Incident Clinical Fractures Research Articles

Predictors of fracture in middle-aged and older adults with type 2 diabetes and overweight or obesity.

Persons with type 2 diabetes have increased fracture risk that existing fracture risk assessment tools underestimate. Identify fracture predictors in persons with type 2 diabetes and overweight or obesity, considering traditional and diabetes-related risk factors. Secondary analysis of the Look AHEAD: Action for Health in Diabetes randomized clinical trial, with randomization from 2001-2004 and fracture follow-up until 2015. Multicenter U.S. study. Men and women 45-75 years old with type 2 diabetes and body mass index≥25 kg/m2. Potential fracture predictors ascertained at randomization included traditional and diabetes-related risk factors (diabetes duration, diabetic neuropathy, antidiabetic medication use, hemoglobin A1c, and renal function). Total hip bone mineral density (BMD) was measured in a subcohort. All incident clinical fractures, ascertained by self-report and centrally adjudicated with medical records review. Over a median 12.2 years follow-up, 649 of the 4,703 participants experienced at least one clinical fracture. Thiazolidinedione use [hazard ratio (HR):1.22, 95% confidence interval (CI):1.02-1.46] and insulin use [HR:1.34, 95% CI:1.08-1.66] were significant diabetes-related predictors of all clinical fractures. When measured in a subcohort (n=1,285), total hip BMD was the strongest modifiable predictor of all clinical fractures [Per 1 standard deviation (SD)=0.1 g/cm2 increase, HR:0.47, 95% CI:0.39-0.58]. Thiazolidinedione and insulin use predict clinical fracture in middle-aged and older persons with type 2 diabetes and overweight or obesity. Evaluating BMD is advisable if these medications are prescribed. Fracture risk prediction tools may consider including thiazolidinedione and insulin use to refine prediction in this population.

Testosterone Treatment and Fractures in Men with Hypogonadism

BackgroundTestosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed.MethodsIn a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated.ResultsThe full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points.ConclusionsAmong middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.)

Long-term use of tenofovir disoproxil fumarate increases fracture risk in elderly patients with chronic hepatitis B

The use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB). Patients with CHB aged ≥60 years receiving entecavir or TDF between January 2008 and December 2022 were identified using a territory-wide database in Hong Kong. The risk of incident fracture in entecavir- and TDF-treated patients before and after month 24 were compared after propensity score matching. A total of 41,531 patients with CHB (mean age 69.8±7.8 years, 61.6% male) receiving entecavir (n= 39,897 [96.1%]) and TDF (n= 1,634 [3.9%]) were analysed. At a median follow-up of 25.3 (9.1-58.5) months, 1,733 (4.2%) patients developed incident fracture. Patients with incident fracture were more likely to have diabetes, hypertension, congestive heart failure, rheumatoid arthritis, osteoporosis, and a history of fracture. Compared with propensity score-matched entecavir-treated patients, the risk of incident fracture in TDF-treated patients was comparable in the first 24 months (weighted subdistribution hazard ratio [sHR] 0.99, 95% CI 0.56-1.73, p= 0.960) but increased after month 24 (weighted sHR 1.80, 95% CI 1.11-2.93, p= 0.019). The 24-, 60-, and 96-month cumulative incidences (95% CI) of fracture in TDF-treated and entecavir-treated patients were 2.3% (1.6%-3.4%) vs. 2.6% (1.9%-3.5%), 6.4% (5.0%-8.2%) vs. 4.7% (3.8%-6.0%), and 10.2% (8.3%-12.6%) vs. 6.8% (5.4%-8.5%), respectively. The risk of fracture increased with TDF treatment for ≥24 months in elderly patients with CHB. Selection of nucleos(t)ide analogues should be individualised based on age and comorbidities. Previous literature suggested that the use of tenofovir disoproxil fumarate (TDF) is associated with a decrease in bone mineral density. However, data on the impact of TDF on long-term incident clinical fracture remains scarce. In this real-world territory-wide study of 41,531 treated patients with chronic hepatitis B in Hong Kong, patients who received TDF were at a higher risk of fracture after 2 years of treatment than those who received entecavir. Given the ageing population of patients with chronic hepatitis B and the rising prevalence of comorbidities, our findings support the current treatment guidelines that recommend selecting antiviral treatment based on age and comorbidities.

Machine-Learning Assessed Abdominal Aortic Calcification is Associated with Long-Term Fall and Fracture Risk in Community-Dwelling Older Australian Women.

Abdominal aortic calcification (AAC), a recognized measure of advanced vascular disease, is associated with higher cardiovascular risk and poorer long-term prognosis. AAC can be assessed on dual-energy X-ray absorptiometry (DXA)-derived lateral spine images used for vertebral fracture assessment at the time of bone density screening using a validated 24-point scoring method (AAC-24). Previous studies have identified robust associations between AAC-24 score, incident falls, and fractures. However, a major limitation of manual AAC assessment is that it requires a trained expert. Hence, we have developed an automated machine-learning algorithm for assessing AAC-24 scores (ML-AAC24). In this prospective study, we evaluated the association between ML-AAC24 and long-term incident falls and fractures in 1023 community-dwelling older women (mean age, 75 ± 3 years) from the Perth Longitudinal Study of Ageing Women. Over 10 years of follow-up, 253 (24.7%) women experienced a clinical fracture identified via self-report every 4-6 months and verified by X-ray, and 169 (16.5%) women had a fracture hospitalization identified from linked hospital discharge data. Over 14.5 years, 393 (38.4%) women experienced an injurious fall requiring hospitalization identified from linked hospital discharge data. After adjusting for baseline fracture risk, women with moderate to extensive AAC (ML-AAC24 ≥ 2) had a greater risk of clinical fractures (hazard ratio [HR] 1.42; 95% confidence interval [CI], 1.10-1.85) and fall-related hospitalization (HR 1.35; 95% CI, 1.09-1.66), compared to those with low AAC (ML-AAC24 ≤ 1). Similar to manually assessed AAC-24, ML-AAC24 was not associated with fracture hospitalizations. The relative hazard estimates obtained using machine learning were similar to those using manually assessed AAC-24 scores. In conclusion, this novel automated method for assessing AAC, that can be easily and seamlessly captured at the time of bone density testing, has robust associations with long-term incident clinical fractures and injurious falls. However, the performance of the ML-AAC24 algorithm needs to be verified in independent cohorts. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Effect of Pelvic External Beam Radiation Therapy on Bone Mineral Density: A Secondary Analysis of a Phase 3 Randomized Controlled Trial

Pelvic radiation therapy may lead to decreased bone mineral density (BMD) and increased risk of fracture that could be of particular concern in patients with prostate cancer who also receive androgen deprivation therapy (ADT). We performed an exploratory analysis of a randomized, double-masked, placebo-controlled trial to determine whether exposure to prior pelvic external beam radiation therapy (XRT) affects BMD and risk of fracture in patients with prostate cancer treated with ADT. Patients with nonmetastatic prostate cancer aged ≥70 years or <70 years with low BMD (T-score < -1) or osteoporotic fracture who had been receiving ADT for ≥12 months were randomly assigned to receive densoumab or placebo every 6 months for 3 years. BMD was measured at baseline and at months 1, 3, 6, 12, 24, and 36. We applied multivariable linear mixed-effects models with an interaction term between the treatment arm and exposure to prior pelvic XRT to evaluate differential XRT effect on percent BMD change between the 2 treatment arms. Among 1407 eligible patients, 31% (n = 447) received prior pelvic XRT. There was no significant difference in any clinical fractures among patients with (5.8%, 26 of 447) or without (5.2%, 50 of 960) prior pelvic XRT (P = .42). Prior pelvic XRT was associated with a significant (0.54%) improvement in BMD (95% CI, 0.05-1.02) in the placebo group and a nonsignificant (0.04%) decline in BMD (95% CI, -0.47 to -0.35) in the denosumab group (interaction P = .007). There was no significant difference in pelvic XRT effect on percent BMD change in the lumbar spine (P = .65) or total hip (P = .39) between the 2 treatment groups. We did not find sufficient evidence to suggest any detrimental effect of pelvic XRT on the treatment effect from denosumab on percent BMD change, with only an approximately 5% incidence of clinical fractures.

Clinical fracture incidence in metastatic hormone-sensitive prostate cancer and risk-reduction following addition of zoledronic acid to androgen deprivation therapy with or without docetaxel: Long-term results from the STAMPEDE trial

Clinical fracture incidence in metastatic hormone-sensitive prostate cancer and risk-reduction following addition of zoledronic acid to androgen deprivation therapy with or without docetaxel: Long-term results from the STAMPEDE trial

Characteristics Associated With 5-Year Fracture Risk Versus 5-Year Mortality Risk Among Late-Life Men.

Identifying late-life men who might benefit from treatment to prevent fracture is challenging given high mortality. Our objective was to evaluate risks of clinical fracture, hip fracture, and mortality prior to fracture among men aged at least 80 years. Study participants included 3 145 community-dwelling men (mean [standard deviation] age 83 [2.8] years) from the Osteoporotic Fractures in Men (MrOS) Study. We used separate multivariable Fine-Gray competing risk models with prespecified risk factors (age, hip bone mineral density [BMD], recent fracture [<5 years], fall history [previous year], and multimorbidity [# conditions]) to estimate subdistribution hazard ratios and absolute 5-year risks of any clinical fracture and mortality prior to clinical fracture. Secondary analysis considered a hip fracture. There were 414 incident clinical fractures and 595 deaths without prior fracture within 5 years. BMD, fall history, and recent fracture were strong predictors of clinical fracture. Age and multimorbidity were strong predictors of mortality before fracture. After accounting for competing risks, age, BMD, and fall history were each associated with both risks of hip fracture and mortality before hip fracture. Model discrimination varied from 0.65 (mortality before fracture) to 0.79 (hip fracture). Estimated mortality differed substantially among men with similar clinical fracture risk due to a modest correlation between fracture risk and competing mortality risk = 0.37. In late-life men, strong risk factors for clinical fracture and hip fracture include fall history, BMD, and recent fracture. Osteoporosis drug treatment decisions may be further enhanced by consideration of fracture risk versus overall life expectancy.

Menopausal hormone therapy reduces the risk of fracture regardless of falls risk or baseline FRAX probability—results from the Women’s Health Initiative hormone therapy trials

SummaryIn a combined analysis of 25,389 postmenopausal women aged 50–79 years, enrolled in the two Women’s Health Initiative hormone therapy trials, menopausal hormone therapy vs. placebo reduced the risk of fracture regardless of baseline FRAX fracture probability and falls history.IntroductionThe aim of this study was to determine if the anti-fracture efficacy of menopausal hormone therapy (MHT) differed by baseline falls history or fracture risk probability as estimated by FRAX, in a combined analysis of the two Women’s Health Initiative (WHI) hormone therapy trials.MethodsA total of 25,389 postmenopausal women aged 50–79 years were randomized to receive MHT (n = 12,739) or matching placebo (n = 12,650). At baseline, questionnaires were used to collect information on falls history, within the last 12 months, and clinical risk factors. FRAX 10-year probability of major osteoporotic fracture (MOF) was calculated without BMD. Incident clinical fractures were verified using medical records. An extension of Poisson regression was used to investigate the relationship between treatment and fractures in (1) the whole cohort; (2) those with prior falls; and (3) those without prior falls. The effect of baseline FRAX probability on efficacy was investigated in the whole cohort.ResultsOver 4.3 ± 2.1 years (mean ± SD), MHT (vs. placebo) significantly reduced the risk of any clinical fracture (hazard ratio [HR] 0.72 [95% CI, 0.65–0.78]), MOF (HR 0.60 [95% CI, 0.53–0.69]), and hip fracture (0.66 [95% CI, 0.45–0.96]). Treatment was effective in reducing the risk of any clinical fracture, MOF, and hip fracture in women regardless of baseline FRAX MOF probability, with no evidence of an interaction between MHT and FRAX (p > 0.30). Similarly, there was no interaction (p > 0.30) between MHT and prior falls.ConclusionIn the combined WHI trials, compared to placebo, MHT reduces fracture risk regardless of FRAX probability and falls history in postmenopausal women.

Differential risk of fracture attributable to type 2 diabetes mellitus according to skeletal site.

Impaired bone quality, especially related to accumulation of advanced glycation end-products (AGEs) and higher incidence of falls contribute substantially to a higher risk of fracture associated with type 2 diabetes mellitus (T2DM). These factors may predispose to fractures more at skeletal sites where impaired bone toughness and falls play a larger pathogenic role (such as hip fractures) compared to skeletal sites where they are less important (such as vertebral fractures). To determine if the associations of T2DM with prevalent and incident vertebral fractures are as strong as they are for hip and other non-vertebral fractures. Amongst 80,238 individuals in the Manitoba Bone Density Program database (mean [SD] age 64.4 [11.1] years, 89.8% female, 8676 with diagnosed T2DM) with a baseline BMD test (1996-2016), we estimated hazard ratios (HRs) for incident clinical fracture at different skeletal sites in those with compared to those without T2DM using Cox proportional hazards models over a mean (SD) 9.0 (5.0) year follow-up period. We also estimated odds ratios for prevalent vertebral fracture on VFA images amongst 9594 individuals (mean [SD] 76 [6.8] years, 1185 with T2DM diagnosis at time of DXA-VFA) and for prior clinical fractures at different skeletal sites using logistic regression models. After multivariable adjustment, T2DM was associated with incident hip (HR 1.63, 95% CI 1.44 to 1.85) and proximal humerus fractures (HR 1.59, 95% CI 1.39 to 1.83), but was not associated with incident forearm fracture (HR 1.00, 95% CI 0.86 to 1.17) and only weakly with incident clinical vertebral fracture (HR 1.16, 95% CI 1.01 to 1.33). Similarly, T2DM was associated with prior hip (OR 1.78, 95% CI 1.21 to 2.61) and prior proximal humerus fracture (OR 1.31, 95% CI 1.02 to 1.68) but not with prior forearm (OR 0.89, 95% CI 0.74 to 1.06) or prevalent vertebral fracture on VFA images (OR 0.91, 95% CI 0.77 to 1.08). T2DM is a stronger risk factor for hip and proximal humerus fractures than for vertebral and wrist fractures. Further research is warranted to determine if the known differences in falls and/or bone quality between T2DM and age-related osteoporosis account for these differential associations.

Estimation of fracture risk by the FRAX tool in patients with systemic lupus erythematosus: a 10-year longitudinal validation study.

Background:The fracture risk assessment tool has been widely used to stratify the 10-year fracture risk to guide therapy. Using the actual fracture data of a 10-year longitudinal cohort of older patients with systemic lupus erythematosus, we reported an underestimation of the tool in predicting major symptomatic osteoporotic fractures. Treatment of osteoporosis in systemic lupus erythematosus should not be based on fracture risk estimation alone. Relevant time-dependent risk factors should be taken into account for an individualized decision.Objective:To compare the observed fracture incidence in a 10-year longitudinal cohort of patients with systemic lupus erythematosus (SLE) with the fracture risk prediction from the fracture risk assessment (FRAX) tool.Methods:Adult patients (⩾40 years) with SLE who had a first DEXA scan performed in 2005–2009 were studied. The 10-year rates of major osteoporotic and hip fractures were estimated by FRAX using clinical data at DEXA with adjustment for prednisolone dosage. The actual incidence of clinical fractures at 10 years was compared with the estimated rates. Factors associated with new fractures were studied by logistic regression.Results:A total of 229 SLE patients were studied (age: 50.2 ± 6.6 years, 93% women). Glucocorticoid was used in 148 (65%) patients at baseline (mean dose: 7.3 ± 6.9 mg/day; 34% ⩾ 7.5 mg/day). Osteoporosis (bone mineral density T score ⩽ –2.5) at the hip, femoral neck, or spine was present in 61 (27%) patients. The estimated 10-year risk of major osteoporotic and hip fractures by FRAX was 3.4 ± 4.5% and 0.95 ± 2.3%, respectively. After 10 years, three patients developed hip fracture, 6 patients had limb fractures and 20 patients had symptomatic vertebral fractures (major osteoporotic fracture 12.7%, hip fracture 1.3%). The actual major osteoporotic fracture rate was significantly higher than the FRAX estimation (12.7% vs 3.4%; p < 0.001). Logistic regression revealed that osteoporosis (odds ratio (OR): 4.07 [1.51–10.9]), previous fragility fracture (OR: 3.18 [1.02–9.90]), and a parental history of fracture (OR: 4.44 [1.16–17.0]) were independently associated with new clinical fractures at 10 years.Conclusion:The FRAX tool underestimates the major clinical fracture risk at 10 years in patients with SLE.

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.

Risk of Fracture Among Older Adults With Primary Hyperparathyroidism Receiving Parathyroidectomy vs Nonoperative Management

Primary hyperparathyroidism (PHPT) contributes to the development and progression of osteoporosis in older adults. The effectiveness of parathyroidectomy for reducing fracture risk in older adults is unknown. To compare the incidence of clinical fracture among older adults with PHPT treated with parathyroidectomy vs nonoperative management. This was a population-based, longitudinal cohort study of all Medicare beneficiaries with PHPT from 2006 to 2017. Multivariable, inverse probability weighted Cox proportional hazards and Fine-Gray competing risk regression models were constructed to determine the association of parathyroidectomy vs nonoperative management with incident fracture. Data analysis was conducted from February 17, 2021, to September 14, 2021. The primary outcome was clinical fracture at any anatomic site not associated with major trauma during the follow-up period. Among the 210 206 Medicare beneficiaries with PHPT (mean [SD] age, 75 [6.8] years; 165 637 [78.8%] women; 183 433 [87.3%] White individuals), 63 136 (30.0%) underwent parathyroidectomy within 1 year of diagnosis, and 147 070 (70.0%) were managed nonoperatively. During a mean (SD) follow-up period of 58.5 (35.5) months, the unadjusted incidence of fracture was 10.2% in patients treated with parathyroidectomy. During a mean (SD) follow-up of 52.5 (33.8) months, the unadjusted incidence of fracture was 13.7% in patients observed nonoperatively. On multivariable analysis, parathyroidectomy was associated with lower adjusted rates of any fracture (hazard ratio [HR], 0.78; 95% CI, 0.76-0.80]) and hip fracture (HR, 0.76; 95% CI, 0.72-0.79). At 2, 5, and 10 years, parathyroidectomy was associated with adjusted absolute fracture risk reduction of 1.2% (95% CI, 1.0-1.4), 2.8% (95% CI, 2.5-3.1), and 5.1% (95% CI, 4.6-5.5), respectively, compared with nonoperative management. On subgroup analysis, there were no significant differences in the association of parathyroidectomy with fracture risk by age group, sex, frailty, history of osteoporosis, or meeting operative guidelines. Fine-Gray competing risk regression confirmed parathyroidectomy was associated with a lower probability of any fracture and hip fracture when accounting for the competing risk of death (HR, 0.84; 95% CI, 0.82-0.85; and HR, 0.83; 95% CI, 0.80-0.85, respectively). This longitudinal cohort study found that parathyroidectomy was associated with a lower risk of any fracture and hip fracture among older adults with PHPT, suggesting a clinically meaningful benefit of operative management in this population.

Incidence of clinical fractures: A 7-year follow-up study in institutionalized adults with epilepsy and intellectual disability

PurposeTo determine the incidence of clinical fractures over seven years of follow-up, in adults with epilepsy and intellectual disability, residing in a long-stay care facility. MethodsIn 2009, all institutionalized adult patients (n = 261) were invited to undergo a Dual-energy X-ray Absorptiometry (DXA) measurement and a Vertebral Fracture Assessment (VFA). Participants were followed over seven years or until date of discharge (in case of moving from the care facility) or date of death. The patients’ medical files were screened for radiology reports and staff notes, to identify clinical fractures. Fracture incidence rates (IR) were determined and compared for subgroups, by calculating incidence rate ratios. Hazard ratios were calculated to identify factors associated with fracture risk, using Cox Proportional Hazards analyses. ResultsA total of 205 patients (124 male, 60.5%) aged between 18 and 88 years (median 48, IQR 34–60) were enrolled. At baseline, 92 patients (44.9%) were diagnosed with osteopenia and 65 (31.7%) with osteoporosis. Between 2009 and 2016, 30 patients (14.6%) deceased and 3 patients (1.5%) left the care facility. During follow-up, 156 clinical fractures were reported in 82 patients (40.0%). Thirty-eight patients (18.5%) had at least one major osteoporotic fracture. Overall, the IR was 11.6 fractures per 100 person-years. Fracture risk was significantly lower in patients who were wheelchair dependent than in patients who were able to walk (p<.001). ConclusionThis study demonstrated that 40% of institutionalized adults with epilepsy and intellectual disability had at least one clinical fracture during seven years of follow-up, despite adequate anti-osteoporosis treatment.

Clinical fracture incidence of rotary and reciprocating NiTi files: A systematic review and meta-regression.

This systematic review was registered in PROSPERO (CRD42017075917) and aimed to investigate whether the available clinical evidence supports the hypothesis that reciprocating motion results in a lower incidence of nickel-titanium files fracture compared to continuous rotation. Clinical studies that reported the incidence of fracture of engine-driven nickel-titanium files were included. The main exposure was the kinematics, and the primary outcome was the incidence of files fracture. The overall incidence of files fracture was 2.27%, with a trend for higher incidence with rotary motion (2.43%) than with reciprocating (1.0%), though without significant differences. Multiple meta-regression models revealed that the use of nickel-titanium files in more than four teeth and less proficient operators were associated with a higher incidence of file fracture. There was no difference in the clinical incidence of fracture of nickel-titanium instruments between reciprocating and rotary motions; however, other factors were identified.

Greater Carboxy-Methyl-Lysine Is Associated With Increased Fracture Risk in Type 2 Diabetes.

Accumulation of advanced glycation end-products (AGE) in bone alters collagen structure and function. Fluorescent AGEs are associated with fractures but less is known regarding non-fluorescent AGEs. We examined associations of carboxy-methyl-lysine (CML), with incident clinical and prevalent vertebral fractures by type 2 diabetes (T2D) status, in the Health, Aging, and Body Composition cohort of older adults. Incident clinical fractures and baseline vertebral fractures were assessed. Cox regression was used to analyze the associations between serum CML and clinical fracture incidence, and logistic regression for vertebral fracture prevalence. At baseline, mean ± standard deviation (SD) age was 73.7 ± 2.8 and 73.6 ± 2.9 years in T2D (n=712) and non-diabetes (n=2332), respectively. Baseline CML levels were higher in T2D than non-diabetes (893 ± 332 versus 771 ± 270 ng/mL, p < 0.0001). In multivariate models, greater CML was associated with higher risk of incident clinical fracture in T2D (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.24-1.79 per 1-SD increase in log CML) but not in non-diabetes (HR 1.03; 95% CI, 0.94-1.13; p for interaction=0.001). This association was independent of bone mineral density (BMD), glycated hemoglobin (hemoglobin A1c), weight, weight loss, smoking, cystatin-C, and medication use. CML was not significantly associated with the odds of prevalent vertebral fractures in either group. In conclusion, higher CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. These results implicate CML in the pathogenesis of bone fragility in diabetes. © 2021 American Society for Bone and Mineral Research (ASBMR).

Saturated and Unsaturated Bone Marrow Lipids Have Distinct Effects on Bone Density and Fracture Risk in Older Adults.

Greater bone marrow adiposity (BMAT) is associated with lower bone mineral density (BMD) and vertebral fractures; less is known about BMAT composition and bone. We studied BMAT composition and bone outcomes in 465 participants from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. BMAT saturation and unsaturation, measured with magnetic resonance spectroscopy, were defined as the ratio of saturated (1.3 ppm peak) or unsaturated (5.3 ppm peak) lipid to total marrow contents, respectively. At baseline and follow-up visits, spine and hip BMD were assessed with quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) and vertebral fractures were identified with DXA. Incident clinical fractures were identified through medical records for up to 8.8 years of follow-up. Associations between BMAT composition and BMD, bone loss, and fractures were evaluated in adjusted regression models. At baseline, mean ± standard deviation (SD) participant age was 81.7 ± 4.3 years, mean BMAT unsaturation was 3.5% ± 1.0%, and mean saturation was 46.3% ± 7.2% in the full cohort (47.7% women). Each SD increase in BMAT saturation was associated with lower trabecular BMD: -23.6% (spine) and -13.0% (total hip) (all p < 0.0001). Conversely, BMAT unsaturation (per SD increase) was associated with higher trabecular BMD: +17.5% (spine) and +11.5% (total hip) (all p < 0.001). BMAT saturation (per SD increase) was associated with greater risk for prevalent (odds ratio [OR] 1.46; 95% confidence interval [CI], 1.11-1.92) and incident (OR 1.55; 95% CI, 1.03-2.34) vertebral fracture. BMAT unsaturation (per SD increase) was associated with lower risk for incident vertebral fracture (OR 0.58; 95% CI, 0.38-0.89). In gender stratified analyses, BMAT saturation and unsaturation had opposite associations with incident clinical fracture among men. In general, saturated marrow lipids were associated with worse skeletal outcomes, whereas unsaturated lipids were associated with better outcomes. We recommend that future studies of marrow fat and skeletal health report measurements of saturated and unsaturated marrow lipids, rather than total marrow fat content alone. © 2022 American Society for Bone and Mineral Research (ASBMR).

Cumulative Endogenous Estrogen Exposure Is Associated With Postmenopausal Fracture Risk: The Women's Health Initiative Study.

We aimed to evaluate the relationship between cumulative endogenous estrogen exposure and fracture risk in 150,682 postmenopausal women (aged 50 to 79 years at baseline) who participated in the Women's Health Initiative. We hypothesized that characteristics indicating lower cumulative endogenous estrogen exposure would be associated with increased fracture risk. We determined ages at menarche and menopause as well as history of irregular menses from baseline questionnaires and calculated years of endogenous estrogen exposure from ages at menarche and menopause. Incident clinical fractures were self-reported over an average 16.7 years of follow-up. We used multivariable proportional hazards models to assess the associations between the estrogen-related variables and incidence of any clinical fracture. In fully adjusted models, those with the fewest years of endogenous estrogen exposure (<30) had an 11% higher risk of developing central body fractures and a 9% higher risk of lower extremity fractures than women with 36 to 40 years of endogenous estrogen exposure (the reference category). In contrast, women with the most years of endogenous estrogen exposure (more than 45 years) had a 9% lower risk of lower extremity fractures than the reference category. Women with irregular (not monthly) menstrual cycles were 7% to 8% more likely to experience lower extremity fractures than women with regular monthly cycles. Our findings support the hypothesis that characteristics signifying lower cumulative endogenous estrogen exposure are associated with higher fracture risk. © 2022 American Society for Bone and Mineral Research (ASBMR).

Total Hip Bone Mineral Density as an Indicator of Fracture Risk in Bisphosphonate-Treated Patients in a Real-World Setting.

ABSTRACTBone mineral density (BMD) is an established measure used to diagnose patients with osteoporosis. In clinical trials, change in BMD has been shown to provide a reliable estimate of fracture risk reduction, and achieved BMD T‐score has been shown to reflect the near‐term risk of fracture. We aimed to test the association between BMD T‐score and fracture risk in patients treated for osteoporosis in a real‐world setting. This retrospective, observational cohort study included Swedish females aged ≥55 years who had a total hip BMD measurement at one of three participating clinics. Patients were separated into two cohorts: bisphosphonate‐treated and bisphosphonate‐naïve prior to BMD measurement, stratified by age and prior nonvertebral fracture status. The primary outcome was cumulative incidence of clinical fractures within 24 months of BMD measurement, with other fracture types included as secondary outcomes. Associations between T‐score and fracture risk were estimated using proportional hazards regression and restricted cubic splines. A total of 15,395 patients were analyzed: 11,973 bisphosphonate‐naïve and 3422 bisphosphonate‐treated. In the 24 months following BMD measurement, 6.3% (95% confidence interval [CI], 5.9–6.7) of bisphosphonate‐naïve and 8.4% (95% CI, 7.5–9.4) of bisphosphonate‐treated patients experienced a clinical fracture. Strong inverse relationships between BMD T‐score and fracture incidence were observed in both cohorts. Among bisphosphonate‐naïve patients, this relationship appeared to plateau around T‐score −1.5, indicating smaller marginal reductions in fracture risk above this value; bisphosphonate‐treated patients showed a more consistent marginal change in fracture risk across the evaluated T‐scores (−3.0 to –0.5). Trends remained robust regardless of age and prior fracture status. This real‐world demonstration of a BMD–fracture risk association in both bisphosphonate‐naïve and bisphosphonate‐treated patients extends evidence from clinical trials and recent meta‐regressions supporting the suitability of total hip BMD as a meaningful outcome for the clinical management of patients with osteoporosis. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The incidence of clinical fractures in adults aged 50 years and older in Spain

Abstract Objective The aim of this study was to quantify the incidence of all clinical fractures, including traumatic and fragility fractures, in patients aged 50 years and older, and to describe their distribution by fracture location, sex and age. Methods The incidence of clinical fractures at 10 hospitals in Catalonia, with a reference population of 3 155 000 inhabitants, was studied. For 1 week, from 30 May to 5 June 2016, we reviewed the discharge reports of the Traumatology section of the Emergency Department to identify all fractures diagnosed in patients ≥50 years of age. As a validation technique, data collection was carried out for 1 year at one of the centres, from 1 December 2015 to 30 November 2016. The fracture incidence, including the 95% CI, was estimated for the entire sample and grouped by fracture type, location, sex and age. Results A total of 283 fractures were identified. Seventy per cent were in women, with a mean age of 72 years. The overall fracture incidence was 11.28 per 1000 person-years (95% CI: 11.10, 11.46), with an incidence of traumatic and fragility fractures of 4.15 (95% CI: 4.04, 4.26) and 7.13 per 1000 person-years (95% CI: 6.99, 7.28), respectively. The incidence of fractures observed in the validation sample coincided with that estimated for the whole of Catalonia. The most common fragility fractures were of the hip, forearm, humerus and vertebrae. Conclusion The results of this study are the first to estimate the incidence of clinical fragility fractures in Spain, grouped by location, age and sex.

Measured height loss predicts incident clinical fractures independently from FRAX: a registry-based cohort study.

FRAX® accepts baseline height and weight as input variables, but does not consider change in these parameters over time. To evaluate the association between measured height or weight loss on subsequent fracture risk adjusted for FRAX scores, risk factors, and competing mortality. Using a dual-energy x-ray absorptiometry (DXA) registry for the Province of Manitoba, Canada, we identified women and men age 40years or older with height and weight measured at the time of two DXA scans. Cox regression analyses were performed to test for a covariate-adjusted association between prior height and weight loss with incident fractures occurring after the second scan using linked population-based healthcare data. The study population consisted of 11,495 individuals (average age 68.0 ± 9.9years, 94.6% women). During median follow-up 6.0years, records demonstrated incident major osteoporotic fracture (MOF) in 869 individuals, hip fractures in 265, clinical vertebral fractures in 207, and any fracture in 1203. Prior height loss was significantly greater in individuals with fracture compared with those without fracture, regardless of fracture site. Mortality was greater in those with prior height loss (HR per SD 1.11, 95% CI 1.06-1.17) or weight loss (HR per SD 1.26, 95% CI 1.19-1.32). Each SD in height loss was associated with increased fracture risk (MOF 12-17%, hip 8-19%, clinical vertebral 28-37%, any fracture 14-19%). Prior weight loss was associated with 21-30% increased risk for hip fracture, but did not increase risk for other fractures. Height loss of 3.0cm or greater more than doubled the risk for subsequent fracture. Prior height loss is associated with a small but significant increase in risk of incident fracture at all skeletal sites independent of other clinical risk factors and competing mortality as considered by FRAX. Prior weight loss only increases risk for subsequent hip fracture.