BACKGROUND

Osteogenesis imperfecta (OI) is a group of connective tissue disease characterized by propensity to fractures following minimal trauma. OI is a lifelong inheritable disease and currently has no definitive cure. Management goals are directed towards prevention of fractures, controlling the symptoms, maximizing independent mobility, and developing optimal bone mass and muscle strength. Bisphosphonates are the mainstay of pharmacologic fracture-prevention therapy for most forms of OI. The University of the Philippines-Philippine General Hospital Bisphosphonate Treatment Program for OI was started in 2006 by the Clinical Genetics Service. For more than a decade now, the program has been serving more than 50 OI patients. This study evaluated the clinical outcomes of the patients who were included in the program to add to the body of knowledge on Filipino patients with OI.

This study sought to determine the clinical outcomes of children with OI on intravenous pamidronate treatment at the Philippine General Hospital (PGH) from January 2010 to December 2018.

The study utilized a retrospective review of medical records of 24 patients diagnosed with OI on pamidronate therapy seen at the PGH from January 2010 to December 2018. Descriptive statistics were used to summarize the demographic and baseline clinical characteristics of the patients. Median annualized fracture rates before and during treatment were calculated and compared. The patient functional mobility before and during pamidronate infusion was classified accordingly based on the Gross Motor Function Classification System (GMFCS) and were compared.

Twenty-four patients, which include seven males and 17 females, with ages at the time of conduct of the study ranging from four years to 11 years, fulfilled the inclusion criteria. There were four patients with OI type I, six with OI type III, 11 with OI type IV and three with OI type V. The annualized long bone fracture rate decreased significantly from a median of 2.0/year (range 1-2.75) to 0.75/year (range 0-1) after more than a year on pamidronate infusion (pCONCLUSION

Cyclic intravenous pamidronate treatment in young children with moderate-severe OI is well tolerated and associated with reduced fracture frequency with a tendency to improvement of gross functional mobility.

Atypical femoral fractures (AFFs) are rare adverse effects of bisphosphonate therapy. We report an unusual case of bilateral diaphyseal AFFs in an antiresorptive-naïve Singaporean Chinese female with Graves’ disease. She presented with complete right AFF requiring surgical fixation, and persistent left incomplete AFF for over four years. Femoral bowing, varus femoral geometry, and ethnic influence likely contributed to the AFFs’ formation. This case may provide insights into the pathogenesis of AFFs in high-risk Asian populations.
Diphosphonates ; Hyperthyroidism

Bacterial infection is a common finding in patients, who develop medication-related osteonecrosis of the jaw (MRONJ) by the long-term and/or high-dose use of anti-resorptive agents such as bisphosphonate (BPs). However, pathological role of bacteria in MRONJ development at the early stage remains controversial. Here, we demonstrated that commensal microbiota protects against MRONJ development in the pulp-exposed periapical periodontitis mouse model. C57/BL6 female mice were treated with intragastric broad-spectrum antibiotics for 1 week. Zoledronic acid (ZOL) through intravenous injection and antibiotics in drinking water were administered for throughout the experiment. Pulp was exposed on the left maxillary first molar, then the mice were left for 5 weeks after which bilateral maxillary first molar was extracted and mice were left for additional 3 weeks to heal. All mice were harvested, and cecum, maxilla, and femurs were collected. ONJ development was assessed using μCT and histologic analyses. When antibiotic was treated in mice, these mice had no weight changes, but developed significantly enlarged ceca compared to the control group (CTL mice). Periapical bone resorption prior to the tooth extraction was similarly prevented when treated with antibiotics, which was confirmed by decreased osteoclasts and inflammation. ZOL treatment with pulp exposure significantly increased bone necrosis as determined by empty lacunae and necrotic bone amount. Furthermore, antibiotics treatment could further exacerbate bone necrosis, with increased osteoclast number. Our findings suggest that the commensal microbiome may play protective role, rather than pathological role, in the early stages of MRONJ development.
Animals ; Bisphosphonate-Associated Osteonecrosis of the Jaw/prevention & control* ; Bone Density Conservation Agents ; Diphosphonates ; Female ; Humans ; Mice ; Microbiota ; Periapical Diseases ; Zoledronic Acid

Objective: To investigate the clinical features of children with chronic nonbacterial osteomyelitis (CNO), and raise awareness among clinicians. Methods: In this retrospective study, 18 patients with CNO who were diagnosed in Children's Hospital of Fudan University from January 2015 to December 2021 were included. Results: Eighteen children with CNO (12 males, 6 females) were identified. Their age at onset was 9 (5, 11) years, the delay in diagnosis was 2 (1, 6) months, and follow-up-was 17 (8, 34) months. The most common symptoms were fever in 14 children, as well as bone pain and (or) arthralgia in 14 children. In terms of laboratory results, normal white blood cell counts were observed at onset in 17 patients; increased erythrocyte sedimentation rate (ESR) in all patients; increased C reactive protein (CRP) over the normal value in 14 patients. Of the 18 patients, 2 had positive antinuclear antibodies, while none had positive human leukocyte antigen-B27 or rheumatoid factor. Imaging examination revealed that all the patients had symmetrical and multifocal skeletal lesions. The number of structural lesions detected by imaging investigation was 8 (6, 11). The most frequently affected bones were tibia in 18 patients and femur in 17 patients. Bone biopsy was conducted in 14 patients and acute or chronic osteomyelitis manifested with inflammatory cells infiltration were detected. Magnetic resonance imaging (MRI) found bone lesions in all the patients and bone scintigraphy were positive in 13 patients. All the patients were treated with nonsteroidal anti-inflammatory drugs, among whom 10 cases also treated with oral glucocorticoids, 9 cases with traditional disease modifying anti-rheumatic drugs, 8 cases with bisphosphonates and 6 cases with tumor necrosis factor inhibitors. The pediatric chronic nonbacterial osteomyelitis disease activity score, increased by 70% or more in 13 patients within the initial 6-month follow-up. Conclusions: The clinical manifestations of CNO are lack of specificity. The first symptom of CNO is fever, with or without bone pain and (or) arthralgia, with normal peripheral blood leukocytes, elevated CRP and (or) ESR. Whole body bone scanning combined with MRI can early detect osteomyelitis at subclinical sites, and improve the diagnostic rate of CNO.
Female ; Male ; Humans ; Child ; Retrospective Studies ; Osteomyelitis/drug therapy* ; Arthralgia ; Diphosphonates ; Fever ; Graft vs Host Disease

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*

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

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

Osteonecrosis of the jaw could occur after intake of bisphosphonate drugs, which are widely used to treat osteoporosis and bone metastasis of malignant tumors. This effect has aroused concern among dentists. In this paper, a case of bisphosphonate-related osteonecrosis caused by implant is reported, and the pathogenesis, diagnosis, prevention, and treatment of bisphosphonate drug-induced osteonecrosis are described through a literature review. The effects of bisphosphonate drug treatment on dental implants are also discussed.
Bisphosphonate-Associated Osteonecrosis of the Jaw ; Bone Density Conservation Agents ; Dental Implants ; Diphosphonates ; Humans ; Osteoporosis

PURPOSE: The purpose of this study was to investigate the radiologic and serologic factors related to postoperative union using intramedullary (IM) internal fixation in atypical femoral fractures (AFF), which are closely related to bisphosphonates (BPs) for osteoporosis. MATERIALS AND METHODS: From February 2008 to December 2016, 65 patients (71 cases) who had undergone IM nail fixation after diagnosis of AFF were enrolled in this study. Patients were divided into group A, who experienced union within 6 months and group B, who did not experience union within 6 months. They were evaluated for duration of BPs use, radiologic factors and serological factors. RESULTS: The mean duration of BPs use was 6.17 years in group A and 8.24 years in group B (p=0.039). In the subtrochanteric area, there were 14 cases (27.5%) in group A and 14 cases (70.0%) in group B. In the femoral shaft, there were 37 cases (72.5%) in group A and 6 cases (30.0%) in group B (p=0.001). On the preoperative, the flexion in the coronal plane was 5.9° (2.1°–9.2°) in group A and 8.0° (3.1°–12.1°) in group B (p=0.041). On the postoperative, conversion to valgus was 15 cases (29.4%), 8 cases (40.0%); conversion to neutral was 34 cases (66.7%) and 8 cases (40.0%); conversion to varus was 2 cases (3.9%) and 4 cases (20.0%), each (p=0.037). The fracture site gap was 1.5 mm (0–2.9 mm) on the front side and 1.2 mm (0–2.2 mm) on lateral side and 2.2 mm (0.9–4.7 mm) and 1.9 mm (0.5–3.5 mm), each (p=0.042, p=0.049). Among serological factors, there was no significant difference between the two groups. CONCLUSION: Factors adversely affecting the union should be recognized before surgery, such as longterm BPs use or a severe degree of bending of the femur in the coronal plane. During surgery, proper reduction and spacing of the fracture site on the coronal plane should allow adequate reduction of the anterior and posterior surfaces. Obtaining anatomic reduction would be most beneficial for union, but if that is not possible, obtaining congenital valgus rather than varus on the coronal plane may be helpful for union.
Diagnosis ; Diphosphonates ; Femoral Fractures ; Femur ; Humans ; Osteoporosis