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Advances in Therapy Jan 2022The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces... (Review)
Review
The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term. Video abstract: Denosumab in the Treatment of Osteoporosis-10 Years Later (MP4 62727 KB).
Topics: Bone Density; Bone Density Conservation Agents; Denosumab; Female; Humans; Osteoporosis; Osteoporosis, Postmenopausal; Osteoporotic Fractures
PubMed: 34762286
DOI: 10.1007/s12325-021-01936-y -
Annals of Internal Medicine Feb 2023The prevalence of osteoporosis is increasing in the United States. (Meta-Analysis)
Meta-Analysis Review
Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians.
BACKGROUND
The prevalence of osteoporosis is increasing in the United States.
PURPOSE
To evaluate low bone mass and osteoporosis treatments to prevent fractures.
DATA SOURCES
Ovid MEDLINE ALL, Ovid Evidence Based Medicine Reviews: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov from 2014 through February 2022.
STUDY SELECTION
Adults receiving eligible interventions for low bone mass or osteoporosis. Randomized controlled trials (RCTs) for fracture outcomes, and RCTs and large observational studies ( ≥1000) for harms.
DATA EXTRACTION
Abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE).
DATA SYNTHESIS
We included 34 RCTs (in 100 publications) and 36 observational studies. Bisphosphonates and denosumab reduced hip, clinical and radiographic vertebral, and other clinical fractures in postmenopausal females with osteoporosis (moderate to high CoE). Bisphosphonates for 36 months or more may increase the risk for atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ), but the absolute risks were low. Abaloparatide and teriparatide reduced clinical and radiographic vertebral fractures but increased the risk for withdrawals due to adverse events (WAEs; moderate to high CoE). Raloxifene and bazedoxifene for 36 months or more reduced radiographic vertebral but not clinical fractures (low to moderate CoE). Abaloparatide, teriparatide, and sequential romosozumab, then alendronate, may be more effective than bisphosphonates in reducing clinical fractures for 17 to 24 months in older postmenopausal females at very high fracture risk (low to moderate CoE). Bisphosphonates may reduce clinical fractures in older females with low bone mass (low CoE) and radiographic vertebral fractures in males with osteoporosis (low to moderate CoE).
LIMITATION
Few studies examined participants with low bone mass, males, or Black-identifying persons, sequential therapy, or treatment beyond 3 years.
CONCLUSION
Bisphosphonates, denosumab, abaloparatide, teriparatide, and romosozumab, followed by alendronate, reduce clinical fractures in postmenopausal females with osteoporosis. Abaloparatide and teriparatide increased WAEs; longer duration bisphosphonate use may increase AFF and ONJ risk though these events were rare.
PRIMARY FUNDING SOURCE
American College of Physicians. (PROSPERO: CRD42021236220).
Topics: Male; Adult; Female; Humans; Aged; Bone Density Conservation Agents; Teriparatide; Alendronate; Osteoporosis, Postmenopausal; Denosumab; Network Meta-Analysis; Fractures, Bone; Osteoporosis; Diphosphonates; Spinal Fractures; Physicians
PubMed: 36592455
DOI: 10.7326/M22-0684 -
The New England Journal of Medicine Oct 2017Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption.
METHODS
We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated.
RESULTS
Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed.
CONCLUSIONS
In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214 .).
Topics: Aged; Alendronate; Antibodies, Monoclonal; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Female; Fractures, Bone; Humans; Incidence; Least-Squares Analysis; Osteoporosis, Postmenopausal; Risk; Spinal Fractures
PubMed: 28892457
DOI: 10.1056/NEJMoa1708322 -
PloS One 2022Maxillofacial trauma can be limited to superficial lacerations, abrasions, and facial bone fractures. The objective of this study was to determine the etiology, pattern,...
INTRODUCTION
Maxillofacial trauma can be limited to superficial lacerations, abrasions, and facial bone fractures. The objective of this study was to determine the etiology, pattern, and predictors of soft tissue and bony injuries.
MATERIALS AND METHODS
This study was conducted in the department of maxillofacial surgery Lady Reading hospital Pakistan from Jan 2019 to June 2021. The nonprobability consecutive sampling technique was used for the selection of patients. All patients were assessed clinically and radiologically. The neurosensory examination was done for any altered sensation, anesthesia, or paresthesia. Motor nerve function was also assessed clinically. Data were analyzed using SPSS version 26. The etiology and pattern of maxillofacial trauma were stratified among age and genders using the chi-square test to see effect modifiers. Tests for regression analysis were also applied. P≤0.05 was considered significant.
RESULTS
A total of 253 patients meeting inclusion criteria were included in this study. The majority of these patients were males, 223 (88.1%), while only 30 (11.9%) were females. The mean age for the group was 25.4 ± 12.6 years. RTAs were the most common causes of trauma (63.6%) followed by assault (15.0%), falls (11.5%), FAIs (5.9%), and sports (0.4%). The most vulnerable skeletal part was the mandible (22.9%) followed by Zygoma (7.1%), significantly predicted by RTAs. Soft tissue laceration analysis showed a high frequency of multiple lacerations (38%) significantly predicted by FAIs. The frequency of trigeminal nerve injury was 5.5% (14 patients) and that of the facial nerve was 1.6% (4 patients). The strongest association of nerve injury was with firearm injury (47%), followed by road traffic accidents and sports injuries.
CONCLUSION
Road traffic accident was the most common etiological factor and mandible fracture was commonly predicted by RTA. Trigeminal nerve injuries were common, frequency of nerve injuries was highly associated with mandible fracture and was predicted by FAI.
Topics: Adolescent; Adult; Causality; Child; Female; Firearms; Humans; Lacerations; Male; Mandibular Fractures; Maxillofacial Injuries; Trigeminal Nerve Injuries; Wounds, Gunshot; Young Adult
PubMed: 36174089
DOI: 10.1371/journal.pone.0275515 -
Journal of Bone Oncology Apr 2022Skeletal-related events (SREs) are complications of bone metastases and carry a significant patient and economic burden. Denosumab is a receptor activator of nuclear... (Review)
Review
Skeletal-related events (SREs) are complications of bone metastases and carry a significant patient and economic burden. Denosumab is a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor approved for SRE prevention in patients with multiple myeloma and patients with bone metastases from solid tumors. In phase 3 trials, denosumab showed superiority to the bisphosphonate zoledronate in reducing the risk of first on-study SRE by 17% (median time to first on-study SRE delayed by 8.2 months) and the risk of first and subsequent on-study SREs by 18% across multiple solid tumor types, including some patients with multiple myeloma. Denosumab also improved pain outcomes and reduced the need for strong opioids. Additionally, a phase 3 trial showed denosumab was noninferior to zoledronate in delaying time to first SRE in patients with newly diagnosed multiple myeloma. Denosumab has a convenient 120 mg every 4 weeks recommended dosing schedule with subcutaneous administration. Rare but serious toxicities associated with denosumab include osteonecrosis of the jaw, hypocalcemia, and atypical femoral fracture events, with multiple vertebral fractures reported following treatment discontinuation. After a decade of real-world clinical experience with denosumab, we are still learning about the optimal use and dosing for denosumab. Despite the emergence of novel and effective antitumor therapies, there remains a strong rationale for the clinical utility of antiresorptive therapy for SRE prevention. Ongoing studies aim to optimize clinical management of patients using denosumab for SRE prevention while maintaining safety and efficacy.
PubMed: 35242510
DOI: 10.1016/j.jbo.2022.100416 -
Dental and Medical Problems 2021Extractions of third molars constitute about 90% of the scheduled surgical procedures performed by oral surgeons. Wisdom tooth surgery is associated with complications,...
BACKGROUND
Extractions of third molars constitute about 90% of the scheduled surgical procedures performed by oral surgeons. Wisdom tooth surgery is associated with complications, such as the lingual and inferior alveolar nerve damage, bleeding, tooth/jaw fractures, tooth displacement into the adjacent anatomical spaces, trismus, infections, and other.
OBJECTIVES
The aim of the study was to analyze complications after wisdom tooth extraction in patients treated at the Department of Oral Surgery of Jagiellonian University Medical College in Kraków, Poland, in the years 2016-2018.
MATERIAL AND METHODS
A retrospective analysis of the medical records of 339 patients treated in the outpatient setting was performed. The inclusion criterion comprised a single extraction of a third molar. The exclusion criteria were multiple extractions, comorbidities and pregnancy. No antibiotic prophylaxis was used. The incidence of post-extraction complications, such as oroantral communication, postoperative hematoma, acute inflammation of the surrounding tissues, trismus, and transient paresthesia in relation to patient gender and age, the developmental stage and location of the removed tooth as well as the type of surgery were studied.
RESULTS
Perioperative complications occurred in 51 (15.0%) cases, and comprised the acute inflammation of the surrounding tissues in 31 patients, trismus after the removal of 13 lower third molars, oroantral communication after the extraction of 5 upper wisdom teeth, and hematoma as well as a transient sensory alteration of the lingual nerve in 1 case each. Complications were more common in patients who had a surgical extraction of a wisdom tooth with root separation and in cases of lower third molar extractions. No statistically significant correlation was found between the patients' age or gender, the developmental stage of the extracted tooth and the number of observed complications.
CONCLUSIONS
Lower third molars and the necessity of surgical extraction with root separation are risk factors for postoperative complications in patients who require wisdom tooth removal. Complications after the removal of third molars are most often inflammatory.
Topics: Humans; Molar, Third; Poland; Retrospective Studies; Tooth Extraction; Tooth, Impacted
PubMed: 33789003
DOI: 10.17219/dmp/127028 -
Annals of Internal Medicine Jul 2019Optimal long-term osteoporosis drug treatment (ODT) is uncertain.
BACKGROUND
Optimal long-term osteoporosis drug treatment (ODT) is uncertain.
PURPOSE
To summarize the effects of long-term ODT and ODT discontinuation and holidays.
DATA SOURCES
Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies.
STUDY SELECTION
48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB).
DATA EXTRACTION
Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy.
DATA SYNTHESIS
Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapy reduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE).
LIMITATION
No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays.
CONCLUSION
Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-term bisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms.
PRIMARY FUNDING SOURCE
National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006).
Topics: Alendronate; Bone Density; Bone Density Conservation Agents; Bone Diseases, Metabolic; Diphosphonates; Drug Administration Schedule; Duration of Therapy; Female; Hip Fractures; Humans; Osteoporosis, Postmenopausal; Osteoporotic Fractures; Spinal Fractures; Zoledronic Acid
PubMed: 31009947
DOI: 10.7326/M19-0533 -
Osteoporosis International : a Journal... May 2018Osteoporosis is a common skeletal disorder characterized by low bone mass, which leads to reduced bone strength and an increased risk of fractures. Anabolic agents have... (Review)
Review
Osteoporosis is a common skeletal disorder characterized by low bone mass, which leads to reduced bone strength and an increased risk of fractures. Anabolic agents have been shown to improve bone mass and decrease fracture risk in osteoporosis patients by directly stimulating osteoblasts to produce new bone. Currently, two anabolic agents are available in the USA: recombinantly produced teriparatide (TPTD), which is the fully active (1-34) amino active sequence of human parathyroid hormone (PTH), and abaloparatide (APTD), a synthetic analog of parathyroid hormone-related peptide (PTHrP). At present, both agents are approved only for treatment of patients with osteoporosis at high risk of fracture. Nonetheless, their anabolic properties have led to off-label application in additional settings which include spine fusion, osteonecrosis of the jaw, arthroplasty, and fracture healing. In this article, we summarize available scientific literature regarding the efficacy, effectiveness, and safety of TPTD in these off-label settings.
Topics: Anabolic Agents; Arthroplasty; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Fracture Healing; Humans; Off-Label Use; Osteoporosis; Spinal Fusion; Teriparatide
PubMed: 29627891
DOI: 10.1007/s00198-018-4507-8 -
Journal of Bone and Mineral Research :... Jan 2016Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit... (Review)
Review
Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.
Topics: Advisory Committees; Age Factors; Diphosphonates; Female; Femoral Fractures; Humans; Imidazoles; Male; Osteoporosis; Risk Factors; Sex Factors; Spinal Fractures; Zoledronic Acid
PubMed: 26350171
DOI: 10.1002/jbmr.2708