Glucocorticoids Increase Fracture Risk and Fracture Prevalence Independently from Bone Mineral Density and Clinical Risk Factors: Results from the Gliwice Osteoporosis (GO) Study

The aim of the study was to establish the influence of glucocorticoids (GC) on fracture risk, probability, and prevalence. A set of 1548 postmenopausal women were divided into study group – treated with GC (n=114, age 66.48±7.6 years) and controls (n=1434, age 66.46±6.83 years). Data on clinical risk factors for osteoporosis and fractures were collected. Hip bone densitometry was performed using a device Prodigy (GE, USA). Fracture probability was established by FRAX, and fracture risk by Garvan algorithm and POL-RISK. Fracture risk and fracture probability were significantly greater for GC-treated women in comparison to controls. In the study group, there were 24, 3, 24, and 6 fractures noted at spine, hip, forearm, and arm, respectively. The respective numbers of fractures reported in controls at those skeletal sites were: 186, 23, 240, and 25. The use of GCs increased significantly prevalence of all major, spine and arm fractures. Also the number of all fractures was affected by GC use. Following factors significantly increased fracture probability: age (OR 1.04 per each year; 95% CI: 1.03–1.06), GC use (OR 1.54; 95% CI: 1.03–2.31), falls (OR 2.09; 95% CI: 1.60–2.73), and FN T-score (OR 0.62 per each unit; 95% CI: 0.54–0.71). In conclusion, in patients treated with GCs the fracture risk, probability, and prevalence were increased. This effect was evident regardless of whether GC therapy is included in the algorithm as a risk factor (FRAX, POL-RISK) or not taken into consideration (Garvan nomogram).

When to Start and Stop Bone-Protecting Medication for Preventing Glucocorticoid-Induced Osteoporosis

Glucocorticoid-induced osteoporosis (GIOP) leads to fractures in up to 40% of patients with chronic glucocorticoid (GC) therapy when left untreated. GCs rapidly increase fracture risk, and thus many patients with anticipated chronic GC exposures should start anti-osteoporosis pharmacotherapy to prevent fractures. In addition to low awareness of the need for anti-osteoporosis therapy among clinicians treating patients with GCs, a major barrier to prevention of fractures from GIOP is a lack of clear guideline recommendations on when to start and stop anti-osteoporosis treatment in patients with GC use. The aim of this narrative review is to summarize current evidence and provide considerations for the duration of anti-osteoporosis treatment in patients taking GCs based on pre-clinical, clinical, epidemiologic, and pharmacologic evidence. We review the pathophysiology of GIOP, outline current guideline recommendations on initiating and stopping anti-osteoporosis therapy for GIOP, and present considerations for the duration of anti-osteoporosis treatment based on existing evidence. In each section, we illustrate major points through a patient case example. Finally, we conclude with proposed areas for future research and emerging areas of interest related to GIOP clinical management.

Exploring the Mechanisms Underlying Drug-Induced Fractures Using the Japanese Adverse Drug Event Reporting Database

Fractures occur when bones become fragile and are subjected to external forces as occurring during falls. The use of drugs that increase bone fragility or fall risk increases the risk of fracture. This study investigates drug-induced fractures reported in the Japanese Adverse Drug Event Report (JADER) database in patients using 4892 drugs. Atypical femur fracture was the most frequently reported fracture, and 58 other fractures were also reported. Using Volcano plots and multiple logistic regression analysis, we identified the risk factors for drug-induced fractures as being female, of older age, higher body mass index, and using one of 90 drugs. The drug groups significantly associated with drug-induced fractures included bone resorption inhibitors, antiviral drugs, dopaminergic drugs, corticosteroids, and sleep sedatives. Principal component analysis was used to examine the relationship between the use of specific drugs and the site of drug-induced fracture. Bone resorption inhibitors and corticosteroids were associated with atypical femur fractures, jaw fractures, and ulna fractures through an osteoclast-mediated process. Other drugs were found to increase fracture risk via non-osteoclast-mediated mechanisms. These findings suggest that many drugs can result in drug-induced fractures through a variety of mechanisms.

Objectively Measured Physical Activity, Sedentary Behavior, and Incident Fracture in Older Women: The OPACH Study

Women aged 65 and older experience nearly three-fourths of the 2 million osteoporotic fractures annually in the US, yet whether accelerometer-measured volumes and intensities of physical activity and sedentary behavior (SB) are associated with reduced fracture risk is understudied. We investigated associations of accelerometer-measured light physical activity (LPA), moderate-to-vigorous physical activity (MVPA), sedentary time (ST), and mean sedentary bout duration (MBD) with incident clinical fractures (hip, vertebral, pelvis, lower leg, upper arm, forearm, and wrist) in the WHI OPACH cohort. Participants (N=6248; mean±SD age=78.6±6.7; 34% Black, 17% Hispanic) without prior hip fracture wore the ActiGraph GT3X+ for 7 days between May 2012-April 2014 and were followed through March 2020 for incident clinical fracture (N=711). Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI), adjusting for age, race-ethnicity, education, alcohol, smoking, height, weight, falls history, RAND-36 physical function, diabetes, thiazide use, prescription osteoporotic therapy, and age at menopause. The HR(95% CI) across MVPA quartiles was 1.00(reference), 1.15(0.93-1.41), 0.90(0.72-1.13), and 0.79(0.61-1.02); p-trend=0.01. The HR(95% CI) for a one-interquartile range increment in MVPA (42 minutes/day) was 0.86(0.76-0.97). Associations were modified by prescription osteoporotic therapy [no: HR=0.77(0.66-0.89), yes: HR=1.03(0.85-1.25); p-interaction=0.01] and varied in magnitude by age[<80: HR=0.78(0.64-0.96), ≥80: HR=0.92(0.79-1.07); p-interaction=0.09], BMI [<30 kg/m2: HR=0.85(0.75-0.97), ≥30 kg/m2: HR=0.90(0.67-1.19); p-interaction=0.08], and race-ethnicity [Black: HR =0.63(0.44-0.89), Hispanic: HR =0.78(0.56-1.09), White: HR =0.92(0.80-1.06); p-interaction=0.16]. LPA, ST, or MBD were not associated with incident fractures. These data suggest that MVPA may reduce and not increase fracture risk and that LPA and SB do not increase fracture risk.

The Impact of Maternal High-Fat Diet on Bone Microarchitecture in Offspring

The incidence of obesity in women of reproductive age has significantly increased over the past 100 years. There is a well-established connection between maternal obesity during pregnancy and an increased risk of developing non-communicable cardiometabolic diseases in her offspring. This mini-review focuses on evidence examining the effect of maternal high-fat diet (HFD) on skeletal development and bone health in later life in offspring. The majority of rodent studies indicate that maternal HFD generally negatively affects both embryonic bone development and bone volume in adult animals. Details surrounding the mechanisms of action that drive changes in the skeleton in offspring remain unclear, although numerous studies suggest that some effects are sex-specific. Human studies in this area are limited but also suggest that HFD during pregnancy may impair bone formation and increase fracture risk during childhood. Given the consequences of low bone mass and deranged bone microarchitecture for offspring, advances in our understanding of the developmental origins of bone health is critical in the battle against osteoporosis.

Osteoporosis Detection by Physical Function Tests in Resident Health Exams: A Japanese Cohort Survey Randomly Sampled from a Basic Resident Registry

Osteoporosis may increase fracture risk and reduce healthy quality of life in older adults. This study aimed to identify an assessment method using physical performance tests to screen for osteoporosis in community dwelling individuals. A total of 168 women aged 50–89 years without diagnosed osteoporosis were randomly selected from the resident registry of a cooperating town for the evaluation of physical characteristics, muscle strength, and several physical performance tests. The most effective combinations of evaluation items to detect osteoporosis (i.e., T-score ≤ −2.5 at the spine or hip) were selected by multivariate analysis and cutoff values were determined by likelihood ratio matrices. Thirty-six women (21.4%) were classified as having osteoporosis. By analyzing combinations of two-step test (TST) score and body mass index (BMI), osteoporosis could be reliably suspected in individuals with TST ≤ 1.30 and BMI ≤ 23.4, TST ≤ 1.32 and BMI ≤ 22.4, TST ≤ 1.34 and BMI ≤ 21.6, or TST < 1.24 and any BMI. Setting cut-off values for TST in combination with BMI represents an easy and possibly effective screening tool for osteoporosis detection in resident health exams.

Persistence with oral bisphosphonates and denosumab among older adults in primary care in Ireland

Summary Gaps in pharmacological treatment for osteoporosis can reduce effectiveness. Among older adults, we found about half of new users of oral bisphosphonate and denosumab persisted with their treatment at 2 years, with few switching to alternative therapy. Persistence is suboptimal and warrants evaluation of interventions to improve this. Purpose Gaps in pharmacological treatment for osteoporosis can reduce effectiveness. This study aimed to estimate persistence rates for oral bisphosphonates and denosumab in older primary care patients and identify factors associated with discontinuation. Methods Older patients newly prescribed oral bisphosphonates or denosumab during 2012–2017 were identified from 44 general practices (GP) in Ireland. Persistence without a coverage gap of >90 days was calculated for both medications from therapy initiation. Factors associated with time to discontinuation were explored using Cox regression analysis. Exposures included age group, osteoporosis diagnosis, fracture history, calcium/vitamin D prescription, number of other medications, health cover, dosing frequency (bisphosphonates) and previous bone-health medication (denosumab). Results Of 41,901 patients, n=1569 were newly initiated on oral bisphosphonates and n=1615 on denosumab. Two-year persistence was 49.4% for oral bisphosphonates and 53.8% for denosumab and <10% were switched to other medication. Having state-funded health cover was associated with a lower hazard of discontinuation for both oral bisphosphonates (HR=0.49, 95% CI=0.36–0.66, p<0.01) and denosumab (HR=0.71, 95% CI=0.57–0.89, p<0.01). Older age group, number of medications and calcium/vitamin D prescription were also associated with better bisphosphonate persistence, while having osteoporosis diagnosed was associated with better denosumab persistence. Conclusion Persistence for osteoporosis medications is suboptimal. Of concern, few patients are switched to other bone-health treatments when denosumab is stopped which could increase fracture risk. Free access to GP services and medications may have resulted in better medication persistence in this cohort. Future research should explore prescribing choices in primary care osteoporosis management and evaluate cost-effectiveness of interventions for improving persistence.

Effects of Erythropoietin in White Adipose Tissue and Bone Microenvironment

Erythropoietin (EPO) is expressed primarily in fetal liver and adult kidney to stimulate red blood cell production. Erythropoietin receptor expression is not restricted to erythroid progenitor cells, and non-erythroid EPO activity includes immune response and bone remodeling. In bone fracture models, EPO administration promotes bone formation and accelerates bone healing. In contrast, in healthy adult mice, exogenous EPO-stimulated erythropoiesis has been concomitant with bone loss, particularly at high EPO, that may be accompanied by increased osteoclast activation. Other EPO-associated responses include reduced inflammation and loss of fat mass with high-fat diet feeding, especially in male mice. While EPO exhibited a sex-dimorphic response in regulation of fat mass and inflammation in obese mice, EPO-stimulated erythropoiesis as well as EPO-associated bone loss was comparable in males and females. EPO administration in young mice and in obese mice resulted in bone loss without increasing osteoclasts, suggesting an osteoclast-independent mechanism, while loss of endogenous EPO decreased bone development and maintenance. Ossicle formation of bone marrow stromal cell transplants showed that EPO directly regulates the balance between osteogenesis and adipogenesis. Therefore, during development, endogenous EPO contributes to normal bone development and in maintaining the balance between osteogenesis and adipogenesis in bone marrow stromal cells, while EPO treatment in mice increased erythropoiesis, promoted bone loss, decreased bone marrow adipogenesis, and increased osteoclast activity. These observations in mouse models suggest that the most prevalent use of EPO to treat anemia associated with chronic kidney disease may compromise bone health and increase fracture risk, especially at a high dose.

Persistence with oral bisphosphonates and denosumab among older adults in primary care in Ireland

ABSTRACTPurposeGaps in pharmacological treatment for osteoporosis can reduce effectiveness. This study aimed to estimate persistence rates for oral bisphosphonates and denosumab in older primary care patients and identify factors associated with discontinuation.MethodsOlder patients newly prescribed oral bisphosphonates or denosumab between 2012 and 2017 were identified from 44 general practices (GP) in Ireland. Persistence without a coverage gap of >90 days was calculated for both medications from therapy initiation. Factors associated with time to discontinuation were explored using Cox regression analysis. Exposures included age-group, osteoporosis diagnosis, fracture history, calcium/vitamin D prescription, number of other medications, health cover, dosing frequency (bisphosphonates) and previous bone-health medication (denosumab).ResultsOf 41,901 patients, n=1,569 newly initiated on oral bisphosphonates and n=1,615 on denosumab. Two-year persistence was 49.4% for oral bisphosphonates and 53.8% for denosumab and <10% were switched to other medication. Having state-funded health cover was associated with a lower hazard of discontinuation for both oral bisphosphonates (HR=0.49, 95%CI=0.36-0.66, p<0.01) and denosumab (HR=0.71, 95%CI=0.57-0.89, p<0.01). Older age-group, number of medications and calcium/vitamin D prescription were also associated with better bisphosphonate persistence while having osteoporosis diagnosed was associated with better denosumab persistence.ConclusionPersistence for osteoporosis medications is sub-optimal. Of concern, few patients are switched to other bone-health treatments when denosumab is stopped which could increase fracture risk. Free access to GP services and medications may have resulted in better medication persistence in this cohort. Future research should explore prescribing choices in primary-care osteoporosis management and evaluate cost-effectiveness of interventions for improving persistence.SUMMARYGaps in pharmacological treatment for osteoporosis can reduce its effectiveness. This study found approximately half of older adults in primary care newly initiated on bisphosphonates or denosumab were still taking these after 2 years. Abrupt discontinuation of denosumab without switching to an alternative is concerning due to increased fracture risk.

Short Oblique Patellar Tunnels for Patellar Fixation Do Not Increase Fracture Risk in MPFL Reconstruction: A Retrospective Cohort Study

Objectives: The current standard of care for recurrent patellar instability is reconstruction of the medial patellofemoral ligament (MPFL), the primary soft tissue constraint to lateral subluxation of the patella. Historically, transpatellar bone tunnels have been associated with increased rates of patella fracture. To avoid this dreaded outcome, many surgeons now employ suture anchors to affix the MPFL graft to the patella. This study aims to evaluate the costs and outcomes associated with short oblique patella tunnels as compared to suture anchor fixation in MPFL reconstruction. Methods: A total of 467 knees in 419 patients undergoing MPFL reconstruction between 2011 and 2018 were included in the study. A single institution electronic medical record queried for all patients undergoing extra-articular ligament reconstruction using Current Procedural Technology codes 27422 and 27427. Chart review of operative reports was utilized to identify those who had undergone MPLF reconstruction. Patients undergoing revision MPFL reconstruction were excluded, as were patients for whom fully transpatellar bone tunnels were employed for patellar fixation. This left two groups: those for whom small, oblique tunnels (n = 277) and suture anchors (n = 190) for patellar fixation were compared. Implant pricing for the 3.2 mm drill bit, suture anchors, and allograft were obtained through publicly available databases and prior published research. Results: Short oblique tunnels showed no significant increase in risk of patellar fracture compared to suture anchors for patellar fixation (P = 1.00). Use of suture anchors was associated with an increased risk of subluxation or dislocation compared to small, oblique tunnels (OR = 3.34, P = 0.021). No significant difference in the need for revision MPFL reconstruction surgery was found (OR = 1.964, P = 0.45) [Table 1]. The cost difference between allo- and autograft in ligament reconstruction has been analyzed in multiple prior studies and found to be $1100. The 3.2mm drill bit used to create the tunnels cost $84 but is reusable, while the average cost of two suture anchors was $500, leading to a material cost savings of $1600 per case in which transpatellar tunnels were used for MPFL autograft fixation when compared to a suture anchor and allograft combination. Regardless of the graft choice, material cost savings exceeds $400 per case simply by conversion to short oblique tunnels rather than suture anchors. Conclusion: The use of small, oblique tunnels with hamstring autograft is a safe and cost effective method for patellar fixation in MPFL reconstruction. Value in healthcare is defined as quality divided by cost. As surgeons and institutions are increasingly judged not only by the quality of the care they provide, but also in its cost, employment of this high-value technique should be considered by surgeons performing MPFL reconstruction.