RESUMO
Prior research has indicated that bisphosphonates (BPs) can improve periodontal disease because of their anti-osteoporosis properties. In vitro studies have shown that BPs induce cytotoxicity, inhibit wound healing, and thus affect periodontal disease. Denosumab and BPs have alternative indications. BP and denosumab are not known to correlate with gingival disorders. We assessed such a relationship by applying Bayesian and nonproportional analyses to data in the US FDA Adverse Event Reporting System (FAERS) database. The study analyzed BPs and denosumab-reported incidents with preferred terms found in the narrow Standardized MedDRA Queries for gingival disorders. A total of 5863 reported cases of gingival disorders were associated with five BPs (alendronate, pamidronate, ibandronate, risedronate, and zoledronate) and denosumab. More than 15% of patients with gingival disorders related to BPs and denosumab other than denosumab were hospitalized over short- or long-term periods. Our findings indicated BPs and denosumab had significant reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) with respect to gingival disorders. Pamidronate had the highest association (ROR = 64.58, PRR = 57.99, IC = 5.71), while the weakest association was found with denosumab (ROR = 3.61, PRR = 3.60, IC = 1.77). Significant associations were found between the six drugs and gingival pain, gingival recession, gingivitis, periodontal disease, and periodontitis. In conclusion, our comprehensive overview of the correlations, clinical characteristics, and prognoses of BPs and denosumab-related gingival disorders suggests that these issues deserve continued surveillance and appropriate management.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Denosumab , Difosfonatos , Doenças da Gengiva , United States Food and Drug Administration , Humanos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Estados Unidos/epidemiologia , Difosfonatos/efeitos adversos , Denosumab/efeitos adversos , Doenças da Gengiva/induzido quimicamente , Doenças da Gengiva/epidemiologia , Feminino , Conservadores da Densidade Óssea/efeitos adversos , Masculino , Pessoa de Meia-Idade , IdosoRESUMO
Osteoporosis remains incurable. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation, while the anabolic agent, teriparatide, does not inhibit bone resorption, and thus they have limited efficacy in preventing osteoporotic fractures and cause some side effects. Thus, there is an unmet need to develop dual antiresorptive and anabolic agents to prevent and treat osteoporosis. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited marrow fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.
Assuntos
Conservadores da Densidade Óssea , Reabsorção Óssea , Difosfonatos , Hidroxicloroquina , Ovariectomia , Animais , Ovariectomia/efeitos adversos , Feminino , Camundongos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Camundongos Endogâmicos C57BL , Anabolizantes/farmacologia , Anabolizantes/uso terapêutico , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/prevenção & controle , Osteoporose/metabolismo , Osteoporose/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismoRESUMO
There are currently no targeted delivery systems to satisfactorily treat bone-related disorders. Many clinical drugs consisting of small organic molecules have a short circulation half-life and do not effectively reach the diseased tissue site. This coupled with repeatedly high dose usage that leads to severe side effects. With the advance in nanotechnology, drugs contained within a nano-delivery device or drugs aggregated into nanoparticles (nano-drugs) have shown promises in targeted drug delivery. The ability to design nanoparticles to target bone has attracted many researchers to develop new systems for treating bone related diseases and even repurposing current drug therapies. In this review, we shall summarise the latest progress in this area and present a perspective for future development in the field. We will focus on calcium-based nanoparticle systems that modulate calcium metabolism and consequently, the bone microenvironment to inhibit disease progression (including cancer). We shall also review the bone affinity drug family, bisphosphonates, as both a nano-drug and nano-delivery system for bone targeted therapy. The ability to target and release the drug in a controlled manner at the disease site represents a promising safe therapy to treat bone diseases in the future.
Assuntos
Osso e Ossos , Sistemas de Liberação de Medicamentos , Nanopartículas , Humanos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Animais , Nanopartículas/uso terapêutico , Nanopartículas/administração & dosagem , Doenças Ósseas/tratamento farmacológico , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Sistemas de Liberação de Fármacos por NanopartículasRESUMO
BACKGROUND: Acute-phase reactions (APRs) are common among people treated for the first time with zoledronate (ZOL). The current view is that both the APRs caused by ZOL and its efficacy are related to the mevalonic acid pathway. However, the relationship between APRs and ZOL efficacy remains unclear. METHODS: This was a prospective observational cohort study involving postmenopausal women with osteoporosis in Shanghai, China, for 1 year. A total of 108 patients with an average age of 67.4 ± 5.8 years were treated with 5 mg intravenous ZOL for the first time. Data on demographic characteristics, APRs, blood counts, bone turnover markers, including C-telopeptide collagen crosslinks (CTX) and N-terminal propeptide of type 1 collagen (PINP), and bone mineral density (BMD) were collected. RESULTS: (1) The results did not reveal a relationship between APRs and changes in bone turnover markers and BMD but showed that changes in body temperature (T) within 3 days after administration were positively correlated with changes in the BMD of the LS at Month 12 (ß = 0.279 P = 0.034). (2) This effect was mediated mainly by changes in serum CTX (b = 0.046, 95% CI [0.0010-0.0091]). (3) The ROC curve revealed that when T increased by 1.95 °C, the sensitivity and specificity of identifying clinically important changes in LS BMD after 1 year were optimized. CONCLUSIONS: In this study, we tested the hypothesis that people with elevated body T after initial ZOL treatment had greater improvements in BMD and better outcomes. TRIAL REGISTRATION: NCT, NCT03158246. Registered 18/05/2017.
Assuntos
Reação de Fase Aguda , Temperatura Corporal , Conservadores da Densidade Óssea , Densidade Óssea , Difosfonatos , Imidazóis , Ácido Zoledrônico , Humanos , Ácido Zoledrônico/uso terapêutico , Ácido Zoledrônico/administração & dosagem , Feminino , Idoso , Estudos Prospectivos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Pessoa de Meia-Idade , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Difosfonatos/uso terapêutico , Difosfonatos/administração & dosagem , Temperatura Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Reação de Fase Aguda/sangue , Resultado do Tratamento , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/diagnóstico , Biomarcadores/sangue , Estudos de Coortes , Valor Preditivo dos TestesRESUMO
Changes in the structure of bone can occur in space as an adaptive response to microgravity and on Earth due to the adaptive effects to exercise, to the aging of bone cells, or to prolonged disuse. Knowledge of cell-mediated bone remodeling on Earth informs our understanding of bone tissue changes in space and whether these skeletal changes might increase the risk for fractures or premature osteoporosis in astronauts. Comparisons of skeletal health between astronauts and aging humans, however, may be both informative and misleading. Astronauts are screened for a high level of physical fitness and health, are launched with high bone mineral densities, and perform exercise daily in space to combat skeletal atrophy as an adaptive response to reduced weight-bearing function, while the elderly display cellular and tissue pathology as a response to senescence and disuse. Current clinical testing for age-related bone change, applied to astronauts, may not be sufficient for fully understanding risks associated with rare and uniquely induced bone changes. This review aims to (i) highlight cellular analogies between spaceflight-induced and age-related bone loss, which could aid in predicting fractures, (ii) discuss why overreliance on terrestrial clinical approaches may miss potentially irreversible disruptions in trabecular bone microarchitecture induced by spaceflight, and (iii) detail how the cellular effects of the bisphosphonate class of drugs offer a prophylactic countermeasure for suppressing the elevated bone resorption characteristically observed during long-duration spaceflights. Thus the use of the bisphosphonate will help protect the bone from structural changes while in microgravity either along with exercise or alone when exercise is not performed, e.g. after an injury or illness.
Assuntos
Astronautas , Difosfonatos , Voo Espacial , Humanos , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Osteoporose , Ausência de Peso/efeitos adversos , Densidade Óssea/efeitos dos fármacosAssuntos
Conservadores da Densidade Óssea , Difosfonatos , Humanos , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Osteoporose/tratamento farmacológicoRESUMO
THE AIM OF THE STUDY: Was to investigate the dynamics of mandibular density in cancer patients during therapy with zolendronic acid. MATERIALS AND METHODS: The study comprised 14 patients who received zolendronic acid at a dosage of 4 mg once every 28 days for bone metastases. In all 14 patients, measurements of mandibular density values on CT scans were performed over time. RESULTS: Using multiple linear regression analysis, a model was developed to predict the effect of the number of zolendronic acid injections «X1¼ on the dynamics of mandibular density «Y¼. The resulting formula for predicting mandibular density is Y = 5.9 X1 + 49 HU. CONCLUSION: The model has limitations due to the study design but still can be used by oncologists and dentists to assess mandibular density in patients taking zolendronic acid.
Assuntos
Conservadores da Densidade Óssea , Difosfonatos , Imidazóis , Mandíbula , Ácido Zoledrônico , Humanos , Feminino , Mandíbula/efeitos dos fármacos , Mandíbula/diagnóstico por imagem , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/farmacologia , Masculino , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Pessoa de Meia-Idade , Difosfonatos/administração & dosagem , Difosfonatos/farmacologia , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Densidade Óssea/efeitos dos fármacos , Idoso , Tomografia Computadorizada por Raios X , AdultoRESUMO
RATIONALE: Zoledronic acid is one of the most commonly used intravenous, highly potent amino diphosphonate salts worldwide and is commonly used in patients with primary or secondary osteoporosis, most of whom are well tolerated. There are currently no reports of severe sepsis induced by zoledronic acid. Here we present the first case of severe sepsis induced by zoledronic acid. We reviewed the literature and found that there is currently a lack of reports on severe sepsis induced by zoledronic acid or other diphosphonates. PATIENT CONCERNS: A 58-year-old woman with severe osteoporosis and Behcet disease developed severe sepsis after treatment with zoledronic acid. DIAGNOSIS: Sepsis, septic shock, acute kidney injury, intestinal infection, Behcet disease. INTERVENTIONS: The patient was given intensive care immediately after admission, and massive fluid infusion to expand blood volume could not maintain normal blood pressure. Metaraminol was added to maintain circulatory stability, piperacillin-tazobactam was used to strengthen anti-infection, and glucocorticoids were used for anti-inflammatory treatment. OUTCOMES: The patient was discharged with improvement and followed up in the outpatient clinic. LESSONS: The inducing mechanism of zoledronic acid is not clear, but when the patient has immunosuppression, the use of zoledronic acid should be cautious and monitored. In conclusion, severe sepsis induced by zoledronic acid is a rare but serious complication, and physicians should be aware of this adverse event in time to avoid serious consequences.
Assuntos
Conservadores da Densidade Óssea , Sepse , Ácido Zoledrônico , Humanos , Ácido Zoledrônico/efeitos adversos , Ácido Zoledrônico/uso terapêutico , Feminino , Pessoa de Meia-Idade , Sepse/tratamento farmacológico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Imidazóis/efeitos adversosRESUMO
BACKGROUND: Epithelial ovarian cancer (EOC) is the eighth most common cancer in women, with poor survival outcomes. Observational evidence suggests that nitrogen-based bisphosphonate (NBB) use may be associated with reduced risk of EOC, particularly the endometrioid and serous histotypes; however, confounding by indication is a concern. An alternative approach to investigate the chemo-preventive potential of NBBs is to emulate a target trial by identifying all women who initiate use of NBBs and investigate the risk of EOC for continued users compared with discontinued users. METHODS: Using population-based linked data, we identified all Australian women aged over 50 years who first used NBBs over 2004-12. We used the year after first use to define treatment for each woman as either continued or discontinued use. We emulated randomization using stabilized inverse probability weights to balance the treatment groups using covariates including age, comorbidities and socioeconomic status. We followed women from treatment assignment until EOC diagnosis, death or 31 December 2013. We assessed the risk of EOC (overall and by histotype) using flexible parametric time-to-event models allowing for time-varying effects, and produced time-varying coefficients. RESULTS: Of the 313â383 women in the study, 472 were diagnosed with EOC during follow-up (261 serous EOC), with an average age at diagnosis of 72 years. Continued use of NBBs was associated with reduced risk of EOC overall (HR = 0.87, 95% CI: 0.69, 1.10), and serous EOC (HR = 0.71, 95% CI: 0.53, 0.96), compared with discontinued treatment, with estimates remaining constant over the 9-year follow-up. CONCLUSIONS: Results from our emulated trial suggest that in women who initiated NBB treatment, those who continued use had 13% and 29% lower hazards of being diagnosed with EOC overall and serous EOC, respectively, compared with women who discontinued use.
Assuntos
Carcinoma Epitelial do Ovário , Difosfonatos , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/epidemiologia , Idoso , Pessoa de Meia-Idade , Austrália/epidemiologia , Difosfonatos/uso terapêutico , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/tratamento farmacológico , Idoso de 80 Anos ou mais , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Nitrogênio , Fatores de RiscoRESUMO
BACKGROUND: Low back pain is one of the most common symptoms of osteoporosis. The pain can seriously affect patients' mood and quality of life; it can also further aggravate bone loss, causing a serious social burden. Minodronate is an oral bisphosphonate that needs to be administered daily. It significantly reduces levels of bone turnover markers (BTMs) and rapidly improves symptoms of low back pain in patients with osteoporosis. Osteoporosis requires long-term treatment, and daily dosing reduces patient compliance. Minodronate has a better safety profile than other bisphosphonates. The objective of the trial is to explore the efficacy and safety of minodronate in the treatment of low back pain in postmenopausal osteoporosis patients. METHODS: This is a single-centre, randomized, open-label controlled trial with a 24-week duration. Seventy-two eligible patients will be randomly divided into 4 groups. Subjects will be randomized at a 1:1 ratio to receive either minodronate (1 mg/day) or alendronate (10 mg/day) every day; senior women (≥ 75 years old) and older women (< 75 years old) will be at a ratio of 1:2. The primary outcome is the time required for the visual analogue scale (VAS) score to decline by ≥ 10 from baseline. The secondary outcome is the changes in VAS scores from baseline, the frequency and dosage of rescue medication, BTMs, bone mineral density (BMD), and variations in upper gastrointestinal (GI) symptom scores from baseline (including heartburn, pain, and bloating). DISCUSSION: This study will provide objective evidence for the efficiency and safety of minodronate. Furthermore, it will be helpful to evaluate the quantitative relationship between BTMs and BMD in patients with osteoporosis under different ages. TRIAL REGISTRATION: This study protocol has been registered with ClinicalTrials.gov ID NCT05645289 ( https://clinicaltrials.gov/search?term=NCT05645289 ) on December 8, 2022. The registry name is Peking University Third Hospital. This study protocol was reviewed and approved by the Peking University Third Hospital Medical Science Research Ethics Committee (M2022465, 2022.08.09, V2.0). The results will be published in scientific peer-reviewed journals. TRIAL STATUS: The protocol was registered at ClinicalTrials.gov (registration number: NCT05645289). Recruitment has started in January 2023 and is still ongoing.
Assuntos
Conservadores da Densidade Óssea , Difosfonatos , Imidazóis , Dor Lombar , Osteoporose Pós-Menopausa , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Feminino , Osteoporose Pós-Menopausa/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Idoso , Difosfonatos/uso terapêutico , Difosfonatos/efeitos adversos , Difosfonatos/administração & dosagem , Resultado do Tratamento , Dor Lombar/tratamento farmacológico , Pessoa de Meia-Idade , Imidazóis/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/administração & dosagem , Medição da Dor , Densidade Óssea/efeitos dos fármacos , Alendronato/uso terapêutico , Alendronato/efeitos adversos , Alendronato/administração & dosagemRESUMO
We aimed to compare the extent of bone turnover suppression between patients with atypical femoral fractures (AFFs) and osteoporotic hip fractures (typical femur fractures, TFFs) using a one-to-one matching strategy. A single-center retrospective comparison of females aged ≥ 60 years who underwent operative treatment for AFFs and TFFs between January 2010 and March 2021 was conducted. Demographic characteristics and clinical data including fracture site, past medical history, bone mineral density (BMD), bisphosphonate (BP) medication history, and serum bone turnover marker (BTM) levels were examined. Moreover, we performed a logistic regression analysis to determine the risk factors for AFFs and a one-to-one matched-pair analysis to compare various BTMs. Overall, 336 consecutive females were included: 113 with AFFs and 213 with TFFs. The mean age, BMI, and lowest BMD T-score were 78.6 years, 22.8 kg/m2, and -3.3, respectively. Patients with AFF were younger, had lower BMD, higher BMI, higher prevalence of rheumatoid arthritis, a greater proportion with previous steroid or BP use, and a longer history of BP use than patients with TFF. The 48:48 matched-pair analysis revealed higher serum 25(OH) vitamin-D (30.5 vs 18.2 ng/mL, P < 0.001) and calcium levels (8.8 vs 8.3 ng/dL, P = 0.009) and lower serum CTX levels (0.33 vs 0.54 ng/mL, P = 0.010) in the AFF group than in the TFF group, suggesting a more suppressed bone remodeling. No differences in the other BTM levels were found. Despite identical histories and durations of BP use, the AFF group exhibited lower CTX levels, suggesting more suppressed bone remodeling. This observation leads us to infer that more suppressed bone remodeling, indicated by lower CTX levels, could be linked to the occurrence of AFFs.
Assuntos
Densidade Óssea , Remodelação Óssea , Fraturas do Fêmur , Fraturas do Quadril , Fraturas por Osteoporose , Humanos , Feminino , Idoso , Remodelação Óssea/efeitos dos fármacos , Fraturas do Fêmur/sangue , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/sangue , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Fatores de Risco , Biomarcadores/sangue , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêuticoRESUMO
BACKGROUND: It is well-known that oral surgical procedures pose a high risk for medication-related osteonecrosis of the jaw in patients taking bisphosphonates. Although some position papers and guidelines have been published with regard to its treatment, few studies have investigated prevention methods. This study investigates the effectiveness of methenolone enanthate, an anabolic steroid, for the prevention of medication-related osteonecrosis of the jaw. METHODS: Thirty-six Wistar rats were divided into three groups. Two experimental groups, Z and ZM, took zoledronic acid for 6 weeks prior to extraction of the left maxillary first molar. The Group ZM also was given methenolone enanthate continuously for 1 week before and 4 weeks after the extraction. The control group was not given any medication. The rats were euthanized 5 weeks after extraction. The extraction socket was evaluated clinically for bone exposure and histologically for inflammation, hyperemia, collagen fibers, epithelialization, number of osteoclasts, and empty lacunae. RESULTS: Six rats died during the experimental research. The bone exposure rate, mean numbers of attached osteoclasts (in 40× magnification), and empty lacunae (in 100× magnification) were 0%, 4%, and 0.8% in Group C; 75%, 1%, and 8% in Group Z; and 10%, 2.1%, and 3% in Group ZM, respectively. Significant differences exist between all groups regarding the number of empty lacunae. There were significant differences between Group C/ZM and Group Z in terms of bone exposure rate, inflammation, hyperemia, collagen fiber organization, and epithelialization. CONCLUSION: In our tested preclinical model, methenolone enanthate has shown potential for preventing medication-related osteonecrosis of the jaw.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Ratos Wistar , Animais , Ratos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Masculino , Ácido Zoledrônico/uso terapêutico , Extração Dentária , Distribuição Aleatória , Osteoclastos/efeitos dos fármacos , Imidazóis/farmacologia , Anabolizantes/uso terapêutico , Dente Molar , Difosfonatos/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Alvéolo Dental/efeitos dos fármacosRESUMO
Bisphosphonates are widely used for the treatment of postmenopausal osteoporosis; however, they cause several long-term side effects, necessitating the investigation of local ways to improve osseointegration in compromised bone tissue. The purpose of this study was to evaluate peri-implant bone repair using implants functionalized with zoledronic acid alone (OVX ZOL group, n = 11), zoledronic acid + teriparatide (OVX ZOL + TERI group, n = 11), and zoledronic acid + ruterpy (OVX ZOL + TERPY group, n = 11) compared to the control group (OVX CONV, n = 11). Analyses included computer-assisted microtomography, qualitative histologic analysis, and real-time PCR analysis. Histologically, all functionalized surfaces improved peri-implant repair, with the OVX ZOL + TERI group standing out. Similar results were found in computerized microtomography analysis. In real-time PCR analysis, however, the OVX ZOL and OVX ZOL + TERPY groups showed better results for bone formation, with the OVX ZOL + TERPY group standing out, while there were no statistical differences between the OVX CONV and OVX ZOL + TERI groups for the genes studied at 28 postoperative days. Nevertheless, all functionalized groups showed a reduced rate of bone resorption. In short, all surface functionalization groups outperformed the control group, with overall better results for the OVX ZOL + TERI group.
Assuntos
Osteoporose , Ácido Zoledrônico , Animais , Ratos , Feminino , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/farmacologia , Osteoporose/tratamento farmacológico , Microtomografia por Raio-X , Osseointegração/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Difosfonatos/administração & dosagem , Osteogênese/efeitos dos fármacosRESUMO
Macrophages are important regulators of bone remodeling, and M1 polarization is observed in the setting of medication-related osteonecrosis of the jaws (MRONJ). Here, we characterize the phenotype of macrophages during early stages of MRONJ development in zoledronate (ZA)-treated mice with periodontal disease and explore the role of rosiglitazone, a drug that has been reported to lower the M1/M2 macrophage ratio, in MRONJ burden. Mice received ZA, and experimental periodontal disease (EPD) was induced around their second left maxillary molar. The mice were euthanized 1, 2, or 4 wk later. Micro-computed tomography and histologic and immunohistochemical analyses were carried out. In a separate experiment, mice were treated with ZA in the absence or presence of rosiglitazone, EPD was induced for 5 wk, and the MRONJ burden was assessed. An M1 predilection was noted in ZA versus vehicle (Veh) mice at 1, 2, or 4 wk after ligature placement. M1 cells were found to be positive for MMP-13, and their presence coincided with disruption of the surrounding collagen network in ZA mice. Rosiglitazone caused a reversal in the M1/M2 polarization in Veh and ZA mice. Rosiglitazone did not cause significant radiographic changes 5 wk after EPD in Veh or ZA animals. Importantly, percentage osteonecrosis and bone exposure were decreased in the rosiglitazone-treated versus nontreated ZA sites 5 wk after EPD. Our data point to an important role of M1 macrophage polarization with an overexpression of MMP-13 in the early phases of MRONJ development and provide insight into the use of interventional approaches promoting an M2 phenotype as a preventative means to alleviate MRONJ burden.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Imidazóis , Macrófagos , Rosiglitazona , Tiazolidinedionas , Microtomografia por Raio-X , Ácido Zoledrônico , Animais , Camundongos , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Ácido Zoledrônico/farmacologia , Macrófagos/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Tiazolidinedionas/uso terapêutico , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Imidazóis/farmacologia , Difosfonatos/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , Conservadores da Densidade Óssea/farmacologia , Modelos Animais de Doenças , Fenótipo , Masculino , Remodelação Óssea/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Doenças Periodontais , Colágeno/metabolismoRESUMO
Anabolic bone agents, such as parathyroid hormone receptor agonists (teriparatide and abaloparatide) and sclerostin-inhibiting monoclonal antibody (romosozumab), are superior at preventing clinically significant fractures and/or vertebral fractures in women with and without severe osteoporosis compared with bisphosphonates.
Assuntos
Conservadores da Densidade Óssea , Osteoporose , Humanos , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Feminino , Anticorpos Monoclonais/uso terapêutico , Fraturas por Osteoporose/prevenção & controle , Fraturas por Osteoporose/etiologia , Proteína Relacionada ao Hormônio Paratireóideo , Teriparatida/uso terapêutico , Difosfonatos/uso terapêuticoRESUMO
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) represents a serious health condition, impacting the lives of many patients worldwide. The condition challenges clinical care due to its complex etiology and limited therapeutic options. A thorough understanding of the pathophysiological and patient-related factors that promote disease development is essential. Recently, the oral microbiome has been implicated as a potential driver and modulating factor of BRONJ by several studies. Modern genomic sequencing methods have provided a wealth of data on the microbial composition of BRONJ lesions; however, the role of individual species in the process of disease development remains elusive. A comprehensive PubMed search was conducted to identify relevant studies on the microbiome of BRONJ patients using the terms "microbiome", "osteonecrosis of the jaws", and "bisphosphonates". Studies focusing on symptoms, epidemiology, pathophysiology, risk factors, and treatment options were included. The principal risk factors for BRONJ are tooth extraction, surgical procedures, and the administration of high doses of bisphosphonates. Importantly, the oral microbiome plays a significant role in the progression of the disease. Several studies have identified alterations of microbial composition in BRONJ lesions. However, there is no consensus regarding bacterial species that are associated with BRONJ across studies. The bacterial genera typically found include Actinomyces, Fusobacterium, and Streptococcus. It is postulated that these microbes contribute to the pathogenesis of BRONJ by promoting inflammation and disrupting normal bone remodeling processes. Current therapeutic approaches are disease-stage-specific and the necessity for more effective treatment strategies remains. This review examines the potential causes of and therapeutic approaches to BRONJ, highlighting the link between microbial colonization and BRONJ development. Future research should seek to more thoroughly investigate the interactions between bisphosphonates, the oral microbiome, and the immune system in order to develop targeted therapies.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Difosfonatos , Microbiota , Humanos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/microbiologia , Microbiota/efeitos dos fármacos , Fatores de Risco , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Boca/microbiologiaRESUMO
Bone-modifying agents (BMAs) are integral to managing patients with advanced cancer. They improve quality of survival by reducing skeletal-related events, treating hypercalcaemia and chemotherapy-induced bone loss (Coleman in Clin Cancer Res 12: 6243s-6249s, 2006), (Coleman in Ann Oncol 31: 1650-1663, 2020). Two decades ago, medication-related osteonecrosis of the jaw (MRONJ) was first reported following BMA therapy (Marx in J Oral Maxillofac Surg 61: 1115-1117, 2003). The risk of MRONJ extends over a decade following BMA treatment with bisphosphonates, complicating dental care such as extractions. In addition, MRONJ has been reported following additional therapies such as antiangiogenic agents, cytotoxic agents, immunotherapy, and targeted agents. The use of BMAs in the curative and adjuvant cancer setting is increasing, consequently the implication of MRONJ is growing. Over the past 20 years, the literature has consolidated major risk factors for MRONJ, the pathophysiology and management strategies for MRONJ. Our review aims to document the development of MRONJ preventative and management strategies in cancer patients receiving a BMA. The authors advocate the incorporation of dental oncology strategies into contemporary cancer care, to optimise long-term quality of survival after cancer treatment.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Humanos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/terapia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/complicações , Fatores de Risco , Antineoplásicos/efeitos adversos , Difosfonatos/efeitos adversos , Doenças Maxilomandibulares/induzido quimicamente , Doenças Maxilomandibulares/terapiaAssuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Feminino , Humanos , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/uso terapêutico , Difosfonatos/efeitos adversos , Difosfonatos/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
Bone-modifying agents are a class of drugs that alleviate a series of bone-related events such as pain, pathologic fracture, spinal cord compression, and hypercalcemia caused by bone metastases, and currently include bisphosphonates and RANKL inhibitors. Due to the widespread use of bone-modifying agents, the adverse effects of them are gradually increasing and affecting patients' quality of life. The Breast Cancer Group, Chinese Medical Doctor Association, and the International Medical Society, Chinese Anti-Cancer Association have organized relevant experts to focus on the treatment of bone metastases of advanced malignant tumors based on evidence-based medicine, discuss the management of adverse reactions to bone-modifying agents and form the consensus. Based on the first Expert Consensus on Safety Management of Bone-modifying Agents in China, this consensus added the definition of osteonecrosis of the jaw related to bone-modifying agents, the occurrence of adverse reactions of bone-modifying drugs reported in the literature, and summarized the clinical experience of clinicians in the management of adverse reactions in practice in recent years, and ultimately, the expert group members discussed and proposed reasonable suggestions to guide clinicians in the safety management of bone-modifying agents.
Assuntos
Conservadores da Densidade Óssea , Neoplasias Ósseas , Consenso , Difosfonatos , Humanos , Neoplasias Ósseas/secundário , Neoplasias Ósseas/tratamento farmacológico , Conservadores da Densidade Óssea/efeitos adversos , Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Ligante RANK/antagonistas & inibidores , China , Qualidade de Vida , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controleRESUMO
OBJECTIVE: To analyze osteoporosis medication prescribing trends across specialties in the context of a Bone Health Clinic. INTRODUCTION: Osteoporosis affects over 10 million adults in the US, taking a significant toll on patients and the healthcare system. Although screening methods and treatments are improving, the disease remains underdiagnosed and undertreated. This study aims to evaluate the prescribing trends of osteoporosis medication among department specialties to delineate the benefits of a bone health clinic. METHODS: Retrospective data collection identified and analyzed patients within the Penn State Health system prescribed one of the following osteoporosis medications: Bisphosphonate, denosumab, romosozumab, teriparatide, abaloparatide, or raloxifene. Date range: 4/18/2016 to 4/14/2021. Data collection identified the specialty origin of prescriptions for osteoporosis medications across various medical specialties (e.g., orthopaedics, family medicine, and internal medicine). RESULTS: 10,736 prescription orders were issued to patients with an average age of 68 years. Non-Hispanic Caucasian patients received 88.6% of prescriptions, followed by Asian (3.4%) and African American (2.2%). Female patients accounted for 87.8% of all prescriptions. The Bone Health Clinic under two orthopaedic providers wrote 3,619 prescriptions, averaging 361.9 prescriptions per provider per year-marking the highest rate among specialties. The clinic prescriptions constituted 33.7% of all prescriptions across specialties. Orthopaedic surgery prescribed the most denosumab, romosozumab, teriparatide, and abaloparatide prescriptions, and had the highest number of male osteoporosis patients compared to other specialties (15.6%), consequently prescribing the most male prescriptions (578). CONCLUSION: Establishing a bone health clinic dedicated to osteoporosis management leads to significantly higher prescription rates per provider, increased utilization of anabolic therapies compared to other specialties, and more male patients being treated-an often-neglected population in osteoporosis.