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

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse event related to administration of antiresorptive or antiangiogenic medications. With the increasing usage of bone-modifying agents in cancer therapy, the incidence of MRONJ enhanced gradually, which affects the life quality of patients and interferes with cancer therapy. In 2019, Multinational Association of Supportive Care in Cancer (MASCC), International Society of Oral Oncology (ISOO) and American Society of Clinical Oncology (ASCO) convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations on practices in the prevention and management of MRONJ in patients with cancer. The present article made an interpretation of Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline so as to provide clinicians with diagnostic and therapeutic approaches for cancer patients with MRONJ.
Bisphosphonate-Associated Osteonecrosis of the Jaw/therapy* ; Bone Density Conservation Agents/adverse effects* ; Humans ; Jaw ; Medical Oncology ; Neoplasms/drug therapy* ; Osteonecrosis/chemically induced* ; Quality of Life

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

OBJECTIVES: To reassess the safety and efficacy of once-weekly teriparatide 56.5 mg in osteoporosis patients with a high fracture risk. METHODS: This postmarketing observational study was conducted at 72 weeks according to the package insert. Of the 3573 Japanese osteoporosis patients in the safety analysis set, 91.80% were women, the mean age was 78.1 years, and 69.89% had a history of prevalent fragility fractures, indicating that a high proportion of patients at high risk of fracture were enrolled. RESULTS: Persistence with weekly teriparatide treatment was 59.36%, and 38.95% at 24 and 72 weeks, respectively. Adverse drug reactions (ADRs) were reported in 898 patients (25.13%), and serious ADRs were reported in 26 patients (0.73%). The most frequent ADRs were nausea, vomiting, and headache. The cumulative incidence of new vertebral fractures 72 weeks after the start of treatment was 3.31%. Increases in the bone mineral density were observed in the lumbar spine, femoral neck, and proximal femur. The serum levels of the bone formation markers, procollagen type I N-terminal propeptide and bone-type alkaline phosphatase, increased slightly at 24 weeks and then decreased to baseline levels. At 24 and 72 weeks, the bone resorption markers, serum cross-linked N-terminal telopeptide of type I collagen and urinary cross-linked N-terminal telopeptide of type I collagen, were the same as or slightly lower than at baseline. Visual analogue scale scores for low back pain also decreased. CONCLUSIONS: The present results showed that once-weekly teriparatide may also be useful for osteoporosis patients with a high risk of fracture.
Alkaline Phosphatase ; Asian Continental Ancestry Group ; Biomarkers ; Bone Density ; Bone Resorption ; Collagen Type I ; Drug-Related Side Effects and Adverse Reactions ; Female ; Femur ; Femur Neck ; Headache ; Humans ; Incidence ; Low Back Pain ; Nausea ; Observational Study ; Osteogenesis ; Osteoporosis ; Product Labeling ; Spine ; Teriparatide ; Vomiting

OBJECTIVE: To investigate the effects of continuous pumping of teriparatide (TPTD) on bone metabolism in ovariectomized and normal mice and provide experimental evidence for the selection of animal models for studying the effects of TPTD and its related peptides on osteoclasts. METHODS: Twenty-four female C57BL mice (6-weeks old) were subjected to ovariectomy (OVX) or sham operation followed 7 days later by continuous pumping of TPTD or the solvent vehicle (VEH) a micropump (SHAM-VEH, SHAM-TPTD, OVX-VEH, and OVX-TPTD groups; =6). Two weeks later, the tibial and femoral bones were harvested for micro-CT scanning to measure the parameters of the tibia and the femoral cortical bone. Histopathological examinations of the tibial tissue were conducted using HE staining and TRAP staining and the number of osteoclasts and the growth plate thickness were determined. The serum Ca2 + levels of the mice were measured. The primary osteoblasts from the cranial bone were treated with estradiol (E2) and TPTD for 48 h, and the expressions of β-catenin and RANKL protein in the cells were analyzed. RESULTS: The trabecular bone mass of OVX mice was significantly lower than that of sham-operated mice ( < 0.05). Continuous TPTD pumping significantly reduced tibial cancellous bone mass and femoral cortical bone area in the sham-operated mice, while in the castrated mice, TPTD pumping increased the cancellous bone mass without changing the cortical bone area. TRAP staining showed that cancellous osteoblasts in the tibia increased significantly in the castrated mice as compared with the sham-operated mice, and TPTD pumping significantly increased the number of cancellous osteoblasts in the sham-operated mice ( < 0.05). In the primary cultured osteoblasts, treatment with both E2 and TPTD obviously lowered the expression of β-catenin and increased the expression of RANKL as compared with TPTD treatment alone. CONCLUSIONS Continuous pumping of TPTD promotes bone resorption in normal mice but does not produce obvious bone resorption effect in the ovariectomized mice, suggesting that castrated mice are not suitable models for studying the effect of TPTD and the related peptides on the osteoclasts.
Animals ; Bone Density ; Bone Density Conservation Agents ; administration & dosage ; pharmacology ; Bone Resorption ; drug therapy ; Bone and Bones ; drug effects ; metabolism ; Female ; Growth Plate ; drug effects ; Mice ; Mice, Inbred C57BL ; Osteoclasts ; drug effects ; Ovariectomy ; RANK Ligand ; metabolism ; Teriparatide ; administration & dosage ; pharmacology ; beta Catenin ; metabolism

OBJECTIVE: To examine the effects of ursolic acid (UA) on mitigating retinoic acid (RA)-induced osteoporosis in rats. METHODS: Fifty female Sprague-Dawley rats were randomly divided into the control group (n=10) and the osteoporosis group (n=40). The 40 osteoporosis rats were induced by 75 mg/(kg•d) RA once daily for 2 weeks, and then were randomly assigned to vehicle control (model), low-, middle-, and high-dose UA [(UA-L, UA-M, UA-H; 30, 60, 120 mg/(kg•d), respectively] groups (10 rats each). UA were administered once daily to the rats from the 3rd weeks for up to 4 weeks by gavage. Bone turnover markers [serum alkaline phosphatase (ALP), osteocalcin (OCN), urine deoxypyridinoline (DPD)] and other parameters, including serum calcium (S-Ca), serum phosphorus (S-P), urine calcium (U-Ca), urine phosphorus (U-P), and bone mineral density (BMD) of the femur, 4th lumbar vertebra and tibia, bone biomechanical properties and trabecular microarchitecture, were measured. RESULTS: The osteoporosis in rats was successfully induced by RA. Compared with the model group, UA-M and UA-H significantly reversed the RA-induced changes in S-P, U-Ca, U-P, ALP, OCN and urine DPD ratio and markedly enhanced the BMD of right femur, 4th lumbar vertebra and tibia (Plt;0.05 or Plt;0.01). Further, biomechanical test and microcomputed tomography evaluation also showed that UA-H drastically improved biomechanical properties and trabecular microarchitecture (Plt;0.05 or Plt;0.01). CONCLUSION UA could promote bone formation, increase osteoblastic activity and reduce osteoclastic activity in rats, indicating that UA might be a potential therapeutic of RA-induced acute osteoporosis.
Animals ; Biomechanical Phenomena ; Bone Density ; drug effects ; Bone Remodeling ; drug effects ; Female ; Osteoporosis ; diagnostic imaging ; drug therapy ; Rats ; Rats, Sprague-Dawley ; Tretinoin ; toxicity ; Triterpenes ; pharmacology ; therapeutic use ; X-Ray Microtomography

Renal Fanconi syndrome (RFS) is caused by generalized proximal tubular dysfunction and can be divided into hereditary and acquired form. Adult-onset RFS is usually associated with drug toxicity or systemic disorders, and modern molecular genetics may explain the etiology of previous idiopathic cases of RFS. Here, we report the case of a 52-year-old woman with RFS whose etiology could not be identified. She presented with features of phosphaturia, renal glucosuria, aminoaciduria, tubular proteinuria, and proximal renal tubular acidosis. Her family history was unremarkable, and previous medications were nonspecific. Her bone mineral density was compatible with osteoporosis, serum intact parathyroid hormone level was mildly elevated, and 25(OH) vitamin D level was insufficient. Her blood urea nitrogen and serum creatinine levels were 8.4 and 1.19 mg/dL, respectively (estimated glomerular filtration rate, 53 mL/min/1.73 m²). Percutaneous renal biopsy was performed but revealed no specific renal pathology, including mitochondrial morphology. No mutation was detected in EHHADH gene. We propose the possibility of involvement of other genes or molecules in this case of adult RFS.
Acidosis, Renal Tubular ; Adult ; Biopsy ; Blood Urea Nitrogen ; Bone Density ; Creatinine ; Drug-Related Side Effects and Adverse Reactions ; Fanconi Syndrome ; Female ; Glomerular Filtration Rate ; Glycosuria, Renal ; Humans ; Hypophosphatemia, Familial ; Middle Aged ; Molecular Biology ; Osteoporosis ; Parathyroid Hormone ; Pathology ; Proteinuria ; Vitamin D

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

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