Clinical Features of 24 Patients With Rebound‐Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases

We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty‐four postmenopausal women with vertebral fracture(s) after denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last denosumab injection. Eighty‐three percent of the patients were treatment naïve, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut‐off of 2 years, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients. © 2017 American Society for Bone and Mineral Research.     

FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab

Romosozumab is a bone‐forming agent with a dual effect of increasing bone formation and decreasing bone resorption. In FRActure study in postmenopausal woMen with ostEoporosis (FRAME), postmenopausal women with osteoporosis received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. One year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Here, we further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T‐score changes from baseline over the 2‐year study and contrast these results with the long‐term BMD gains seen with denosumab during Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (n = 3591 placebo, n = 3589 romosozumab), most romosozumab‐treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T‐score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo‐to‐denosumab: 0.38 and 0.17), with the 2‐year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p < 0.001), with fewer fractures consistently observed across other fracture categories. The data support the clinical benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive therapy. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

The Interaction of Acute-Phase Reaction and Efficacy for Osteoporosis After Zoledronic Acid: HORIZON Pivotal Fracture Trial

Zoledronic acid (ZOL) as a yearly infusion is effective in reducing fracture risk. An acute-phase reaction (APR), consisting of flu-like symptoms within 3 days after infusion, is commonly seen. The objective of this analysis was to investigate whether APR occurrence influences drug efficacy. This analysis uses data from the 3-year randomized clinical trial, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). APRs were identified as adverse events within 3 days of first infusion with higher frequency in ZOL than placebo. To compare mean 3-year change in bone mineral density (BMD) in ZOL versus placebo, among women with and without APR, t tests were used. Logistic regression was used to examine the relationship between APR occurrence and odds of incident morphometric vertebral fracture. Cox regression was used to determine the risk of nonvertebral and hip fractures for women with versus without APR. Logistic and Cox models were used to determine the risk of incident fracture in ZOL versus placebo for women with and without an APR. The analysis included 3862 women in the ZOL group and 3852 in placebo, with 42.4% in ZOL versus 11.8% in placebo experiencing an APR. The difference in BMD mean change for ZOL versus placebo was similar for women with and without an APR (all p interaction >0.10). Among ZOL women, those with APR had 51% lower vertebral fracture risk than those without (odds ratio [OR] = 0.49, p < 0.001). A similar but nonsignificant trend was observed for nonvertebral and hip fracture (relative hazard [RH] = 0.82, p = 0.10; RH = 0.70, p = 0.22, respectively). There was a greater treatment-related reduction in vertebral fracture risk among women with APR (OR = 0.19) than those without (OR = 0.38) (p interaction = 0.01). Our results suggest that women starting ZOL who experience an APR will have a larger reduction in vertebral fracture risk with ZOL. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment

Although treat-to-target strategies are being discussed in osteoporosis, there is little evidence of what the target should be to reduce fracture risk maximally. We investigated the relationship between total hip BMD T-score and the incidence of nonvertebral fracture in women who received up to 10 years of continued denosumab therapy in the FREEDOM (3 years) study and its long-term Extension (up to 7 years) study. We report the percentages of women who achieved a range of T-scores at the total hip or femoral neck over 10 years of denosumab treatment (1343 women completed 10 years of treatment). The incidence of nonvertebral fractures was lower with higher total hip T-score. This relationship plateaued at a T-score between -2.0 and -1.5 and was independent of age and prevalent vertebral fractures, similar to observations in treatment-naïve subjects. Reaching a specific T-score during denosumab treatment was dependent on the baseline T-score, with higher T-scores at baseline more likely to result in higher T-scores at each time point during the study. Our findings highlight the importance of follow-up BMD measurements in patients receiving denosumab therapy because BMD remains a robust indicator of fracture risk. These data support the notion of a specific T-score threshold as a practical target for therapy in osteoporosis. © 2019 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)     

Prediction of Osteoporotic Fractures in Elderly Individuals: A Derivation and Internal Validation Study Using Healthcare Administrative Data

In Canada and other countries, osteoporosis is monitored as part of chronic disease population surveillance programs. Although fractures are the principal manifestation of osteoporosis, very few algorithms are available to identify individuals at high risk of osteoporotic fractures in current surveillance systems. The objective of this study was to derive and validate predictive models to accurately identify individuals at high risk of osteoporotic fracture using information available in healthcare administrative data. More than 270,000 men and women aged ≥66 years were randomly selected from the Quebec Integrated Chronic Disease Surveillance System. Selected individuals were followed between fiscal years 2006–2007 and 2015–2016. Models were constructed for prediction of hip/femur and major osteoporotic fractures for follow-up periods of 5 and 10 years. A total of 62 potential predictors measurable in healthcare administrative databases were identified. Predictor selection was performed using a manual backward algorithm. The predictive performance of the final models was assessed using measures of discrimination, calibration, and overall performance. Between 20 and 25 predictors were retained in the final prediction models (eg, age, sex, social deprivation index, most of the major and minor risk factors for osteoporosis, diabetes, Parkinson's disease, cognitive impairment, anemia, anxio-depressive disorders). Discrimination of the final models was higher for the prediction of hip/femur fracture than major osteoporotic fracture and higher for prediction for a 5-year than a 10-year period (hip/femur fracture for 5 years: c-index = 0.77; major osteoporotic fracture for 5 years: c-index = 0.71; hip/femur fracture for 10 years: c-index = 0.73; major osteoporotic fracture for 10 years: c-index = 0.68). The predicted probabilities globally agreed with the observed probabilities. In conclusion, the derived models had adequate predictive performance in internal validation. As a final step, these models should be validated in an external cohort and used to develop indicators for surveillance of osteoporosis. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997–2016) and SIDIAP (2007–2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m², aged 40 years or older were identified. New bisphosphonate users were propensity score–matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 The Authors. Journal of Bone and Mineral Research published byWiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Bisphosphonate Use Is Protective of Radiographic Knee Osteoarthritis Progression Among those With Low Disease Severity and Being Non-Overweight: Data From the Osteoarthritis Initiative

Antiresorptive medications have been explored for treating knee osteoarthritis (OA); however, little data exist on the effects of today's more potent nitrogen-containing oral bisphosphonates on radiographic disease-progression in patients with varying disease-severity, especially those who are not overweight. The primary objective of this cohort study was to determine if the use of bisphosphonates is protective against 2-year radiographic-progression of knee OA in Osteoarthritis Initiative (OAI) participants, stratified by baseline radiographic disease status. Secondary objectives were to examine effects in non-overweight participants (body mass index [BMI] < 25 kg/m²) and cumulative bisphosphonate exposure effects. We identified female OAI participants aged ≥50 years and excluded those missing baseline radiograph readings, bisphosphonate use information, or all clinical questionnaire information at baseline. Participants reporting bisphosphonate use (69% alendronate) were propensity-matched 1:1 to non–bisphosphonate users and followed until first radiographic knee OA progression (1-unit increase in Kellgren and Lawrence [KL] grade) or data were censored (first missed visit or end of 2-year follow-up). Discrete-time logistic regression models estimated hazard ratios (HRs) between bisphosphonate users versus nonusers, with an interaction term for baseline KL grade (KL <2 or KL ≥2). We identified 1977 eligible women (n = 346 bisphosphonate users). Propensity-matched results indicated that bisphosphonate users with KL grade <2 were protected against progression (HR_KL<2 0.53; 95% CI, 0.35 to 0.79), while bisphosphonate use was not associated with radiographic progression in those with KL grade ≥2 (HR_KL≥2 1.06; 95% CI, 0.83 to 1.35). When restricting analyses to those with BMI <25 kg/m², effects were strengthened (HR_KL<2 0.49 [95% CI, 0.26 to 0.92]; HR_KL≥2 0.69 [95% CI, 0.33 to 1.26]). Duration of bisphosphonate use had no effect on progression, though sample size was limited. Bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight, but less so for those with more advanced disease or more weight-bearing joint stress. © 2020 American Society for Bone and Mineral Research (ASBMR).     

A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains

Discontinuation of denosumab is associated with a rapid return of bone mineral density (BMD) to baseline and an increased risk of multiple vertebral fractures. No subsequent treatment regimen has yet been established for preventing either loss of BMD or multiple vertebral fractures after denosumab discontinuation. The aim of this 8-year observational study was to investigate the effect of a single zoledronate infusion, administered 6 months after the last denosumab injection, on fracture occurrence and loss of BMD. We report on 120 women with postmenopausal osteoporosis who were treated with 60 mg denosumab every 6 months for 2 to 5 years (mean duration 3 years) and then 5 mg zoledronate 6 months after the last denosumab injection. All patients were evaluated clinically, by dual-energy X-ray absorptiometry (DXA) and vertebral fracture assessment (VFA), before the first and after the last denosumab injection and at 2.5 years (median) after denosumab discontinuation. During this off-treatment period, 3 vertebral fractures (1.1 per 100 patient-years) and 4 nonvertebral fractures (1.5 per 100 patient-years) occurred. No patients developed multiple vertebral fractures. Sixty-six percent (confidence interval [CI] 57% to 75%) of BMD gained with denosumab was retained at the lumbar spine and 49% (CI 31% to 67%) at the total hip. There was no significant difference in the decrease of BMD between patients with BMD gains of >9% versus <9% while treated with denosumab. Previous antiresorptive treatment or prevalent fractures had no impact on the decrease of BMD, and all bone loss occurred within the first 18 months after zoledronate infusion. In conclusion, a single infusion of 5 mg zoledronate after a 2- to 5-year denosumab treatment cycle retained more than half of the gained BMD and was not associated with multiple vertebral fractures, as reported in patients who discontinued denosumab without subsequent bisphosphonate treatment. © 2020 American Society for Bone and Mineral Research.     

Spinal Loading Patterns From Biomechanical Modeling Explain the High Incidence of Vertebral Fractures in the Thoracolumbar Region

Vertebral fractures occur most frequently in the mid‐thoracic and thoracolumbar regions of the spine, yet the reasons for this site‐specific occurrence are not known. Our working hypothesis is that the locations of vertebral fracture may be explained by the pattern of spine loading, such that during daily activities the mid‐thoracic and thoracolumbar regions experience preferentially higher mechanical loading compared to other spine regions. To test this hypothesis, we used a female musculoskeletal model of the full thoracolumbar spine and rib cage to estimate the variation in vertebral compressive loads and associated factor‐of‐risk (load‐to‐strength ratio) throughout the spine for 119 activities of daily living, while also parametrically varying spine curvature (high, average, low, and zero thoracic kyphosis models). We found that nearly all activities produced loading peaks in the thoracolumbar and lower lumbar regions of the spine, but that the highest factor‐of‐risk values generally occurred in the thoracolumbar region of the spine because these vertebrae had lower compressive strength than vertebrae in the lumbar spine. The peaks in compressive loading and factor‐of‐risk in the thoracolumbar region were accentuated by increasing thoracic kyphosis. Activation of the multifidus muscle fascicles selectively in the thoracolumbar region appeared to be the main contributor to the relatively high vertebral compressive loading in the thoracolumbar spine. In summary, by using advanced musculoskeletal modeling to estimate vertebral loading throughout the spine, this study provides a biomechanical mechanism for the higher incidence of fractures in thoracolumbar vertebrae compared to other spinal regions. © 2017 American Society for Bone and Mineral Research.     

Bariatric surgery increases the rate of major fracture: self-controlled case series study in UK Clinical Practice Research Datalink

Conflicting results exist about the relationship between bariatric surgery and fracture risk. Also, prediction of who is at increased risk of fracture after bariatric surgery is not currently available. Hence, we used a combination of a self-controlled case series (SCCS) study to establish the association between bariatric surgery and fracture, and develop a prediction model for postoperative fracture risk estimation using a cohort study. Patients from UK Primary care records from the Clinical Practice Research Datalink GOLD linked to Hospital Episode Statistics undergoing bariatric surgery with body mass index (BMI) ≥30 kg/m² between 1997 and 2018 were included in the cohort. Those sustaining one or more fractures in the 5 years before or after surgery were included in the SCCS. Fractures were considered in three categories: (i) any except skull and digits (primary outcome); (ii) major (hip, vertebrae, wrist/forearm, and humerus); and (iii) peripheral (forearm and lower leg). Of 5487 participants, 252 (4.6%) experienced 272 fractures (of which 80 were major and 135 peripheral) and were included in the SCCS analyses. Major fracture risk increased after surgery, incidence rate ratios (IRRs) and 95% confidence intervals (CIs): 2.77 (95% CI, 1.34–5.75) and 3.78 (95% CI, 1.42–10.08) at ≤3 years and 3.1 to 5 years postsurgery when compared to 5 years prior to surgery, respectively. Any fracture risk was higher only in the 2.1 to 5 years following surgery (IRR 1.73; 95% CI, 1.08–2.77) when compared to 5 years prior to surgery. No excess risk of peripheral fracture after surgery was identified. A prediction tool for major fracture was developed using 5487 participants included in the cohort study. It was also internally validated (area under the receiver-operating characteristic curve [AUC ROC] 0.70) with use of anxiolytics/sedatives/hypnotics and female as major predictors. Hence, major fractures are nearly threefold more likely after bariatric surgery. A simple prediction tool with five variables identifies high risk patients for major fracture. © 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).     

Fracture Risk After Bariatric Surgery: Roux‐en‐Y Gastric Bypass Versus Adjustable Gastric Banding

The long‐term consequences of bariatric surgery on fracture risk are unclear but are likely to vary by procedure type. In physiologic studies, Roux‐en‐Y gastric bypass (RYGB) and adjustable gastric banding (AGB) have differential effects on rates of bone loss. Therefore, our objective was to compare fracture risk in obese adults after RYGB and AGB procedures. Using claims data from a US commercial health plan, we analyzed rates of nonvertebral fractures within a propensity score–matched cohort (n = 15,032) of morbidly obese adults who received either RYGB or AGB surgery between 2005 and 2013. A total of 281 nonvertebral fractures occurred during a mean follow‐up time of 2.3 ± 1.9 years. RYGB patients had an increased risk of nonvertebral fracture (hazard ratio [HR] = 1.43, 95% confidence interval [CI] 1.13–1.81) compared with AGB patients. In fracture site–specific analyses, RYGB patients had increased risk of fracture at the hip (HR = 1.54, 95% CI 1.03–2.30) and wrist (HR = 1.45, 95% CI 1.01–2.07). Nonvertebral fracture risk associated with RYGB manifested >2 years after surgery and increased in subsequent years, with the highest risk in the fifth year after surgery (HR = 3.91, 95% CI 1.58–9.64). In summary, RYGB is associated with a 43% increased risk of nonvertebral fracture compared with AGB, with risk increasing >2 years after surgery. Fracture risk should be considered in risk/benefit discussions of bariatric surgery, particularly among patients with high baseline risk of osteoporosis who are deciding between RYGB and AGB procedures. © 2017 American Society for Bone and Mineral Research.     

A Pooled Analysis of Fall Incidence From Placebo-Controlled Trials of Denosumab

Recent studies suggest that the RANK/RANKL system impacts muscle function and/or mass. In the pivotal placebo-controlled fracture trial of the RANKL inhibitor denosumab in women with postmenopausal osteoporosis, treatment was associated with a lower incidence of non-fracture-related falls (p = 0.02). This ad hoc exploratory analysis pooled data from five placebo-controlled trials of denosumab to determine consistency across trials, if any, of the reduction of fall incidence. The analysis included trials in women with postmenopausal osteoporosis and low bone mass, men with osteoporosis, women receiving adjuvant aromatase inhibitors for breast cancer, and men receiving androgen deprivation therapy for prostate cancer. The analysis was stratified by trial, and only included data from the placebo-controlled period of each trial. A time-to-event analysis of first fall and exposure-adjusted subject incidence rates of falls were analyzed. Falls were reported and captured as adverse events. The analysis comprised 10,036 individuals; 5030 received denosumab 60 mg subcutaneously once every 6 months for 12 to 36 months and 5006 received placebo. Kaplan–Meier estimates showed an occurrence of falls in 6.5% of subjects in the placebo group compared with 5.2% of subjects in the denosumab group (hazard ratio = 0.79; 95% confidence interval 0.66–0.93; p = 0.0061). Heterogeneity in study designs did not permit overall assessment of association with fracture outcomes. In conclusion, denosumab may reduce the risk of falls in addition to its established fracture risk reduction by reducing bone resorption and increasing bone mass. These observations require further exploration and confirmation in studies with muscle function or falls as the primary outcome. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..     

Clinical Utility of Computer-Aided Diagnosis of Vertebral Fractures From Computed Tomography Images

Osteoporotic vertebral compression fractures (VCFs) are a risk factor for morbidity and mortality, frequently asymptomatic and often present in computed tomography (CT) scans performed for unrelated conditions. Computer-aided diagnosis (CAD) of VCF from such images can potentially improve identification and treatment of osteoporosis. This single-blinded, single tertiary center study compared a CAD (Zebra Medical Vision®) to an adjudicated imaging specialist reevaluation using a retrospective consecutive sample of abdominal and thoracic CT scans (n = 2357) performed as part of routine care. Subjects over 50 years between January 1, 2019 and May 12, 2019 were included. Duplicates and unanalyzable scans were excluded resulting in a total of 1696 CT scans. The sensitivity, specificity, and accuracy were calculated for all VCF and for Genant grades 2 or 3 (ie, height loss of >25%) using imaging specialist as the gold standard. Prestudy VCF reporting by hospital-rostered radiologist was used to calculate the number of scans needed to screen (NNS) to detect one additional VCF using CAD. Prevalence of any VCF was 24% (406/1696) and of Genant 2/3 VCF was 18% (280/1570). The sensitivity and specificity were 54% and 92%, for all fractures, respectively, and 65% and 92% for Genant 2/3 fractures, respectively. Accuracy for any VCF, and for detection of Genant 2/3 VCF, was 83% and 88%, respectively. Of 221 CAD-detected VCFs, 133 (60.2%) were reported prestudy resulting in 88 additional fractures (72 Genant 2/3) being identified by CAD. NNS to detect one additional VCF was 19 scans for all fractures and 23 for Genant 2/3 fractures. Thus, the CAD tested in this study had a high specificity with moderate sensitivity to detect incidental vertebral fractures in CT scans performed for routine care. A low NNS suggests it is an efficient tool to assist radiologists and clinicians to improve detection and reporting of vertebral fractures. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Objectively‐Verified Parental Non‐Hip Major Osteoporotic Fractures and Offspring Osteoporotic Fracture Risk: A Population‐Based Familial Linkage Study

Parental hip fracture (HF) is associated with increased risk of offspring major osteoporotic fractures (MOFs; comprising hip, forearm, clinical spine or humerus fracture). Whether other sites of parental fracture should be used for fracture risk assessment is uncertain. The current study tested the association between objectively‐verified parental non‐hip MOF and offspring incident MOF. Using population‐based administrative healthcare data for the province of Manitoba, Canada, we identified 255,512 offspring with linkage to at least one parent (238,054 mothers and 209,423 fathers). Parental non‐hip MOF (1984–2014) and offspring MOF (1997–2014) were ascertained with validated case definitions. Time‐dependent multivariable Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs). During a median of 12 years of offspring follow‐up, we identified 7045 incident MOF among offspring (3.7% and 2.5% for offspring with and without a parental non‐hip MOF, p < 0.001). Maternal non‐hip MOF (HR 1.27; 95% CI, 1.19 to 1.35), paternal non‐hip MOF (HR 1.33; 95% CI, 1.20 to 1.48), and any parental non‐hip MOF (HR 1.28; 95% CI, 1.21 to 1.36) were significantly associated with offspring MOF after adjusting for covariates. The risk of MOF was even greater for offspring with both maternal and paternal non‐hip MOF (adjusted HR 1.61; 95% CI, 1.27 to 2.02). All HRs were similar for male and female offspring (all p_interaction >0.1). Risks associated with parental HF only (adjusted HR 1.26; 95% CI, 1.13 to 1.40) and non‐hip MOF only (adjusted HR 1.26; 95% CI, 1.18 to 1.34) were the same. The strength of association between any parental non‐hip MOF and offspring MOF decreased with older parental age at non‐hip MOF (p_trend = 0.028). In summary, parental non‐hip MOF confers an increased risk for offspring MOF, but the strength of the relationship decreases with older parental age at fracture. © 2016 American Society for Bone and Mineral Research.     

Prevalent Vertebral Fractures on Chest CT: Higher Risk for Future Hip Fracture

Subclinical or undiagnosed vertebral fractures on routine chest computed tomography (CT) may be useful for detecting patients at increased risk of future hip fractures who might benefit from preventive interventions. We investigated whether prevalent vertebral fractures on routine chest CT are associated with future hip fractures. From a source population of 5679 patients ≥40 years old undergoing chest CT in one of three Dutch hospitals between 2002 and 2005, patients hospitalized for hip fractures (n = 149) during a median follow‐up of 4.4 years were identified. Following a case‐cohort design, a random sample of 576 patients was drawn from the source population and added to the cases. In this group, the presence and severity of vertebral fractures was determined using semiquantitative vertebral fracture assessment and multivariate case‐cohort appropriate Cox modeling. We found that cases were older (69 versus 63 years) and more often female (48% versus 38%) than the source population. Compared with those with no fracture, patients with any vertebral fracture had triple the risk of future hip fracture (age‐ and gender‐adjusted hazard ratio [HR] = 3.1, 95% confidence interval [CI] 2.1–4.7). This HR rose to 3.8 (CI 2.6–5.6) if mild fractures were discounted. Future fracture risk increased significantly with increasing severity of vertebral fracture status: from mild (HR = 2.4, CI 1.5–3.7) and moderate (HR = 4.8, CI 2.5–9.2) to severe (HR = 6.7, CI 2.9–15.5). The same was true for having higher cumulative fracture grades: 1 to 3 (HR = 2.7, CI 1.8–4.1), 4 to 6 (HR = 4.8, CI 2.2–10.5), or ≥7 (HR = 11.2, CI 3.7–34.6). In conclusion, prevalent vertebral fractures on routine clinical chest CT are associated with future hip fracture risk. © 2014 American Society for Bone and Mineral Research.     

Inflammatory Markers and the Risk of Hip and Vertebral Fractures in Men: the Osteoporotic Fractures in Men (MrOS)

Cytokines play major roles in regulating bone remodeling, but their relationship to incident fractures in older men is uncertain. We tested the hypothesis that men with higher concentrations of pro‐inflammatory markers have a higher risk of fracture. We used a case‐cohort design and measured inflammatory markers in a random sample of 961 men and in men with incident fractures including 120 clinical vertebral, 117 hip, and 577 non‐spine fractures; average follow‐up 6.13 years (7.88 years for vertebral fractures). We measured interleukin (IL)‐6, C‐reactive protein (CRP), tumor necrosis factor alpha (TNFα), soluble receptors (SR) of IL‐6 (IL‐6SR) and TNF (TNFαSR1 and TNFαSR2), and IL‐10. The risk of non‐spine, hip, and clinical vertebral fracture was compared across quartiles (Q) of inflammatory markers using Cox proportional hazard models with tests for linear trend. In multivariable‐adjusted models, men with the highest (Q4) TNFa cytokine concentrations and their receptors had a 2.0–4.2‐fold higher risk of hip and clinical vertebral fracture than men with the lowest (Q1). Results were similar for all non‐spine fractures, but associations were smaller. There was no association between CRP and IL‐6SR and fracture. Men in the highest Q of IL‐10 had a 49% lower risk of vertebral fracture compared with men in Q1. Among men with ≥3 inflammatory markers in the highest Q, the hazard ratio (HR) for hip fractures was 2.03 (95% confidence interval [CI] 1.11–3.71) and for vertebral fracture 3.06 (1.66–5.63). The HRs for hip fracture were attenuated by 27%, 27%, and 15%, respectively, after adjusting for appendicular lean mass (ALM), disability, and bone density, suggesting mediating roles. ALM also attenuated the HR for vertebral fractures by 10%. There was no association between inflammation and rate of hip BMD loss. We conclude that inflammation may play an important role in the etiology of fractures in older men. © 2016 American Society for Bone and Mineral Research.     

Patterns of Load-to-Strength Ratios Along the Spine in a Population-Based Cohort to Evaluate the Contribution of Spinal Loading to Vertebral Fractures

Vertebral fractures (VFx) are common among older adults. Epidemiological studies report high occurrence of VFx at mid-thoracic and thoracolumbar regions of the spine; however, reasons for this observation remain poorly understood. Prior reports of high ratios of spinal loading to vertebral strength in the thoracolumbar region suggest a possible biomechanical explanation. However, no studies have evaluated load-to-strength ratios (LSRs) throughout the spine for a large number of activities in a sizeable cohort. Thus, we performed a cross-sectional study in a sample of adult men and women from a population-based cohort to: 1) determine which activities cause the largest vertebral LSRs, and 2) examine patterns of LSRs along the spine for these high-load activities. We used subject-specific musculoskeletal models of the trunk to determine vertebral compressive loads for 109 activities in 250 individuals (aged 41 to 90 years, 50% women) from the Framingham Heart Study. Vertebral compressive strengths from T₄ to L₄ were calculated from computed tomography–based vertebral size and bone density measurements. We determined which activities caused maximum LSRs at each of these spinal levels. We identified nine activities that accounted for >95% of the maximum LSRs overall and at least 89.6% at each spinal level. The activity with the highest LSR varied by spinal level, and three distinct spinal regions could be identified by the activity producing maximum LSRs: lateral bending with a weight in one hand (upper thoracic), holding weights with elbows flexed (lower thoracic), and forward flexion with weight (lumbar). This study highlights the need to consider a range of lifting, holding, and non-symmetric activities when evaluating vertebral LSRs. Moreover, we identified key activities that produce higher loading in multiple regions of the spine. These results provide the first guidance on what activities to consider when evaluating vertebral load-to-strength ratios in future studies, including those examining dynamic motions and the biomechanics of VFx. © 2020 American Society for Bone and Mineral Research (ASBMR).