outcomes, with significance set at p < 0.05. Among 330,175 MM hospitalizations, 3.48% had VDD. VDD was more prevalent among 50-75 year olds (61.72% vs 59.74%), females (53.36% vs 44.34%), Blacks (23.34% vs 22.94%), Whites (65.84% vs 65.79%), higher income brackets (26.13% vs 23.85%), and those with comorbidities like hypertension (71.12% vs 69.89%), dyslipidemia (42.47% vs 34.98%), obesity (13.63% vs 10.19%), and alcohol abuse (1.61% vs 1.34%). In regression analysis, VDD in MM patients correlated with higher morbidity (adjusted odds ratio (aOR): 1.24, 95% confidence interval (95% CI): 1.14-1.36) and major disability (aOR: 1.26, 95% CI: 1.20-1.30). MM patients with VDD exhibit worse outcomes, underscoring the importance of recognizing and managing VDD promptly. Further prospective studies are needed to validate our findings and explore the impact of vitamin D supplementation on MM patient outcomes.

Some features of osteogenesis in ankylosing spondylitis and the possibilities of treatment with bisphosphonates

Despite the high efficacy of currently available targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) and biologic DMARDs (bDMARDs), approximately 40 % of patients with ankylosing spondylitis (AS) fail to achieve treatment goals according to clinical, laboratory and imaging tests. In addition, comorbidities in AS, which require an integrated approach involving different specialists, may limit the use of such therapy. In view of the above, as well as the peculiarities of bone metabolism in AS, new therapeutic approaches for this disease have recently been sought, one of which is the use of bisphosphonates. This article discusses some aspects of bone metabolism and unconventional therapeutic options – the use of bisphosphonates in AS complicated by severe comorbidities, in patients with insufficient efficacy of bDMARDs and/or DMARDs.

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

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

Assessment and management of fracture risk in men with prostate cancer taking androgen deprivation therapy: a retrospective observational primary care database study.

Prostate Cancer (PCa) is the commonest cancer in the UK. Androgen deprivation therapy (ADT) is a mainstay of treatment. It increases fragility fractures causing a huge burden to patients and the NHS. As men live longer with PCa, many require prolonged ADT. Reducing fracture risks and improving cancer survivorship is becoming increasingly important. Primary care plays an important role. To evaluate how fracture risk of PCa patients taking ADT (PCa-ADT) was assessed and managed in primary care. A retrospective multi-practice database study. PCa patients were identified using SNOMED codes from five sociodemographically diverse practices (registered population 49 400). Data were extracted by hand-searching records, including hospital letters, and included: demographics; a 10-year fragility fracture score (FRAX); NOGG intervention threshold; DEXA requests; and use of bisphosphonates. Of the 261 PCa patients identified, 6% were Black African/Caribbean and 89% White British. Half had been prescribed ADT, 28% being current users. No fracture risk assessment was documented for any patients. ADT current users had significantly increased FRAX scores for both major osteoporotic fractures (MOF) (9.61%±1.12%) and hip fracture (HF) (5.30%±1.02%) compared with PCa patients without ADT (7.08%±0.57% [MOF] and 3.06%±0.46% [HF], P<0.001). For ADT current users, 39% showed intermediate fracture risk (NOGG amber), warranting a DEXA scan, with only 30% performed. Patients in more affluent areas received more DEXA scans and bisphosphonate treatment. Osteoporosis is underdiagnosed and undertreated in men with PCa-ADT, especially in those with deprived backgrounds. There is an unmet need to manage the fracture prevention in this population.

#2536 Bisphosphonates as a tacrolimus-sparing strategy in kidney transplantation: insights from a retrospective analysis

Abstract Background and Aims The chronic toxicity of tacrolimus makes its sparing a crucial consideration for kidney transplant recipients (KTRs). Previous research has indicated a positive association between bisphosphonate use and favorable graft outcomes in KTRs. Therefore, our study aimed to investigate whether bisphosphonate use impacts the relationship between tacrolimus trough levels (TTLs) and graft outcomes in KTRs. Method We conducted a retrospective study encompassing 1,657 KTRs who were administered tacrolimus-based immunosuppressive therapy. The primary exposure was characterized by a time-dependent cross-product of TTLs (low TTLs vs. normal-high TTLs with a reference of 6 ng/mL) and the use of bisphosphonate. The study had two primary outcomes: (1) overall graft loss, defined as either the occurrence of patient death or conversion to kidney replacement therapy, and (2) reaching an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73 m². Results Over a cumulative total of 11,211.8 person-years, overall graft loss were observed in 183 patients, equating to 11.0% of the cohort. In multivariable Cox regression analysis, it was noted that normal to high TTLs, in the absence of bisphosphonate use, were associated with a reduced risk of overall graft loss (HR, 0.61; 95% CI, 0.43-0.87) compared to low TTLs without bisphosphonate use. The use of bisphosphonate in conjunction with normal to high TTLs correlated with an even further diminished risk of overall graft loss (HR, 0.36; 95% CI, 0.16-0.83) in comparison to low TTLs without bisphosphonate use. In low TTLs, the administration of bisphosphonates was associated with a reduced risk of overall graft loss than bisphosphonate non-use (HR, 0.26; 95% CI, 0.14-0.49). Similarly, this trend was observed in cases where the eGFR was below 30 ml/min/1.73 m². Conclusion The use of bisphosphonate was associated with favorable graft outcomes, even with a low TTLs. Incorporating bisphosphonate to a conventional immunosuppressant regimen Could potentially reduce tacrolimus requirement.

Equivalence in osteoporosis workup and management after femoral neck fracture fixation and vertebral compression fracture cement augmentation: A single-center retrospective study highlighting persistent underdiagnosis and undertreatment

BackgroundThe purpose of this study was to evaluate pre- and post-fracture medical management of osteoporosis among patients who underwent surgical fixation of femoral neck fractures (FNF) and vertebral compression fractures (VCF), and to investigate if there is a difference in treatment, management, and subsequent fractures between FNF and VCF patients. MethodsPatients who underwent surgical fixation of FNF or VCF were retrospectively reviewed at a minimum 1 year follow up. Patients were excluded if their fracture was caused by high energy trauma or malignancy, <50 years-old, deceased, or lost to follow up. Patient demographics such as age, sex, BMI, American Society of Anesthesiology Physical Status Classification System and Charleston Comorbidity index were recorded. Management of osteoporosis, including medication regimen and dual-energy X-ray absorptiometry (DEXA) scans were assessed preoperatively and at minimum one year follow up. Subsequent fractures were also recorded. ResultsIn the analysis of 370 patients (74.7% FNF, 25.2% VCF), demographics showed a predominantly female population (mean age 78.1). Preoperatively, 21.6% were diagnosed with osteoporosis, consistent between FNF and VCF. Postoperatively, there were no significant differences in new osteoporosis diagnoses, bisphosphonate use, or subsequent fractures. VCF patients, however, were more likely to receive denosumab and post-operative DEXA scans (p < 0.05). Within a year, 6.2% experienced subsequent fractures, with no significant FNF-VCF difference. Only 12.7% received appropriate post-operative osteoporosis treatment, 27.1% had DEXA scans, and 25% had a recorded osteoporosis diagnosis. Multivariable analysis highlighted pre-fracture osteoporosis diagnosis as the sole predictor for post-operative DEXA scans and anti-osteoporotic medication (p < 0.001). ConclusionsThis study suggests that factors beyond the type of fragility fracture may influence subsequent fracture risk and anti-osteoporotic medication administration in elderly patients. These findings underscore the importance of a comprehensive approach to fracture risk assessment and treatment decisions in this population. Level of evidenceIII.

Does the use of bisphosphonates during pregnancy affect fetal outcomes? A systematic review.

This systematic review aimed to determine the effects of maternal exposure to bisphosphonates (BPs) during pregnancy on neonatal outcomes. It aimed to disclosfe the impact of BPs on neonates and identify aspects that require further investigation. A comprehensive search of PubMed, Science Direct, LILACS, EMBASE, and Web of Science was conducted until August 2022, with no time restrictions. The selection criteria included studies published in English that evaluated pregnant women who were exposed to BPs. From an initial pool of 2169 studies, 13 met the inclusion criteria for this systematic review. These studies collectively included 106 women (108 pregnancies) who were exposed to BPs either before orduring pregnancy. A summary of the key characteristics of the selected studies and the risk of bias assessment are provided. Exposure to BPs occurs at various stages of pregnancy, with different indications for BP treatment. The most frequently reported neonatal outcomes were spontaneous abortion, congenital malformations, hypocalcemia, preterm birth, and low birth weight. Although previous reports have linked BPs before or during pregnancy with adverse neonatal outcomes, these associations should be interpreted with caution. Given the complexity of these findings, further research is necessary to provide more definitive insights to guide clinical decisions regarding the use of BPs in pregnant women.

Beta-adrenergic receptor antagonist propranolol prevents bisphosphonate-related osteonecrosis of the jaw by promoting osteogenesis

Background/purposeBisphosphonate-related osteonecrosis of the jaw (BRONJ), a complication arising from the use of bisphosphonates (BPs), inflicts long-term suffering on patients. Currently, there is still a lack of effective treatments. This study aimed to explore the preventive effects of propranolol (PRO) on BRONJ in vitro and in vivo, given PRO's potential in bone health enhancement. Materials and methodsIn vitro, effect of PRO on zoledronic acid (ZA)-pretreated bone marrow mesenchymal stem cells (BMSCs) was detected by cell counting kit-8, alkaline phosphatase (ALP) staining, alizarin red staining, real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. In vivo, forty mice were divided into four groups: control, ZA, PRO, and ZA-PRO. The maxillary extraction sockets sides were analyzed with micro-CT and histomorphometry. Hematoxylin-eosin (H&E), Masson staining, immunofluorescence staining of ALP, bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (RUNX2) and TUNEL staining were performed. ResultsPRO increased proliferation and osteogenic differentiation of BMSCs. PRO stimulated bone formation and facilitated the healing process in zoledronic acid-induced osteonecrosis of jaw in mouse model. Compared with ZA group, control and PRO group showed more BMP2+, RUNX2+, and ALP+ cells (P < 0.05). However, PRO rescued the decreased expression of ALP, RUNX2, BMP2 due to ZA and decreased the expression of TUNEL (P < 0.05). ConclusionThe findings suggest that propranolol may offer a promising preventive strategy against BRONJ by enhancing bone regeneration. This research contributes to the understanding of the pathogenesis of BRONJ and opens avenues for potential treatments of BRONJ focusing on β-adrenergic signaling.

Atypical Metatarsal Fractures: Report of Five Clinical Cases.

Atypical fractures are well elucidated when they occur in the femur and are related to the use of bisphosphonates. Prolonged therapy with this drug leads to excessive suppression of bone remodeling, which makes the bone more brittle. In general, they are caused by minimal trauma or are atraumatic. This type of fracture is also reported in other bony sites, such as the metatarsus. Some reports and studies on atypical metatarsal fractures have been published, but further investigations are required to better understand this type of fracture and establish the proper diagnosis, treatment and conduct. The present study is a report of five cases of patients who presented metatarsal fractures during therapy with bisphosphonates. All patients were female, had osteoporosis as a preexisting disease, were taking bisphosphonates, presented fractures that were either atraumatic or caused by minimal trauma, and the imaging examination showed a transverse meta-diaphyseal fracture of the fifth metatarsal shaft with thickening of the lateral cortex, image characteristics similar to the criteria used by the American Society for Bone and Mineral Research (ASMBR) to define atypical femur fractures.

Effect of Oral Bisphosphonate Drug Holiday on Mortality Following Hip Fracture.

Current clinical guidelines recommend a drug holiday after extended use of oral bisphosphonates. However, no studies have investigated the effect of drug holidays before hip fractures on postfracture mortality. This work aimed to investigate the effect of a drug holiday on postfracture mortality in patients with extended use of oral bisphosphonates. This retrospective, population-based cohort study took place among all patients with hip fractures in Victoria, Australia, from 2014 to 2018. Patients were adherent to oral alendronate or risedronate for 5 years or more prior to hip fracture. Group-based trajectory modeling categorized patients into different bisphosphonate usage after 5-year good adherence. The main outcome measure was postfracture mortality. We identified 365 patients with good adherence (medication possession ratio ≥80%) to oral alendronate/risedronate for 5 years or more. Most patients (69%) continued to use oral bisphosphonates until admission for hip fracture; 17% had discontinued for 1 year and 14% had discontinued for 2 years. Postfracture mortality was higher in patients who had discontinued risedronate for 1 year (hazard ratio [HR] 2.37; 95% CI, 1.24-4.53) and 2 years (HR 3.08; 95% CI, 1.48-6.41) prior to hip fracture. No increase or decrease in postfracture mortality was observed in patients who had discontinued alendronate for 1 year (HR 0.59; 95% CI, 0.29-1.18) or 2 years (HR 1.05; 95% CI, 0.57-1.93) prior to hip fracture. Postfracture mortality is higher in people who discontinue risedronate, but not alendronate, for 1 or 2 years after being adherent to treatment for at least 5 years. The type of bisphosphonate may be a factor to consider when planning drug holidays.

Long-term therapy with bisphosphonates: review of clinical studies

The purpose of this scientific literature review was to examine clinical recommendations for the duration of bisphosphonate therapy in patients with osteoporosis who have experienced osteoporotic fractures if they remain at high risk after 3–5 years of taking them. An electronic search of electronic databases was conducted, as well as a hand search of journals. A total of 94 publications were examined. 17 publications were included in the review. We concluded that patients who stopped taking bisphosphonates had a 20–40% higher risk of new clinical fractures and nearly twice the risk of vertebral fractures compared with the treatment period, indicating that a drug holiday is recommended not for all patients receiving therapy. However, long-term therapy with alendronate and zoledronic acid has been shown to reduce the risk of fractures in women with osteoporosis. The persistent increase in spinal bone mineral density with long-term bisphosphonate use may explain the lower incidence of vertebral fractures in patients on therapy long-term compared with patients who discontinued therapy after 3 years.

Hip &amp; Pelvis

The April 2024 Hip &amp; Pelvis Roundup360 looks at: Impaction bone grafting for femoral revision hip arthroplasty with the Exeter stem; Effect of preoperative corticosteroids on postoperative glucose control in total joint replacement; Tranexamic acid in patients with a history of venous thromboembolism; Bisphosphonate use may be associated with an increased risk of periprosthetic hip fracture; A balanced approach: exploring the impact of surgical techniques on hip arthroplasty outcomes; A leap forward in hip arthroplasty: dual-mobility bearings reduce groin pain; A new perspective on complications: the link between blood glucose and joint infection risks.

Long-term bisphosphonates use and atypical femoral fracture

Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration, increasing the risk of fractures. As the global incidence of osteoporosis rises, it has become a pressing concern for healthcare professionals. Long-term use of bisphosphonates (BPs), commonly prescribed for osteoporosis, has been associated with atypical femur fractures (AFFs). While AFFs are relatively rare, they are a serious concern due to their potential complications.

Impact of Osteoporosis on Autogenous Bone Graft Resorption

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

Is there an advantage to delayed molar implant placement in those with chronic apical periodontitis?

This paper is a single-centre, double-blinded, prospective randomised control trial, comparing immediate vs delayed implant placement clinically and radiographically in patients with chronic periodontitis, specifically assessing the molar region. Seventy-four patients were recruited to the study over a one-year period, all of whom returned for follow up throughout the study. The study adhered to the principles outlined in the Declaration of Helsinki and obtained ethical approval from the affiliated University Hospital of Qingdao. Written consent was gained from patients in line with the CONSORT guidance. The patients were recruited from the Department of Oral and Maxillofacial Surgery at the University of Qingdao between January 2019 and January 2020. The study included anyone above the age of 18, who had a molar with chronic apical periodontitis and lesions of less than 8 mm. Exclusions included pregnancy, uncontrolled diabetes, smokers, bisphosphonate use, history of head/neck tumours, coagulation disorders, and acute infections of adjacent teeth/tissue. Of the patients who met the inclusion criteria, all were randomly numbered by a stomatologist and placed into either the control group or the experimental group by a computerised system (Microsoft Excel). This study looked at the placement of 74 implants in 74 patients, including 40 female and 34 malepatients in total. The delayed implant placement allowed for healing of 3 months in the mandible and 6 months in the maxilla. The width of the implants placed was 6 mm and the lengths were between 7 mm and 12 mm.The periodontal probing depth, modified sulcus bleeding index, andmodified plaque index were all clinically examined. In terms of other parameters assessed, CBCT was used to look at alveolar bone mass. All surgery and implant placement was carried out by the same surgeon and the clinical measurements were all taken by one dentist. The results showed no significant difference in implant stability quotient immediately and 6 months post-surgery (0.110 and 0.066, respectively), when comparing the experimental and control group. Similarly, there was no significant difference in PD, mSBI or mPI between the groups. On assessment of CBCT scans however there was a significant difference between the two groups in the buccal horizontal marginal bone loss (P = 0.003), lingually there was not. Vertical bone loss also showed no significant difference in comparison. At one-year post-implant placement, there was a survival rate of 100% in both groups assessed. IBM SPSS statistics was used for statistical analysis. Multiple tests including the Shapirowilk test, the student t-test and the Mann-Whitney U-test were carried out on the data and all statistical tests were two tailed. Statistical significance was set at <0.05 throughout study of results. The conclusion of this study suggests that immediate implant placement in chronic periodontitis patients, specifically in the molar region, may be clinically viable. With flap surgery and complete removal of inflammatory granulation tissue, the study suggests no significant disadvantage to alveolar bone healing or osseointegration. The various limiting factors of this study should be taken into consideration, and it must be highlighted that longer and larger studies are necessary to allow for more accurate understanding of the long-term outcomes.

Abstract 4207: Zoledronic acid reduces quiescent bone-disseminated human ER+ breast cancer tumor cell burden and estrogen-responsiveness in a pre-clinical model

Abstract Unique to early-stage ER+ breast cancer, ER+ tumor cells already bone disseminated at time of diagnosis can remain dormant at this site until an initiating event (e.g., activating ESR1 mutation acquisition) allows for osteolytic bone metastases (BMET) progression even decades later. Adjuvant use of anti-resorptive bisphosphonates, but not denosumab, reduces BMET risk in post-menopausal women with early stage breast cancer, suggesting protective effects may be unrelated to changes in bone turnover. Pre-clinical modeling of dormant, bone-disseminated ER+ breast cancer cells may enhance our understanding and thus our ability to better target these inherently treatment-resistant cells. In studies reported here, a model of bone-disseminated ER+ dormancy was characterized and used to query effects of zoledronic acid (ZA) on dormant cells. When female nude mice were inoculated (intracardiac) with human ER+ MCF-7 cells labelled with DiD, a membrane dye that dissipates with each cell division, DiD-positive tumor cell number in harvested tibial bone marrow remained unchanged from 24 hours to 28 days post-tumor cell inoculation. When 17ß-estradiol (E2) treatment (0.72 mg 60-day pellets) was initiated on D28 following tumor cell inoculation, detectable DiD+ tumor cell number in harvested tibial bone marrow increased 1.8-fold within one week (D35 vs. D28, p &amp;lt; 0.0001), consistent with initiation of E2-stimulated proliferation, and osteolytic, histology-confirmed BMET appeared subsequently with 60% incidence by 6-weeks post-start of E2 treatment. When mice were instead zoledronic acid-treated during the 28d dormancy period (70 ug/kg subcutaneously on D7 and on D21 post-inoculation), DiD-positive cell number in marrow harvested on D28 was reduced by more than half vs. vehicle-treated controls (p&amp;lt; 0.05). Moreover, DiD-positive cell numbers on D35, one week after start of E2-treatment, remained unchanged in tibial marrow of ZA-treated mice and were thus substantially (3.8-fold) lower than controls (p&amp;lt; 0.001). When followed for 6-weeks after initiation of E2 treatment, no osteolytic BMET were detected in ZA-treated mice. In toto, these results recapitulate clinical findings, thus validating the methodologic approach, and suggest that in addition to reducing dormant ER+ tumor cell burden in bone, bisphosphonates may also alter their estrogen responsiveness. Acknowledgements: Special thanks to undergraduates Alyssa Magee and Geethika Ameneni for assistance with data acquisition, and the METAvivor Foundation and NIH-NCI (NCI R03 CA181893, R01 CA174926, P30 CA023074, T32 CA009213) for financial support. Citation Format: Julia N. Cheng, Jennifer B. Frye, Susan A. Whitman, Janet L. Funk. Zoledronic acid reduces quiescent bone-disseminated human ER+ breast cancer tumor cell burden and estrogen-responsiveness in a pre-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4207.

Current vision on mechanism of action of bisphosphonates. The effect of long-term administration of bisphosphonates on bone tissue (preclinical studies)

Osteoporosis (OP) is one of the common chronic diseases in the elderly, which requires long–term therapy. Bisphosphonates (BP) belong to the first-line choice medications for the treatment of OP, however, prolonged period of bisphosphonates use has been associated with increased risk of atypical femoral fractures (AFFs), medication-related osteonecrosis of the jaw (MRONJ) and the impact on fracture healing, which attracts increased attention to the current widespread use of them.The article presents the existing classes of BP according to their chemical structure and mechanism of action, differences in their antiresorptive potencies. The data of studies on animal models on the effect of BP on the mechanical properties of bone, fracture repair, as well as the development of MRONJ are presented.

Postoperative Bisphosphonates Use is Associated with Reduced Adverse Outcomes After Primary Total Joint Arthroplasty of Hip and Knee: A Nationwide Population-Based Cohort Study.

Bisphosphonates have been associated with a decreased risk of revision surgery after total joint arthroplasty of the hip or knee (TJA) because of their effects on decreased periprosthetic bone loss and prosthetic migration. However, the results in the early literature are inconsistent, and the influence of bisphosphonates on associated complications and subsequent TJA remains unknown. This study investigated the association between the use of bisphosphonates and the risk of adverse outcomes after primary TJA. This matched cohort study utilized the National Health Insurance Research Database in Taiwan to identify patients who underwent primary TJA over a 15-year period (January 2000-December 2015 inclusive). Study participants were further categorized into two groups, bisphosphonate users and nonusers, using propensity score matching. The Kaplan-Meier curve analysis and adjusted hazard ratios (aHRs) of revision surgery, adverse outcomes of primary surgery and subsequent TJA were calculated using Cox regression analysis. This study analyzed data from 6485 patients who underwent total hip arthroplasty (THA) and 20,920 patients who underwent total knee arthroplasty (TKA). The risk of revision hip and knee arthroplasty was significantly lower in the bisphosphonate users than in the nonusers (aHR, 0.54 and 0.53, respectively). Furthermore, the risk of a subsequent total joint arthroplasty, adverse events and all-cause mortality were also significantly reduced in the bisphosphonate users. This study, involving a large cohort of patients who underwent primary arthroplasties, revealed that bisphosphonate treatment may potentially reduce the risk of revision surgery and associated adverse outcomes. Furthermore, the use of bisphosphonates after TJA is also associated with a reduced need for subsequent arthroplasty.Research Registration Unique Identifying Number (UIN): ClinicalTrials.gov Identifier-NCT05623540 ( https://clinicaltrials.gov/show/NCT05623540 ).

Bone pattern changes in post liver transplant patients using bisphosphonates.

To identify radiographic findings suggestive of drug-induced osteonecrosis and evaluate radiomorphometric patterns indicative of changes in bone mineral density in individuals transplanted for liver disorders using bisphosphonates. The study group included panoramic x-rays of liver transplant patients who are being monitored and who present a clinical status of osteoporosis and use bisphosphonates. The control group was made up of liver transplant patients who did not have osteoporosis. On panoramic radiographs, mental index (MI) and mandibular cortical index (MCI) and the presence of radiographic anomalies suggestive of osteonecrosis were evaluated. There were significant statistical results when comparing the groups in relation to the decrease in bone mineral density (BMD) with MCI-C3 (p=0.036), however, there were none in relation to MI (p=0.14). There were no valid statistical results when relating MCI (p=0.94) and MI (p=0.66) with reduced BMD and use of bisphosphonates. Liver transplant individuals using bisphosphonates present greater radiographic signs of bone sclerosis suggestive of a greater propensity to develop osteonecrosis of the jaw and an increased risk of presenting changes suggestive of reduced bone mineral density on panoramic radiographs when compared to liver transplant individuals not using bisphosphonates.

Treatment of Bisphosphonate-related Osteonecrosis of Jaw (BRONJ) in Rabbit Model: A Proof-of-concept Animal Study Comparing Angiogenesis Factor Versus Autologous Bone Marrow-derived Osteoblasts (ABMDO)

Objective We created Bisphosphonate-related Osteonecrosis of Jaw (BRONJ) in rabbits and treated them with an angiogenesis factor or autologous bone marrow derived osteoblasts (ABMDO) to assess the efficacy of the treatment by Micro-computerized Tomography (M-CT) and histopathology. Materials and Methods Thirty female New Zealand rabbits were procured and were divided into three groups of 10 animals each. The number of animals to achieve statistical significance was based on the reported studies. Group I was control group (C), Group II was Osteoblast group (O), and Group III was angiogenesis group (P). In all Groups, BRONJ was produced. At 8 weeks of tooth extraction, BRONJ was confirmed histologically and radiologically in two rabbits from each group of animals. Group I received 0.5 of normal saline, Group II received a single dose of 5 million osteoblasts suspended in 0.5 ml, and Group III received 5 mg of angiogenesis factor thrice weekly for three weeks. The healing of BRONJ was assessed using M-CT and histopathology. Results In O and P groups, the extraction sockets healed and closed with normal-looking tissue, whereas in the C (control) group, suppuration with an area of necrosis was observed. Micro-CT analysis of socket revealed an exaggeration on non-mineralized soft tissue volume in the C group, whereas most of the bone promotion parameters were improved in the O and P groups with statistical difference (P&lt;0.001) for the parameters bone volume, bone surface area, trabecular number and trabecular thickness. Histologically, the element of healing was represented by reactive bone formation and fibrosis, which were more prominent in groups O and P as compared to the control group. Conclusion Our study shows that ABMDO and angiogenesis factor have a robust potential to heal BRONJ. Clinical Relevance The study shows angiogenesis factor and osteoblasts heals BRONJ and warrant sincere human trials to tackle this unrelenting complication of bisphosphonates use.