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

OBJECTIVE: To summarize the pathological characteristics of medication-related osteonecrosis of the jaw (MRONJ) specimens after jaw curettage or jaw osteotomy treatment and to comprehensively analyze the relationship between the different pathological features, treatment methods, and treatment effects to provide new ideas for effective treatment of MRONJ in clinical work. METHODS: The clinical and pathological data were collected from 23 patients with MRONJ who were treated with curettage (18 patients) and jaw osteotomy (5 patients) at the Department of Oral and Maxillofacial Surgery of Peking University Hospital of Stomatology between June 2014 and December 2015. The pathological characteristics of MRONJ were summarized and analyzed with treatment effects based on various surgical treatment methods. The diagnostic criteria and disease staging of MRONJ were determined according to the 2014 American Association of Oral and Maxillofacial Surgeon's Position Paper. RESULTS: In this study, 5 patients have treated with jaw segmental osteotomy, and all of them were in stage Ⅲ; the other 18 patients were treated with jaw curettage, including 5 patients in stage Ⅱ and 13 patients in stage Ⅲ. The pathological features of MRONJ in five cases of jaw segmental osteotomy were divided into three adjacent regions from shallow to deep: inflammation region (IR), sclerosis region (SR), and bone remodeling layer (BRL). Moreover, three types of pathological features of specimens from traditional curettage were defined as type 1 (IR), type 2 (IR + SR), and type 3 (IR + SR + BRL). The pathological features of the patients treated with jaw curettage were: type Ⅰ, 38.9% (7/18); type Ⅱ, 44.4% (8/18); type Ⅲ, 16.7% (3/18). Complete healing was achieved in 5 patients treated with jaw segmental osteo-tomy. Moreover, 2 cases with type Ⅰ, 1 case with type Ⅱ, and 1 with type Ⅲ completely healed after jaw curettage, while 5 cases with type Ⅰ, 7 cases with type Ⅱ, and 2 cases with type Ⅲ experienced recurrence after surgery. CONCLUSION Pathological features of continuous regions of inflammation, sclerosis, and bone remodeling layer were identified from shallow to deep, based on the microscopic observation of jaw segmental osteotomy samples. Insufficient removal of the sclerotic region during jaw curettage that blocks the required blood, nutritional factors, and mesenchymal stem cells seems to be a common cause for failed treatment of MRONJ after curettage surgery.
Humans ; Bisphosphonate-Associated Osteonecrosis of the Jaw/etiology* ; Sclerosis/complications* ; Wound Healing ; Treatment Outcome ; Inflammation/complications* ; Bone Density Conservation Agents/adverse effects* ; Diphosphonates/adverse effects*

Bone-modifying agents currently include bisphosphonates and desumumab, which are the main drugs for the treatment of malignant tumor bone metastasis, hypercalcemia and osteoporosis. Due to its wide clinical application, the adverse events of this kind of drugs are gradually increasing and affecting the quality of life of patients. Therefore, it needs to arouse the attention of the majority of medical personnel. Based on the substantial evidence, the expert committee has thoroughly discussed the management of adverse reactions of bone modifying agents and put forward reasonable suggestions, to guide clinicians in the safety management of such drugs.
Bone Density Conservation Agents/adverse effects* ; Consensus ; Diphosphonates/adverse effects* ; Humans ; Osteoporosis/drug therapy* ; Quality of Life ; Safety Management

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

OBJECTIVETo investigate the effect of thalidomide on the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ).

METHODSThirty-six rats were randomly divided into groups A, B and C, and treated with saline, zoledronate and zoledronate plus thalidomide, respectively. Three weeks later, the left maxillary first molars of the rats were extracted. Four and eight weeks after tooth extraction, samples were harvested for evaluation of osteonecrosis of the jaws, microvessel density, and cell apoptosis.

RESULTSAt both of the time points, no exposed dead bone was observed at the extraction socket areas in the rats except for some small fistulas in groups B and C. Histological examination confirmed the absence of dead bone in group A, whereas small areas of dead bone were observed around the extraction socket in groups B and C. Compared with those in group A, the percentage of empty lacunae and the area of dead bone were significantly increased (P<0.01), whereas bone lacunae density was significantly decreased (P<0.01) in groups B and C at both time points. Microvessel density in groups B and C were also significantly decreased (P<0.01) by 25.87% and 55.27% at week 4, and by 45.62% and 72.84% at week 8, respectively; the apoptotic cells in groups B and C increased by 54.80% and 87.89% at week 4 (P<0.01), and by 208.08% and 250.58% at week 8 (P<0.01), respectively.

CONCLUSIONThalidomide can aggravate zoledronate-induced early-stage BRONJ, and their osteonecrosis-inducing effect of the jaw may be attributed, at least partly, to the inhibition of angiogenesis.

Animals ; Apoptosis ; Bisphosphonate-Associated Osteonecrosis of the Jaw ; pathology ; Bone Density ; Diphosphonates ; Disease Models, Animal ; Imidazoles ; Molar ; Neovascularization, Physiologic ; Rats ; Thalidomide ; adverse effects ; Tooth Extraction

INTRODUCTIONWe evaluated reduced back pain in a multiethnic population treated with teriparatide and/or antiresorptives in real-life clinical settings over 12 months.

METHODSThis prospective observational study comprised 562 men and postmenopausal women (mean age 68.8 years) receiving either teriparatide (n = 230), antiresorptives (raloxifene or bisphosphonates; n = 322), or both (n = 10) for severe osteoporosis. The primary endpoint was the relative risk of new/worsening back pain at six months.

RESULTSAt baseline, a higher proportion of teriparatide-treated than antiresorptive-treated patients had severe back pain (30.9% vs. 17.7%), extreme pain/discomfort (25.3% vs. 16.8%), extreme anxiety/depression (16.6% vs. 7.8%) and were confined to bed (10.0% vs. 5.3%). Teriparatide-treated patients had higher visual analog scale (VAS) scores for pain (5.8 ± 2.42 vs. 5.1 ± 2.58) and lower mean European Quality of Life-5 Dimensions (EQ-5D) scores (37.7 ± 29.15 vs. 45.5 ± 31.42) than antiresorptive-treated patients. The incidence of new/worsening back pain at six months for patients on teriparatide and antiresorptives was 9.8% and 10.3% (relative risk 0.99, 95% confidence interval 0.80-1.23), respectively. The incidence of severe back pain at 12 months was 1.3% and 1.6% in the teriparatide and antiresorptive treatment groups, respectively. Teriparatide-treated patients had lower mean VAS (2.71 ± 2.21 vs. 3.30 ± 2.37) and EQ‑5D (46.1 ± 33.18 vs. 55.4 ± 32.65) scores at 12 months. More teriparatide-treated patients felt better (82.7% vs. 71.0%) and were very satisfied with treatment (49.4% vs. 36.8%) compared to antiresorptive-treated patients.

CONCLUSIONPatients treated with either teriparatide or antiresorptives had similar risk of new/worsening back pain at six months.

Aged ; Back Pain ; complications ; diagnosis ; ethnology ; Bone Density Conservation Agents ; adverse effects ; Diphosphonates ; adverse effects ; Ethnic Groups ; Female ; Humans ; International Cooperation ; Male ; Middle Aged ; Osteoporosis ; complications ; drug therapy ; Prospective Studies ; Quality of Life ; Raloxifene Hydrochloride ; adverse effects ; Surveys and Questionnaires ; Teriparatide ; adverse effects ; Time Factors ; Treatment Outcome

Zoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastasis. This case report illustrates an undesirable consequence from prolonged usage of zoledronic acid in bone metastasis prevention. Periprosthetic acetabular fracture in a patient treated with zoledronic acid for 7 years was reported. The clinical presentation, radiographic and pathological results were described. This is a rare complication after total hip arthroplasty which should not be ignored especially in patients who received long term bisphosphonate.
Acetabulum/*injuries/pathology/surgery ; Aged ; Arthroplasty, Replacement, Hip/*adverse effects ; Bone Density Conservation Agents/*adverse effects/pharmacology ; Bone Neoplasms/prevention & control/secondary ; Bone Remodeling/drug effects ; Breast Neoplasms/pathology ; Diphosphonates/*adverse effects/pharmacology ; Female ; Fractures, Spontaneous/chemically induced/etiology ; Hip Prosthesis ; Humans ; Imidazoles/*adverse effects/pharmacology ; Osteoarthritis, Hip/*surgery ; Periprosthetic Fractures/*chemically induced/etiology ; Prosthesis Failure ; Reoperation

Aromatase Inhibitors ; adverse effects ; therapeutic use ; Bone Density ; drug effects ; Bone Density Conservation Agents ; therapeutic use ; Breast Neoplasms ; drug therapy ; Calcium ; therapeutic use ; Diphosphonates ; therapeutic use ; Female ; Fractures, Bone ; chemically induced ; prevention & control ; Humans ; Imidazoles ; therapeutic use ; Osteoporosis, Postmenopausal ; chemically induced ; diagnosis ; prevention & control ; Postmenopause ; Vitamin D ; therapeutic use