Medication-related osteonecrosis of the jaw (MRONJ) is primarily associated with administering antiresorptive or antiangiogenic drugs. Despite significant research on MRONJ, its pathogenesis and effective treatments are still not fully understood. Animal models can be used to simulate the pathophysiological features of MRONJ, serving as standardized in vivo experimental platforms to explore the pathogenesis and therapies of MRONJ. Rodent models exhibit excellent effectiveness and high reproducibility in mimicking human MRONJ, but classical methods cannot achieve a complete replica of the pathogenesis of MRONJ. Modified rodent models have been reported with improvements for better mimicking of MRONJ onset in clinic. This review summarizes representative classical and modified rodent models of MRONJ created through various combinations of systemic drug induction and local stimulation and discusses their effectiveness and efficiency. Currently, there is a lack of a unified assessment system for MRONJ models, which hinders a standard definition of MRONJ-like lesions in rodents. Therefore, this review comprehensively summarizes assessment systems based on published peer-review articles, including new approaches in gross observation, histological assessments, radiographic assessments, and serological assessments. This review can serve as a reference for model establishment and evaluation in future preclinical studies on MRONJ.
Animals ; Bisphosphonate-Associated Osteonecrosis of the Jaw/drug therapy* ; Bone Density Conservation Agents/adverse effects* ; Diphosphonates/therapeutic use* ; Humans ; Reproducibility of Results ; Rodentia

BACKGROUND: Clinical observational studies revealed that 99Tc-methylene diphosphonate (99Tc-MDP) could reduce joint pain and swollenness in rheumatoid arthritis (RA) patients. This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of 99Tc-MDP plus methotrexate (MTX) vs. MTX alone or 99Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA. METHODS: Eligible patients with moderate to severely active RA were randomized to receive 99Tc-MDP plus MTX (n = 59) vs. MTX (n = 59) alone or 99Tc-MDP (n = 59) alone for 48 weeks from six study sites across four provinces in China. The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score at week 48. RESULTS: At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX + 99Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or 99Tc-MDP group (47.5%) (P = 0.03 for MTX + 99Tc-MDP vs. MTX, and MTX + 99Tc-MDP vs.99Tc-MDP, respectively). The participants in the MTX + 99Tc-MDP group and the 99Tc-MDP group had significantly less important radiographic progression than the participants in the MTX group over the 48 weeks (MTX + 99Tc-MDP vs. MTX: P = 0.03, 99Tc-MDP vs. MTX: P = 0.03, respectively). There was no significant difference in terms of adverse events (AEs) among the groups. No serious AEs were observed. CONCLUSIONS: This study demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of AEs. Additional clinical studies of 99Tc-MDP therapy in patients with RA are warranted. TRIAL REGISTRATION Chictr.org, ChiCTR-IPR-14005684; http://www.chictr.org.cn/showproj.aspx?proj=10088.
Antirheumatic Agents/therapeutic use* ; Arthritis, Rheumatoid/drug therapy* ; China ; Diphosphonates ; Double-Blind Method ; Drug Therapy, Combination ; Humans ; Methotrexate/therapeutic use* ; Technetium/therapeutic use* ; Treatment Outcome

Giant cell tumors(GCT) of bone is benign bone tumors with aggressive and osteolytic activity. As traditional treatment of GCT, removal of bone graft is disease with high local recurrence rate, and could reduce local recurrence by auxiliary means. Different surgical methods such as prosthesis replacement, wide resection and En-bloc resection could be selected for different parts of giant cell tumor of bone, based on the lesion location, size, extent of invasion, recurrence rate. For patients with special region of GCT of bone with removed incompletely and high surgical risk expected, arterial embolism could be performed. The application of bisphosphonates and denosumab are mainly used in treating recurrent, refractory, special parts, metastatic giant cell tumor of bone will bring new hope of treatment for giant cell tumor of bone, due to lower the recurrence rate. Chemotherapy is mainly used in the treatment of metastasis and malignant bone tumor. Radiotherapy for recurrent or unresectable bone giant cell tumor can control tumor progression, but there is the possibility of malignancy. While long-term follow-up studies and long-term results of applications of bisphosphonates and denosumab are lacking, new methods and development of new drugs are still be needed to treat patients with giant cell tumor of bone and also bring about more hope.
Bone Neoplasms ; drug therapy ; surgery ; Denosumab ; therapeutic use ; Diphosphonates ; therapeutic use ; Giant Cell Tumor of Bone ; drug therapy ; surgery ; Humans ; Neoplasm Recurrence, Local ; Treatment Outcome

BackgroundMineral and bone disorder is one of the severe complications in kidney transplant recipients (KTRs). Previous studies showed that bisphosphonates had favorable effects on bone mineral density (BMD). We sought to compare different bisphosphonate regimens and rank their strategies.

MethodsWe searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to April 01, 2017, for randomized controlled trials (RCTs) comparing bisphosphonate treatments in adult KTRs. The primary outcome was BMD change. We executed the tool recommended by the Cochrane Collaboration to evaluate the risk of bias. We performed pairwise meta-analyses using random effects models and network meta-analysis (NMA) using Bayesian models and assessed the quality of evidence.

ResultsA total of 21 RCTs (1332 participants) comparing 6 bisphosphonate regimens were included. All bisphosphonates showed a significantly increased percentage change in BMD at the lumbar spine compared to calcium except clodronate. Pamidronate with calcium and Vitamin D analogs showed improved BMD in comparison to clodronate with calcium (mean difference [MD], 9.84; 95% credibility interval [CrI], 1.06-19.70). The combination of calcium and Vitamin D analogs had a significantly lower influence than adding either pamidronate or alendronate (MD, 6.34; 95% CrI, 2.59-11.01 and MD, 6.16; 95% CrI, 0.54-13.24, respectively). In terms of percentage BMD change at the femoral neck, both pamidronate and ibandronate combined with calcium demonstrated a remarkable gain compared with calcium (MD, 7.02; 95% CrI, 0.30-13.29 and MD, 7.30; 95% CrI, 0.32-14.22, respectively). The combination of ibandronate with calcium displayed a significant increase in absolute BMD compared to any other treatments and was ranked best.

ConclusionsOur NMA suggested that new-generation bisphosphonates such as ibandronate were more favorable in KTRs to improve BMD. However, the conclusion should be treated with caution due to indirect comparisons.

Bone Density ; drug effects ; Diphosphonates ; adverse effects ; therapeutic use ; Female ; Humans ; Kidney Transplantation ; adverse effects ; Male ; Osteoporosis ; prevention & control ; Randomized Controlled Trials as Topic

Medication-related osteonecrosis of the jaw (MRONJ) is a severe complication of bisphosphonates (BPs) or other targeted agent therapies. MRONJ appears as exposed bone, pus, and swelling in the oral and maxillofacial regions. However, neither surgery nor conservative therapy can eliminate symptoms thoroughly. In addition to BPs, several antiresorptive and antiangiogenic agents, such as denosumab and bevacizumab, as well as targeted agents, such as sunitinib and temsirolimus, can cause osteonecrosis of  the  jaw according to the literature. This review aims to summarize the research progress on these new drugs.
Angiogenesis Inhibitors ; therapeutic use ; Bisphosphonate-Associated Osteonecrosis of the Jaw ; drug therapy ; Bone Density Conservation Agents ; adverse effects ; Denosumab ; therapeutic use ; Diphosphonates ; Humans

Osteoporosis is a major, growing healthcare issue. This is especially of concern in an ageing population like that of Singapore. Osteoporotic patients are at risk of fractures, which can result in increased morbidity and mortality. The use of antiresorptive therapy with bisphosphonates or denosumab has been proven to reduce fracture risk. However, the use of these medications has rarely been associated with the development of osteonecrosis of the jaw, a potentially debilitating condition affecting one or both jaws. Appropriate understanding of the patient's antiresorptive therapy regime, as well as early institution of preventive dental measures, can play an important role in preventing medication-related osteonecrosis of the jaw (MRONJ). Regular monitoring and prompt referral to specialist care is warranted for patients with established MRONJ.
Aged ; Bone Density Conservation Agents ; adverse effects ; therapeutic use ; Denosumab ; adverse effects ; therapeutic use ; Diphosphonates ; adverse effects ; therapeutic use ; Humans ; Jaw Diseases ; chemically induced ; prevention & control ; Osteonecrosis ; chemically induced ; prevention & control ; Osteoporosis ; complications ; drug therapy ; Osteoporotic Fractures ; complications ; drug therapy ; Risk Factors ; Singapore ; Treatment Outcome

Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.
Bone Density Conservation Agents/therapeutic use* ; Bone Neoplasms/secondary* ; Denosumab/therapeutic use* ; Diphosphonates/therapeutic use* ; Endothelins/antagonists & inhibitors* ; Humans ; Male ; Prostatic Neoplasms/pathology* ; Protein Kinase Inhibitors/therapeutic use* ; Radioisotopes/therapeutic use* ; Radiopharmaceuticals/therapeutic use* ; Radium/therapeutic use* ; Samarium/therapeutic use* ; Strontium Radioisotopes/therapeutic use*

OBJECTIVETo investigate the clinical efficacy and safety of conventional dose and reduction dose of bortezomib in combination with bisphosphonates for treating patients with multiple myeloma ostespathy.

METHODSA total of 150 patients with multiple myeloma ostespathy were chosen in the period from March 2011 to July 2015 and randomly were divided into 2 groups: A group (75 cases) and B group (75 cases). The patients in A and B groups were treated with conventional dose of bortezomib and reduction dose of bortezomib on the basis of bisphosphonates respectively and the clinical efficacy, the improvement rate of life quality, NRS score, levels of IL-6 and CRP before and after treatment, and the adverse effects of 2 groups were compared.

RESULTSThere was no significant difference in the clinical efficacy between 2 groups (P<0.05). The improvement rate of patients life quality in B group was significantly better than that in A group (P>0.05). There was no significant difference in the NRS score, levels of IL-6 and CRP after treatment between 2 groups (P>0.05). There was no significant difference in the incidence of neutrophil reduction and thrombocytopenia between 2 groups (P<0.05). The incidence of BiPN, nausea and vomiting, herpes zoster and fatigue of B group was significantly lower than that in A group (P<0.05).

CONCLUSIONConventional dose and reduction dose of bortezomib in combination with bisphosphonates for treating patients with multiple myeloma ostespathy possess the same effects, including pain relief and disease progression control; but the reduction dose of bortezomib application can efficiently improve the life quality of patients and reduce the risk of adverse reactions.

Antineoplastic Agents ; administration & dosage ; therapeutic use ; Bortezomib ; administration & dosage ; chemistry ; therapeutic use ; C-Reactive Protein ; analysis ; Diphosphonates ; administration & dosage ; therapeutic use ; Disease Progression ; Humans ; Interleukin-6 ; analysis ; Multiple Myeloma ; drug therapy

BACKGROUNDSystemic administration of bisphosphonates has shown promising results in the treatment of osteonecrosis of the femoral head (ONFH). However, few studies have evaluated the efficacy of local zoledronate (ZOL) administration in the treatment of ONFH. The purpose of this study was to investigate whether local administration of bisphosphonate-soaked hydroxyapatite (HA) could improve bone healing in an experimental rabbit model of ONFH.

METHODSThis experimental study was conducted between October 2014 and June 2015. Forty-five rabbits underwent simulated ONFH surgery. Immediately following surgery, they were divided into three groups: model (untreated, n = 15), HA (treated with HA alone, n = 15), and HA + ZOL (treated with HA soaked in a low-dose ZOL solution, n = 15). Histological, immunohistochemical, and quantitative analyses were performed to evaluate bone formation and resorption 2, 4, and 8 weeks after surgery.

RESULTSGross bone matrix and hematopoietic tissue formation were observed in the HA + ZOL group 4 weeks after surgery. The immunohistochemical staining intensities for 5-bromodeoxyuridine, runt-related transcription factor 2, osteocalcin, osteopontin, and osteoprotegerin were significantly higher in the HA + ZOL group than that in the model (P < 0.001, P< 0.001, P< 0.001, P< 0.001, and P = 0.018, respectively) and HA groups (P = 0.003, P = 0.049, P< 0.001, P = 0.020, and P = 0.019, respectively), whereas receptor activator of the nuclear factor-κB ligand staining intensity was significantly lower in the HA + ZOL group than that in the model and HA groups (P = 0.029 and P = 0.015, respectively) 4 weeks after surgery. No significant differences in bone formation or bone resorption marker expression were found between the three groups 2 or 8 weeks after surgery (P > 0.05).

CONCLUSIONSLocal administration of HA soaked in a low-dose ZOL solution increased new bone formation while inhibiting bone resorption in an animal model of ONFH, which might provide new evidence for joint-preserving surgery in the treatment of ONFH.

Animals ; Diphosphonates ; administration & dosage ; therapeutic use ; Durapatite ; administration & dosage ; therapeutic use ; Female ; Femur Head Necrosis ; drug therapy ; metabolism ; Imidazoles ; administration & dosage ; therapeutic use ; Immunohistochemistry ; Male

OBJECTIVETo observe the effect and mechanisim of zoledronate sodium on periprosthetic osteolysis in rat induced by polyethylene particles.

METHODSTotal 30 adult male SD rats, weighting from 250 to 300 g, were selected and randomly divided into three groups: blank control group, model control group and zoledronate sodium group respectively, 10 animals for each group. No treatment was performed in the blank control group. In model control group and zoledronate sodium group, the modle of periprosthetic osteolysis in rats were made by implanting polyethylene particles and titanium rods into their right femurs. After operation, rats in zoledronate sodium group were administered with zoledronate sodium (0.1 mg/kg each week) through subcutaneous injection for 8 weeks, then the blood was obtained and all experimental animals were sacrificed to get the right femur specimens. The femur BMD, IL-1β, IL-6, TNF-α, serum TRACP5b and CTX-I were detected.

RESULTSCompared with the model control group, the femur BMD was increased, while IL-1β, IL-6 and TNF-α were all decreased in zoledronate sodium group; the serum TRACP5b and CTX-I level were both reduced in zoledronate sodium group.

CONCLUSIONThe zoledronate sodium could effectively inhibit periprosthetic osteolysis in rats induced by polyethylene particles, which might be realized by inhibiting the activity of osteoclasts and the expression of IL-1β, IL-6 and TNF-α. It provides a new method to treat periprosthetic osteolysis of the artificial joint prosthesis.

Animals ; Bone Density ; drug effects ; Collagen Type I ; analysis ; Cytokines ; analysis ; Diphosphonates ; therapeutic use ; Imidazoles ; therapeutic use ; Joint Prosthesis ; Male ; Osteolysis ; drug therapy ; Peptides ; analysis ; Polyethylene ; pharmacology ; Rats ; Rats, Sprague-Dawley