Etiopatogenia e tratamento da osteonecrose dos maxilares induzida por medicamentos: aspectos essenciais ao dentista / Etiopathogenesis and treatment of medication-related osteonecrosis of the jaw: essential aspects for the dentist

A osteonecrose dos maxilares induzida por medicamentos (MRONJ) caracteriza-se por exposição óssea ou osso que pode ser sondado através de fístula intra ou extraoral, em região maxilofacial, e que não cicatriza dentro de oito semanas. A MRONJ é uma condição rara e debilitante que pode causar dor, disfagia e odor desagradável na cavidade oral, afetando pacientes com histórico ou sob uso contínuo de terapia antirreabsortiva, isolada ou associada a imunomoduladores ou drogas antiangiogênicas, mas sem histórico de radioterapia nos maxilares. O objetivo desta revisão narrativa de literatura é compilar os principais aspectos sobre a etiopatogenia da MRONJ e as opções terapêuticas disponíveis. A etiologia da MRONJ é multifatorial, complexa, e não está totalmente compreendida, não havendo um tratamento definitivo, mas diversas modalidades terapêuticas que visam o controle da dor e da progressão da osteonecrose. Conclui-se com essa revisão que o entendimento da etiopatogenia da MRONJ pelo cirurgião-dentista lhe permite adotar medidas preventivas, bem como o conhecimento das modalidades terapêuticas disponíveis lhe possibilita oferecer o manejo adequado para seu paciente, conforme o estágio da doença.

Medication-related osteonecrosis of the jaw (MRONJ) is characterized by exposed bone or bone that can be probed through an intra or extraoral fistula, in the maxillofacial region, which does not heal within eight weeks. MRONJ is a rare and debilitating condition that can cause pain, dysphagia and unpleasant odor in the oral cavity, affecting patients with a history or continuous use of antiresorptive therapy, alone or associated with immunomodulators or antiangiogenic drugs, but without a history of radiotherapy to the jaws. The aim of this narrative literature review is to compile the main aspects about the etiopathogenesis of MRONJ and the available therapeutic options. The etiology of MRONJ is multifactorial, complex, and is not fully understood, with no definitive treatment, but several therapeutic modalities that aim to control pain and the progression of osteonecrosis. It is concluded from this review that the understanding of the etiopathogenesis of MRONJ by the dental surgeon allows him to adopt preventive measures, as well as the knowledge of the therapeutic modalities available allows him to offer the appropriate management for his patient, depending on the stage of the disease.

Lipophilic bisphosphonates reduced cyst burden and ameliorated hyperactivity of mice chronically infected with Toxoplasma gondii.

The current treatments for toxoplasmosis are only active against fast-growing tachyzoites, present in acute infections, with little effect on slow-growing bradyzoites within tissue cysts, present in latent chronic infections. The mitochondrion of Toxoplasma gondii is essential for its survival, and one of the major anti-parasitic drugs, atovaquone, inhibits the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase site. Coenzyme Q (also known as ubiquinone [UQ]) consists of a quinone head and a lipophilic, isoprenoid tail that anchors UQ to membranes. The synthesis of the isoprenoid unit is essential for cell growth and is inhibited by lipophilic bisphosphonates, which inhibit the parasite growth. In this work, we investigated the effect of lipophilic bisphosphonates on the chronic stages of T. gondii. We discovered that three lipophilic bisphosphonates (BPH-1218, BPH-1236, and BPH-1238), effective for the acute infection, were also effective in controlling the development of chronic stages. We showed effectiveness by testing them against in vitro cysts and in vivo derived tissue cysts and, most importantly, these compounds reduced the cyst burden in the brains of chronically infected mice. We monitored the activity of infected mice non-invasively and continuously with a novel device termed the CageDot. A decrease in activity accompanied the acute phase, but mice recovered to normal activity and showed signs of hyperactivity when the chronic infection was established. Moreover, treatment with atovaquone or BPH-1218 ameliorated the hyperactivity observed during the chronic infection.IMPORTANCETreatment for toxoplasmosis is challenged by a lack of effective drugs to eradicate the chronic stages. Most of the drugs currently used are poorly distributed to the central nervous system, and they trigger allergic reactions in a large number of patients. There is a compelling need for safe and effective treatments for toxoplasmosis. Bisphosphonates (BPs) are analogs of inorganic pyrophosphate and are used for the treatment of bone disorders. BPs target the isoprenoid pathway and are effective against several experimental parasitic infections. Some lipophilic BPs can specifically inhibit the mitochondrial activity of Toxoplasma gondii by interfering with the mechanism by which ubiquinone is inserted into the inner mitochondrial membrane. In this work, we present the effect of three lipophilic BPs against T. gondii chronic stages. We also present a new strategy for the monitoring of animal activity during disease and treatment that is non-invasive and continuous.

Idiopathic Juvenile Osteoporosis: A Case Report and Literature Review.

This case report describes the rare occurrence of idiopathic juvenile osteoporosis (IJO) in an 11-year-old boy with bone fragility and fractures, particularly in the thoracic and lumbar vertebrae. After excluding discernible underlying causes, the diagnosis was confirmed using clinical and radiological assessments. Treatment commenced with oral bisphosphonates, leading to notable bone mineral density (BMD) improvements and the absence of subsequent fractures. IJO presents diagnostic challenges owing to its multifaceted nature, necessitating the exclusion of other common causes of pediatric osteoporosis. Although the pathophysiology of IJO remains poorly understood, this case underscores the potential efficacy of bisphosphonate therapy in managing the condition and improving patient outcomes. Notably, the patient's symptoms ameliorated as puberty commenced, aligning with the typical IJO patterns reported in the literature. Although the long-term impact of bisphosphonate treatment in pediatric IJO cases warrants further investigation, this case exemplifies the potential to enhance the quality of life of affected individuals.

Imaging aspects of maxillomandibular bone alterations in patients with multiple myeloma treated with bisphosphonates: A systematic review.

Purpose: Multiple myeloma (MM) is a rare cancer that is typically managed with bisphosphonates to slow bone resorption and prevent skeletal complications. This study aimed to identify imaging patterns in MM patients receiving bisphosphonate therapy. Materials and Methods: This systematic review included studies investigating maxillomandibular bone alterations based on imaging examinations in MM patients treated with bisphosphonates. The selected studies were qualitatively assessed using the Critical Appraisal Tools from SUMARI. Results: Six studies, involving 669 MM patients, were included, with 447 receiving bisphosphonate treatment. The majority were treated with pamidronate, zoledronate, or a combination of both. Seventy patients developed medication-related osteonecrosis of the jaw (MRONJ), predominantly in the mandible, characterized by the presence of bony sequestrum, bone sclerosis, increased periodontal ligament space, osteolytic lesions, and osteomyelitis as observed in imaging analyses. For non-MRONJ lesions, the mandible also exhibited the highest frequency of asymptomatic bone alterations. These ranged from "punched-out" osteolytic lesions or "soap bubble" lesions to solitary bone lesions, areas of bone sclerosis, abnormalities of the hard palate, osteoporosis, non-healed alveoli, and cortical bone rupture. Conclusion: MM patients treated with bisphosphonates display radiographic patterns of maxillomandibular bone lesions. These patterns aid in diagnosis and facilitate early and targeted treatment, thereby contributing to improved morbidity outcomes for these patients.

Bilateral lumbar pedicle fracture in a patient receiving long-term bisphosphonate therapy: a case report with pathological evaluation.

BACKGROUND: Bilateral pedicle fractures of the lumbar spine are uncommon and are typically associated with strenuous activities, traumatic events, or previous spinal surgery. This study reported a case of bilateral pedicle fracture in a patient with a long history of osteoporosis treatment with bisphosphonate and included a histological evaluation of the bone. CASE PRESENTATION: An 82-year-old woman with no history of trauma presented to our hospital with back pain that had worsened over the previous month. Computed tomography and magnetic resonance imaging revealed bilateral pedicle fractures of the third lumbar vertebra. She had osteoporosis and had been taking bisphosphonates for 9 years. The patient underwent posterior lumbar fusion, and her symptoms improved. Bone biopsy results from the spinous process revealed few osteoblasts and an absence of osteoclasts, indicating low bone turnover. CONCLUSIONS: Long-term use of bisphosphonates may contribute to the development of atypical bilateral pedicle fractures in patients with osteoporosis.

Diagnosis and Management of Atypical Femoral Fractures and Medication-Related Osteonecrosis of the Jaw in Patients with Osteoporosis.

Anti-osteoporosis treatments reduce fracture risk but maybe associated with rare adverse events with long-term use such as atypical femoral fractures (AFFs) and medication-related osteonecrosis of the jaw (MRONJ). AFFs are rare but more likely with prolonged bisphosphonate use, whereas MRONJ incidence is higher in cancer patients on high-dose antiresorptive therapy. Following diagnosis, effective treatment options are available to manage both of these rare complications. An individualized treatment approach is advised with close monitoring.

Long-term administration of alendronate sodium caused an atypical femoral shaft fracture in a 36-year-old woman: a case report and literature review.

Long-term bisphosphonate therapy is associated with atypical or insufficiency fractures, particularly in the proximal femur. We observed a case of an atypical femoral shaft fracture in a patient with a long-term history of alendronate therapy. A 36-year-old woman was admitted with a complaint of pain in her right mid-thigh following low-energy trauma. She had been taking alendronate for more than 15 years. X-rays indicated a fracture of the right femoral shaft. The patient was treated with proximal femoral nail antirotation (PFNA) fixation. This case highlights concerns regarding long-term bisphosphonate therapy and its potential complications.

Concurrent Oral Squamous Cell Carcinoma and Bisphosphonate-Related Osteonecrosis of the Maxilla: A Case Report and Literature Review.

INTRODUCTION: Bisphosphonates (BPs) are widely used for osteoporosis and cancer-induced bone diseases due to their antiresorptive properties, yet they pose risks such as medication-related osteonecrosis of the jaw (MRONJ). METHODS: We present a unique case of concurrent oral squamous cell carcinoma (SCC) and MRONJ in a 72-year-old female chronically treated with oral ibandronate for osteoporosis. Following a dental extraction, she developed a nonhealing wound in the maxilla. Following conservative treatment, the patient underwent a maxillectomy and extensive tissue reconstructions to control her infection and address suspicions of an underlying malignancy. RESULTS: Histopathological examinations confirmed simultaneous osteonecrosis and well-differentiated SCC in the maxillary sinus and surrounding tissues. Despite multiple surgeries, the patient's disease progressed rapidly. Upon examining the literature for patients with a history of BP use diagnosed with MRONJ and/or SCC, a total of 16 cases report a diagnostic dilemma between MRONJ and locoregional SCC. Three of the 16 cases report a final diagnosis of concurrent MRONJ and SCC. This report is the fourth reported case of concurrency to date. CONCLUSIONS: The patient's complex clinical course underscores the diagnostic challenges and therapeutic dilemmas in managing concurrent MRONJ and SCC, highlighting the need for vigilant monitoring and interdisciplinary collaboration in similar cases.

Multiple Stress Fractures in a Young Cancer Patient on Long-Term Zoledronic Acid: A Case Report and Review of Literature.

Bisphosphonates are commonly used in the treatment of osteoporosis and metastatic cancer patients with bone complications. Stress fractures are a well-known complication of long-term bisphosphonate treatment. Cancer patients receive much higher cumulative doses of bisphosphonates than osteoporotic patients and are subject to a higher risk of bisphosphonate-associated stress fractures. While there is an increasing number of reports of bisphosphonate-associated atypical femoral fractures (AFFs) and non-femoral stress fractures in osteoporotic patients, reports of such fractures in cancer patients are much rarer, especially non-femoral stress fractures. We present the first case report of an atypical subtrochanteric femur fracture following a sequential bilateral Jones fracture in a young non-osteoporotic patient with metastatic breast cancer after 12 years of zoledronic therapy. She sustained a left Jones fracture after seven years of zoledronic acid therapy and a right Jones fracture after 11 years of zoledronic acid therapy. She continued receiving regular zoledronic acid after these stress fractures and sustained a right subtrochanteric fracture after 12 years of zoledronic acid therapy. Both Jones fractures were treated conservatively, while the right subtrochanteric fracture was surgically fixed. Zoledronic acid was stopped after she sustained the AFF. This study highlights the need to look out for stress fractures beyond the commonly reported AFFs and atypical ulnar fractures when administering zoledronic acid to cancer patients.

Differential effects of alendronate on chondrocytes, cartilage matrix and subchondral bone structure in surgically induced osteoarthritis in mice.

Bisphosphonates (BP) are considered a treatment option for osteoarthritis (OA) due to reduction of OA-induced microtrauma in the bone marrow, stabilization of subchondral bone (SB) layer and pain reduction. The effects of high-dose alendronate (ALN) treatment on SB and articular cartilage after destabilization of the medial meniscus (DMM) or Sham surgery of male C57Bl/6J mice were analyzed. We performed serum analysis; histology and immunohistochemistry to assess the severity of OA and a possible pain symptomatology. Subsequently, the ratio of bone volume to total volume (BV/TV), epiphyseal trabecular morphology and the bone mineral density (BMD) was analyzed by nanoCT. Serum analysis revealed a reduction of ADAMTS5 level. The histological evaluation displayed no protective effect of ALN-treatment on cartilage erosion. NanoCT-analysis of the medial epiphysis revealed an increase of BV/TV in ALN-treated mice. Only the DMM group had significantly higher SB volume accompanied by decreased subchondral bone surface. Furthermore Nano-CT analysis revealed an increase in trabecular density and number, a decreased BMD and reduced osteophyte formation in the ALN mice. ALN treatment affected bone micro-architecture by reducing osteophytosis with simultaneous increasing subchondral bone plate thickness, trabecular thickness and BMD. Accordingly, ALN cannot be considered as a potential treatment strategy in general, however in a subgroup of patients with high bone turnover in an early-stage of OA, ALN might be an option when applied during a restricted time frame.

A Displaced Atypical Femoral Fracture Healed Without Anti-osteoporotic Agents in a Case of Ankylosing Spondylitis.

Bone loss leading to osteoporosis is a well-known feature in patients with ankylosing spondylitis (AS), with the prevalence of osteoporosis varying widely across different studies. However, there is still no consensus on the treatment of osteoporosis in AS patients. A 67-year-old male, a case of AS under medication control, had taken oral bisphosphonate for about seven years for suspected osteoporosis due to compression fracture at T12 and discontinued for disproportionately high dual-energy X-ray absorptiometry T-score (11.0 SD). He had been well until his right hip painful disability developed after a fall at home with a resultant right subtrochanteric transverse fracture with medial cortical spike, fulfilling features of atypical femoral fractures five months later. Open reduction and internal fixation with a cephalomedullary femoral nail were performed smoothly on the same day, and the fracture healed slowly and eventually one year later with only supplementation of calcium with vitamin D.

"Unraveling a rare encounter: Gorham's disease in an 88-year-old female".

INTRODUCTION AND IMPORTANCE: Gorham syndrome, or Gorham-Stout disease, is a rare disorder characterized by spontaneous and persistent bone resorption without any known cause, leading to severe complications [2]. The clinical presentation of this condition varies widely, complicating efforts in diagnosis and treatment. In our case report, we present the story of an 88-year-old woman who bravely and gracefully faced the challenges caused by Gorham syndrome. Despite prior treatments, her condition worsened, emphasizing the need for tailored approaches. CASE PRESENTATION: The patient's symptoms extended to bilateral shoulders, affecting daily living. Physical examination revealed tenderness, swelling, and muscle wasting. Her blood investigation showed vitamin D deficiency and imaging confirmed complete humeral head resorption. CASE DISCUSSION: Her case highlights the limitations of standard therapies. Variable presentations underscore the importance of thorough evaluation. Radiographic evidence revealed severe bone destruction, emphasizing the disability caused by Gorham syndrome. CONCLUSION: Recognition of the disease as early as possible, correct diagnosis, and effective management are essential. This patient's story highlights the importance of the multi-faceted treatment approach for patients with Gorham Syndrome: medical treatment, supportive care, compassion, and tenacity to improve the quality of life.

Risk of first hip fracture under treatment with zoledronic acid versus alendronate: a NOREPOS cohort study of 88,000 Norwegian men and women in outpatient care.

We aimed to investigate the risk of hip fracture associated with zoledronic acid treatment compared to alendronate on a population level. The risk of hip fracture was lower in women using zoledronic acid and higher in women who had discontinued treatment. The findings support the effectiveness of intravenous bisphosphonate. PURPOSE: To investigate whether zoledronic acid (ZOL) was associated with a lower risk of the first hip fracture than alendronate (ALN) in Norway using real-world data. METHODS: Nationwide data on drugs dispensed in outpatient pharmacies were individually linked with all hospital-treated hip fractures. Individuals aged 50-89 years without previous hip fracture were included at their first filling of a prescription for ALN or ZOL during 2005-2016. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) for first hip fracture by time-varying exposure to ZOL versus ALN were estimated in sex-stratified flexible parametric survival analyses. Covariates included time-varying accumulated ALN exposure and comorbidity level expressed by the prescription-based Rx-Risk Comorbidity Index, marital status, education, and residential urbanity. RESULTS: Of 75,250 women who initiated treatment, 72,614 (96.5%) were exposed to ALN and 6366 (8.5%) to ZOL. Of 12,739 men who initiated treatment, 12,311 (96.6%) were exposed to ALN and 784 (6.2%) to ZOL. In women, the HR for first hip fracture was 0.75 (95% CI: 0.61-0.91) for ZOL versus ALN. In men, the corresponding HR was 0.59 (95% CI: 0.32-1.07). Discontinued treatment was associated with increased risk compared with current ALN treatment in women (HR: 1.33; 95% CI: 1.24-1.42, men: HR 1.13 (95% CI: 0.95-1.35)). CONCLUSIONS: In women, the risk of first hip fracture when treated with ZOL was 25% lower than when treated with ALN. Discontinued treatment was associated with a 33% increase in hip fracture risk. Similar, albeit statistically non-significant, results were observed in men.

The Potential of Enamel Matrix Derivative in Countering Bisphosphonate-Induced Effects in Osteoblasts.

The suppressive effect of bisphosphonates (BPs) on bone metabolism is considered to be a major cause of medication-related osteonecrosis of the jaw (MRONJ). Enamel matrix derivative (EMD) stimulates and activates growth factors, leading to the regeneration of periodontal tissues. In this study, we aimed to explore the potential of EMD in reversing the detrimental effects of BPs on human fetal osteoblasts (hFOBs) and osteosarcoma-derived immature osteoblasts (MG63s) by assessing cell viability, apoptosis, migration, gene expression, and protein synthesis. While the suppressive effect of zoledronate (Zol) on cell viability and migration was observed, the addition of EMD significantly mitigated this effect and enhanced cell viability and migration. Furthermore, an increased apoptosis rate induced by Zol was decreased with the addition of EMD. The decreased gene expression of alkaline phosphatase (ALP), osteocalcin (OC), and the receptor activator of nuclear factors kappa-B ligand (RANKL) caused by BP treatment was reversed by the co-addition of EMD to hFOB cells. This trend was also observed for ALP and bone sialoprotein (BSP) levels in MG63 cells. Furthermore, suppressed protein levels of OC, macrophage colony-stimulating factor (M-CSF), BSP, and type 1 collagen (COL1) were recovered following the addition of EMD. This finding suggests that EMD could mitigate the effects of BPs, resulting in the recovery of cell survival, migration, and gene and protein expression. However, the behavior of the osteoblasts was not fully restored, and further studies are necessary to confirm their effects at the cellular level and to assess their clinical usefulness in vivo for the prevention and treatment of MRONJ.

Bone health ECHO case report: Orbital inflammation after zoledronate infusion.

Prior to the initiation of intravenous bisphosphonate therapy for osteoporosis, the impact on ocular health is not routinely discussed with patients. This is due to the scarcity of data on the association between bisphosphonates and ocular side effects, resulting in lack of provider awareness to effectively counsel patients. Furthermore, there is little consensus among clinicians on the safety of re-challenging with intravenous bisphosphonate treatment following ocular complications. This is a case report of a patient who developed orbital inflammation four days after receiving a zoledronate infusion. This case was discussed amongst health care providers and osteoporosis experts during a meeting of Bone Health Extension for Community Healthcare Outcomes (ECHO) virtual platform, which was established in 2015.

Effect of bisphosphonate on bone microstructure, mechanical strength in osteoporotic rats by ovariectomy.

BACKGROUND: Bisphosphonate (BP) can treat osteoporosis and prevent osteoporotic fractures in clinical. However, the effect of BP on microstructure and mechanical properties of cortical and trabecular bone has been taken little attention, separately. METHODS: In this study, BP was used to intervene in ovariectomized female SD rats. The femoral micro-CT images were used to measure the structural parameters and reconstruct the 3D models in volume of interest. The structural parameters of cortical and trabecular bone were measured, and the mechanical properties were predicted using micro-finite element analysis. RESULTS: There was almost no significant difference in the morphological structure parameters and mechanical properties of cortical bone between normal, ovariectomized (sham-OVX) and BP intervention groups. However, BP could significantly improve bone volume fraction (BV/TV) and trabecular separation (Tb.SP) in inter-femoral condyles (IT) (sham-OVX vs. BP, p < 0.001), and had no significant effect on BV/TV in medial and lateral femoral condyles (MT, LT). Similarly, BPs could significantly affect the effective modulus in IT (sham-OVX vs. BP, p < 0.001), and had no significant difference in MT and LT. In addition, the structural parameters and effective modulus showed a good linear correlation. CONCLUSION: In a short time, the effects of BP intervention and osteoporosis on cortical bone were not obvious. The effects of BP on trabecular bone in non-main weight-bearing area (IT) were valuable, while for osteoporosis, the main weight-bearing area (MT, LT) may improve the structural quality and mechanical strength of trabecular bone through exercise compensation.

Impact of anti-fracture medications on bone material and strength properties: a systematic review and meta-analysis.

Background and aims: Reduced bone mineral density (BMD) and microarchitectural deterioration contribute to increased fracture risk. Although the effects of anti-fracture medications (AFMs) on BMD are well-documented, their impact on bone material properties (BMPs) remains poorly characterized. Accordingly, we conducted a systematic review and meta-analysis to evaluate the effects of AFMs on BMPs. Based on data availability, we further categorized AFMs into anti-resorptives, bisphosphonates alone, and strontium ranelate subgroups to perform additional analyses of BMPs in osteoporotic patients. Methods: We did a comprehensive search of three databases, namely, PubMed, Web of Science, and Google Scholar, using various permutation combinations, and used Comprehensive Meta-Analysis software to analyze the extracted data. Results: The 15 eligible studies (randomized and non-randomized) compared the following: (1) 301 AFM-treated patients with 225 on placebo; (2) 191 patients treated with anti-resorptives with 131 on placebo; (3) 86 bisphosphonate-treated patients with 66 on placebo; and (4) 84 strontium ranelate-treated patients with 70 on placebo. Pooled analysis showed that AFMs significantly decreased cortical bone crystallinity [standardized difference in means (SDM) -1.394] and collagen maturity [SDM -0.855], and collagen maturity in cancellous bone [SDM -0.631]. Additionally, anti-resorptives (bisphosphonates and denosumab) significantly increased crystallinity [SDM 0.387], mineral-matrix ratio [SDM 0.771], microhardness [SDM 0.858], and contact hardness [SDM 0.952] of cortical bone. Anti-resorptives increased mineral-matrix ratio [SDM 0.543] and microhardness [SDM 0.864] and decreased collagen maturity [SDM -0.539] in cancellous bone. Restricted analysis of only bisphosphonate-treated studies showed a significant decrease in collagen maturity [SDM -0.650] in cancellous bone and an increase in true hardness [SDM 1.277] in cortical bone. In strontium ranelate-treated patients, there was no difference in BMPs compared to placebo. Conclusion: Collectively, our study suggests that AFMs improve bone quality, which explains their anti-fracture ability that is not fully accounted for by increased BMD in osteoporosis patients.

Nitrogen-containing bisphosphonate induces enhancement of OPG expression and inhibition of RANKL expression via inhibition of farnesyl pyrophosphate synthase to inhibit the osteogenic differentiation and calcification in vascular smooth muscle cells.

BACKGROUND: Nitrogen-containing bisphosphonate(N-BP)had been found to inhibit the osteogenic differentiation and calcification in vascular smooth muscle cells (VSMCs), but the mechanism is not clear. We intend to verify that N-BP induces enhancement of OPG expression and inhibition of RANKL expression via inhibition of farnesyl pyrophosphate synthase(FPPS) to inhibit the osteogenic differentiation and calcification in VSMCs. METHODS: ß-glycerophosphate (ß-GP) was used to induce the osteogenic differentiation and calcification in VSMCs. VSMCs were treated with N-BP or pretreated with downstream products of farnesyl pyrophosphate synthase(FPPS) in mevalonate pathway, such as farnesol (FOH) or geranylgeraniol (GGOH). Alizarin red S staining and determination of calcium content were used to detect calcium deposition.Western Blotting were used to detect expressions of proteins(OPG and RANKL ) and osteogenic marker proteins (Runx2 and OPN). RESULTS: ß-GP induced the osteogenic differentiation and calcification in VSMCs, increased RANKL protein expression and had no significant effect on OPG protein expression. With the treatment of N-BP, the expression of OPG protein was increased and expression of RANKL protein was decreased in VSMCs undergoing osteogenic differentiation and calcification. In addition, N-BP reduced the osteogenic marker proteins (Runx2 and OPN) expression and calcium deposition in VSMCs undergoing osteogenic differentiation and calcification. These effects of N-BP on the osteogenic differentiation and calcification in VSMCs were concentration-dependent, which could be reversed by the downstream products of FPPS, such as FOH or GGOH. CONCLUSION: N-BP increases OPG expression and decreases RANKL expression via inhibition of FPPS to inhibit the osteogenic differentiation and calcification in VSMCs.

A retrospective case series on bisphosphonate related osteonecrosis of the jaw in 20 cats.

Introduction: This retrospective study highlights the salient aspects of a series of feline patients affected with bisphosphonate related osteonecrosis of the jaw. Though more commonly published in human literature, this presentation is rare in cats. The authors hope that this study will assist in making this a more globally known entity with subsequent improved prognosis. Methods: Data was retrospectively obtained from the medical records between 2015 and 2021 of 20 cats with Medication Related Osteonecrosis of the Jaw. Data included patient information, clinical history, presenting complaint, systemic diseases, details referable to hypercalcemia and treatment thereof, bisphosphonate specifics (dose and duration), clinical presentation of the lesion, diagnostic testing including radiographic and histopathologic descriptions, treatment, and outcome. Results: Pertinent results include that all 20 cats who developed Medication Related Osteonecrosis of the Jaw had been treated for idiopathic hypercalcemia with the bisphosphonate medication alendronate. Eighty-five percent of the cases had prior dental extractions at the site of MRONJ lesion. Ninety-five percent of the affected cats required a surgical procedure to control the disease. Thirty-five percent of cases required at least one revision surgery after the initial procedure was performed. Diagnosis of MRONJ was made by a correlation of diagnostic findings and patient history. No single diagnostic, or combination was pathognomonic for lesion diagnosis. As well, there were no statistically significant associations between patient variables assessed and the overall patient outcome. Discussion: The case series reveals that cats with feline idiopathic hypercalcemia treated with alendronate may be at a risk for development of MRONJ, a serious oral condition with significant morbidity. Prior dental extraction sites in patients concurrently treated with bisphosphonate medications were often associated with MRONJ lesions. Therefore, any needed dental surgery should be performed prior to the use of bisphosphonates where possible. The authors have also included a relevant comparative literature review.