A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Osteosarcopenia: Prevalence and 10-Year Fracture and Mortality Risk - A Longitudinal, Population-Based Study of 75-Year-Old Women.

Osteosarcopenia is the coexistence of low bone mass and sarcopenia. In older women, its prevalence is not well described, and it is unknown if sarcopenia is additive to low bone mass for fracture and mortality risk. The study investigated prevalence of osteosarcopenia and if osteosarcopenia is associated with higher fracture and mortality risk than low bone mass alone in older community-dwelling women. The longitudinal, population-based OPRA Cohort (n = 1044), all aged 75 at inclusion, followed for 10 years. Using WHO and EWGSOP2 definitions for low bone mass (T-score < -1.0 femoral neck) and sarcopenia (knee strength; appendicular lean muscle mass) women were categorized (1) Normal, (2) Low bone mass (LBM), and 3) Osteosarcopenia (probable; confirmed). Risk of hip, major osteoporotic fracture, and mortality were estimated. Osteosarcopeniaconfirmed prevalence increased from age 75 to 80 and 85 from 3.0% (29/970) to 4.9% (32/656) to 9.2% (33/358) but prevalence is potentially 2-4 times higher (11.8%, 13.4%, 20.3%) based on osteosarcopeniaprobable. Having osteosarcopeniaprobable significantly increased 10-year risk of hip fracture (HRadj 2.67 [1.34-5.32]), major osteoporotic fracture (HRadj 2.04 [1.27-3.27]), and mortality (HRadj 1.91 [1.21-3.04]). In contrast, LBM increased osteoporotic fracture risk (HRadj 2.08 [1.46-2.97], but not hip fracture (HRadj 1.62 [0.92-2.85]) or mortality (HRadj 0.94 [0.64-1.38]). Median time-to-hip fracture was 7.6 years (normal), 6.0 years (LBM), and 5.7 years (osteosarcopeniaprobable). Prevalence of confirmed osteosarcopenia is almost 10% at age 85. Probable osteosarcopenia significantly increased risk of hip and major osteoporotic fractures and mortality more so than low bone mass alone.

Reduced fracture incidence in patients having surgery for primary hyperparathyroidism.

OBJECTIVE: The indication of surgery in primary hyperparathyroidism has been controversial, as many patients experience mild disease. The primary aim was to evaluate fracture incidence in a contemporary population-based cohort of patients having surgery for primary hyperparathyroidism. The secondary aim was to investigate whether preoperative serum calcium, adenoma weight or multiglandular disease influence fracture incidence. DESIGN: A retrospective cohort study with population controls. Primary outcomes, defined by discharge diagnoses and prescriptions, were any fracture and fragility fracture, secondary outcomes were multiple fractures anytime and osteoporosis. Subjects were followed 10 years pre- and up to 10 years postoperatively (or 31 December 2015). Multiple events per subject were allowed. Fracture incidence rate ratios (IRRs) for patients pre- and postoperatively were tabulated and evaluated with mixed-effects Poisson regression. Secondary outcomes were evaluated using conditional logistic regression. PATIENTS: A Swedish nationwide cohort of patients having surgery for primary hyperparathyroidism (n = 5009) from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery between 2003 and 2013 was matched with population controls (n = 14,983). Data were cross-linked with Statistics Sweden and the National Board of Health and Welfare. MEASUREMENTS: Preoperative serum calcium and adenoma weight at pathological examination. RESULTS: Patients had an increased incidence rate of any fracture preoperatively, IRR 1.27 (95% confidence interval: 1.11-1.46), highest in the last year before surgery. Fracture incidence was not increased postoperatively. Serum calcium, adenoma weight and multiglandular disease were not associated with fracture incidence. CONCLUSIONS: Fracture incidence is higher in patients with primary hyperparathyroidism but is normalized after surgery.

Frailty and osteoporosis in patients with hip fractures under the age of 60-a prospective cohort of 218 individuals.

Research on younger patients with hip fractures is limited. This study adds knowledge on patient and injury characteristics, and DXA was investigated at the time of the fracture. Risk factors for osteoporosis and fractures were numerous among young patients, and osteoporosis was markedly more prevalent than in the general population. INTRODUCTION: Knowledge on younger patients with hip fractures is limited. Common preconceptions are that they suffer fractures due to high-energy trauma, alcohol or substance use disorder but not associated to osteoporosis. We aimed to descriptively analyze the characteristics of young and middle-aged patients with hip fractures and examine bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) at the time of the fracture. METHODS: A prospective multicenter cohort study on adult patients with hip fractures below age 60 collected detailed information on patient characteristics regarding demographics, trauma mechanism, previous fractures, comorbidity and medication, and lifestyle factors. DXA results were compared to population-based reference data. RESULTS: The cohort contains 91 women and 127 men, median age 53 (IQR 47-57). Most fractures, 83%, occurred in patients aged 45-59. Two-thirds of all fractures resulted from low-energy trauma. Half of the patients had prior fractures after age 20. Thirty-four percent were healthy, 31% had one previous disease, and 35% had multiple comorbidities. Use of medication associated with increased fracture risk was 32%. Smoking was prevalent in 42%, harmful alcohol use reported by 29%, and signs of drug-related problems by 8%. Osteoporosis according to WHO criteria was found in 31%, osteopenia in 57%, and normal BMD in 12%. CONCLUSION: In patients with hip fractures below age 60, risk factors for osteoporosis and fractures were numerous. Moreover, the prevalence of osteoporosis was markedly higher than in the general population. We suggest that young and middle-aged patients with hip fractures undergo a thorough health investigation including DXA, regardless of trauma mechanism.

Gaps and alternative surgical and non-surgical approaches in the bone fragility management: an updated review.

Osteoporotic fractures are one of the major problems facing healthcare systems worldwide. Undoubtedly, fragility fractures of the hip represent a far greater burden in terms of morbidity, mortality, and healthcare costs than other fracture sites. However, despite the significant impact on the health and quality of life of older adults, there is a general lack of awareness of osteoporosis, which results in suboptimal care. In fact, most high-risk individuals are never identified and do not receive adequate treatment, leading to further fragility fractures and worsening health status. Furthermore, considering the substantial treatment gap and the proven cost-effectiveness of fracture prevention programs such as Fracture Liaison Services, urgent action is needed to ensure that all individuals at high risk of fragility fracture are adequately assessed and treated. Based on this evidence, the aim of our review was to (i) provide an overview and comparison of the burden and management of fragility fractures, highlighting the main gaps, and (ii) highlight the importance of using alternative approaches, both surgical and non-surgical, with the aim of implementing early prevention of osteoporotic fractures and improving the management of osteoporotic patients at imminent and/or very high risk of fracture.

Bone Turnover Marker Profiling and Fracture Risk in Older Women: Fracture Risk from Age 75 to 90.

PURPOSE: A major challenge in osteoporosis is to identify individuals at high fracture risk. We investigated six bone turnover markers (BTMs) to determine association with specific fracture types; the time-frame for risk prediction and whether these are influenced by age at assessment. METHODS: Population-based OPRA cohort (n = 1044) was assessed at ages 75, 80, 85 and fractures documented for up to 15 years. Six BTMs were analyzed at each time-point (N-terminal propeptide of type I collagen, PINP; total osteocalcin, OC; bone-specific alkaline phosphatase, BALP; C-terminal telopeptide of type I collagen, CTX; tartrate-resistant acid phosphatase 5b, TRAcP5b; urinary osteocalcin). Hazard ratios (HR) for any, major osteoporotic, vertebral and hip fractures were calculated as short (1, 2, 3 years) and long-term risk (5, 10, 15 years). RESULTS: At 75 year, high CTX levels were associated with an increased risk of all fractures, including major osteoporotic fractures, across most time-frames (HRs ranging: 1.28 to 2.28). PINP was not consistently associated. Urinary osteocalcin was consistently associated with elevated short-term risk (HRs ranging: 1.83-2.72). Other BTMs were directionally in accordance, though not all statistically significant. BTMs were not predictive for hip fractures. Association of all BTMs attenuated over time; at 80 year none were associated with an increased fracture risk. CONCLUSION: CTX, urinary OC and TRAcP5b are predictive for fracture in a 1 to 3 year, perspective, whereas in the long-term or above age 80 years, BTMs appear less valuable. Resorption markers, particularly CTX, were more consistently associated with fracture risk than formation markers in the very elderly.

Bone mineral density in haemophilia - a multicentre study evaluating the impact of different replacement regimens.

AIM: The aim of this study was to investigate if prophylactic treatment in severe haemophilia impact on bone mineral densisty (BMD) in adults with haemophilia A/B. METHODS: Subjects with haemophilia (n = 120) underwent bone-density measurement and clinical data was collected. BMD in subjects with severe haemophilia on high-dose prophylaxis (n = 41) was compared to BMD in subjects with mild haemophilia (n = 33) and to severe haemophilia treated with intermediate-dose prophylaxis (n = 32) or on-demand replacement therapy (n = 14). RESULTS: Subjects with severe haemophilia on high-dose prophylaxis showed BMD at total hip comparable to subjects with mild haemophilia (median BMD 955.8 and 977.4 mg/cm2 (P = .17), respectively). No difference in BMD was found related to type of prophylactic regimen (median BMD 955.8 and 942.4 mg/cm2 , in high-dose and intermediate dose groups, respectively; P = .70). Subjects with severe disease treated on-demand had significantly lower BMD compared to subjects on a high-dose prophylactic regimen (median BMD 771.8 and 955.8 mg/cm2 (P = .001), respectively). BMD decreased significantly with age, regardless of severity of haemophilia disease. In a multivariate analysis, adjusted for disease status and age, type of prophylactic regimen was not significantly associated with osteoporosis development. CONCLUSION: We show that BMD differs in persons with severe haemophilia on propylaxis as compared to those treated on-demand, but that type of prophylactic regimen does not reflect on BMD. The difference between treatment groups was mainly explained by an age difference between groups. However, patients on prophylaxis displayed a high degree of normal BMD not far from mild haemophilia at comparative age.

Closing the Osteoporosis Care Gap.

PURPOSE OF REVIEW: This review outlines the scope of the problem in osteoporosis care and secondary fracture prevention and describes fracture prevention strategies, with a focus on the frail elderly. RECENT FINDINGS: Despite heightened awareness among patients and clinicians alike and the availability of efficacious anti-osteoporosis medications, osteoporosis is still underdiagnosed and undertreated. However, the introduction of systematic risk assessment and secondary fracture prevention programmes has gained momentum, and evidence of success is accumulating. We possess today the knowledge required to close the osteoporosis care gap. The basic components in a secondary prevention model are similar in all health care settings, number one being a dedicated fracture coordinator, with anti-osteoporosis medications and multifaceted falls prevention as cornerstones, particularly in the frailest, both in the near and long-term. Initiation of structured care pathways including the key elements - identification, investigation, intervention and follow-up of adherence - demonstrably reduces re-fracture rates and is cost-effective.

Knee pain in young adult women- associations with muscle strength, body composition and physical activity.

BACKGROUND: Knee pain is studied mostly in older age groups, although in young adults it may be an indicator of future impaired musculoskeletal health. Therefore, the aim of this study was to examine the longitudinal association between knee pain and thigh muscle strength in young adult women and to explore the associations between muscle strength, body composition, physical activity and knee pain. METHODS: The PEAK-25 cohort consists of women aged 25 at baseline (N=1064). At the 10-year follow-up n=728 attended for DXA-measured body composition and muscle strength assessment and n=797 answered the questionnaire on health and lifestyle. Independent samples t-test was used to compare women with and without knee pain, Spearman correlation was used to test the longitudinal association between strength and knee pain. RESULTS: Knee pain was reported by one third of the women at follow-up (n=260, 33%), although physical activity levels were similar in those with and without pain (high level 50 vs 45 % (p= 0.18). Body composition differed, however. Women with knee pain had higher BMI (25.6 vs 24.1), fat mass index (9.2 vs 8.2) and % total body fat mass (34.7 vs 33.2). Simultaneously, they had lower % lean mass (total body 61.5 vs 62.8; legs 20.6 vs 21.0) and lower thigh muscle strength (extensors 184.9 vs 196.8, flexors 96.6 vs 100.9, p<0.05), but slightly higher hamstrings-to -quadriceps ratio (0.53 vs 0.51, p=0.04). Muscle strength at baseline weakly correlated with knee pain at follow-up (extensor rs= -0.04; flexor -0.02, p>0.2). Overweight women had higher absolute thigh muscle strength, but lower weight-adjusted strength than normal weight women (p<0.001). Leg lean mass explained 26-34% of the variation in muscle strength and adjustment for physical activity level had little effect. CONCLUSION: Knee pain is already common among women in their mid-thirties. Lower thigh muscle strength in the mid-twenties was not associated with future knee pain, however women with knee pain tended to have lower thigh muscle strength and a body composition of higher body fat combined with lower lean mass. Maintaining a healthy body composition and adequate thigh muscle strength may be beneficial for knee joint health.

Frailty and prediction of recurrent falls over 10 years in a community cohort of 75-year-old women.

BACKGROUND: Frailty captures the age-related declines in health leading to increased vulnerability, including falls which are commonplace in older women. The relationship between frailty and falls is complex, with one leading to the other in a vicious cycle. AIMS: This study addresses the gap in understanding how patterns of frailty and falls propensity interact, particularly in those who have not yet entered the falls-frailty cycle. METHODS: The Osteoporosis Risk Assessment cohort consists of 1044 community-dwelling women aged 75, with 10 years of follow-up. Investigations were performed and a frailty index constructed at baseline, 5 and 10 years. Falls were self-reported for each previous 12 months. Analysis was two-directional, firstly based on frailty status and second, based on falls status. Recurrent falls was the primary outcome. RESULTS: Baseline frailty was a significant predictor of recurrent falls after 5 and 10 years [(OR 2.55 (1.62-3.99); 3.04 (1.63-5.67)]. Among women who had no history of falls at age 75, frailty was a stronger predictor of falls at 5 years [OR 3.06 (1.59-5.89)] than among women who had previously fallen. DISCUSSION: Frailty is significantly associated with recurrent falls and most pronounced in those who are frail but have not yet fallen. CONCLUSIONS: This suggests that frailty should be an integral part of falls-risk assessment to improve identification of those at risk of becoming fallers.

Patient-related outcome, fracture displacement and bone mineral density following distal radius fracture in young and older men.

BACKGROUND: Distal radius fractures can adversely affect wrist function; for men with this fracture, the role played by fracture severity, age and osteoporosis on fracture outcome has not been sufficiently studied. OBJECTIVE: To describe patient-reported outcome and the association with bone integrity, fracture severity and future fracture risk among young and older men with distal radius fracture. METHODS: This prospective study includes 133 men with acute distal radius fracture, mean age 54 (range 21-88), who were followed for 12 months. They were categorized as younger (< 65) and older (65+). Main outcome was DASH (Disability of the Arm, Shoulder and Hand) at 12 months; DASH > 15 was defined as poor outcome. Fractures were classified and radiographic displacement identified at initial presentation and follow-up. BMD was measured and FRAX 10-year probability of fracture calculated. RESULTS: Disability was higher in older men (DASHmedian 10 vs 2; p = 0.002); a clinically meaningful difference (ΔDASH = 10, p = 0.017) remained after adjustment for displacement, fracture classification and treatment method. Almost 50% of older men vs 14% in younger had poor outcome, p < 0.001. Bone mineral density did not independently predict outcome. Older men with a displaced fracture at initial presentation had greater disability (DASHmedian, IQR 45, 14;73) and risk of fracture (FRAXmajor osteoporotic 14, 8;21). CONCLUSION: Men over the age of 65 with a distal radius fracture are more likely to have post-fracture disability regardless of radiographic appearance. Fracture displacement, indicating impaired bone strength, is also more common and associated with an increased risk of fracture within 10-years. Secondary fracture prevention should therefore be considered in men presenting with distal radius fracture.

Vitamin D Intervention and Bone: A Randomized Clinical Trial in Fair- and Dark-skinned Children at Northern Latitudes.

OBJECTIVES: The aim of the study was to evaluate vitamin D status and effects of vitamin D intervention on bone mineral density (BMD) and content (BMC) in children with fair and dark skin in Sweden during winter. METHODS: In a 2-center prospective double-blinded randomized intervention study 5- to 7-year-old children (n = 206) with fair and dark skin in Sweden (55°N-63°N) received daily vitamin D supplements of 25 µg, 10 µg, or placebo (2 µg) during 3 winter months. We measured BMD and BMC for total body (TB), total body less head (TBLH), femoral neck (FN), and spine at baseline and 4 months later. Intake of vitamin D and calcium, serum 25-hydroxy vitamin D (S-25[OH]D), and related parameters were analyzed. RESULTS: Despite lower S-25(OH)D in dark than fair-skinned children, BMD of TB (P = 0.012) and TBLH (P = 0.002) and BMC of TBLH (P = 0.04) were higher at baseline and follow-up in those with dark skin. Delta (Δ) BMD and BMC of TB and TBLH did not differ between intervention and placebo groups, but FN-BMC increased more among dark-skinned children in the 25 µg (P = 0.038) and 10 µg (P = 0.027) groups compared to placebo. We found no associations between Δ S-25(OH)D, P-parathyroid hormone, P-alkaline phosphatase, and Δ BMD and BMC, respectively. CONCLUSIONS: BMD and BMC remained higher in dark- than fair-skinned children despite lower vitamin D status. Even though no difference in general was found in BMD or BMC after vitamin D intervention, the increase in FN-BMC in dark-skinned children may suggest an influence on bone in those with initially insufficient vitamin D status.

Peak Bone Mass and Quantitative Ultrasound Bone Properties in Young Adulthood: A Study in the PEAK-25 Cohort of Women.

Peak bone mass is normally reached in the third decade of life. Previously, in the population-based PEAK-25 cohort (n = 1061, age 25.5 ± 0.2), we demonstrated that bone mineral density in the population-based PEAK-25 cohort is comparatively high; therefore, this study aimed to determine if the calcaneus microarchitecture mirrored this. In the process, we describe normative quantitative ultrasound (QUS) values for 25-yr-old women and the relationship between QUS values and extremes of body weight. QUS variables speed of sound (SOS), broadband ultrasound attenuation (BUA), and stiffness index were measured. Young adult values were based on the manufacturer-supplied QUS reference values. Analyses were performed in the cohort as a whole, and additionally, to understand the relationship between body weight and QUS values in young women, the variables were categorized into octiles for weight or body mass index (BMI) and the lowest and highest octiles were compared. In the cohort, SOS values, reflecting bone density, were higher (108 ± 18%), whereas BUA values, reflecting bone complexity, were lower (90 ± 14%) compared to the young adult reference population. SOS did not correlate with body weight or BMI. In the cohort, overall correlations between BUA weight, and BMI were small and positive (Pearson's r coefficients 0.261 and 0.197, respectively; p < 0.001), although in the low-weight group, r coefficients were higher (r = 0.313 and 0.268; p < 0.05). In contrast, in the high-weight group, correlation with BUA values tended to be small, negative, and nonsignificant. Correlation between QUS and dual-energy X-ray absorptiometry-measured bone mineral density was low to moderate and significant at all skeletal sites (r = 0.37-0.52). Whereas coefficients tended to be higher in the low-weight group, the reverse was apparent for the low-BMI group. In these 25-yr-old women, a comparatively high dual-energy X-ray absorptiometry-measured bone mass is offset by less complex bone structures assessed by QUS. This may have implications for later osteoporosis assessment and future fracture risk.

Risk and predictors of fractures in early rheumatoid arthritis - A long term follow up study of an inception cohort.

OBJECTIVES: To examine the risk of fractures in a cohort of patients with newly diagnosed rheumatoid arthritis (RA), compared to the background population, and predictors of fractures detectable early in RA. METHODS: An inception cohort of patients with RA (N = 233; 164 women/69 men, recruited 1995-2005) was evaluated according to a structured program, including repeated clinical assessments and measures of bone mineral density (BMD), from diagnosis to 10 years later. Matched population controls were identified using the national census register. Fractures through 2019 were identified based on ICD codes. Cox regression models were used to assess the risk of fractures in RA patients compared with controls, and for assessment of potential predictors for fractures in the RA population. RESULTS: RA patients had an increased risk of fractures (fully adjusted hazard ratio (HR) 1.52, 95 % CI 1.13; 2.06). In the RA cohort, high age, low body mass index, and low BMD were significant baseline predictors of future fractures in multivariate analyses, but baseline RA disease characteristics were not. Worse disability (i.e. higher Health Assessment Questionnaire (HAQ) scores) over time was significantly associated with increased risk of fractures (age-sex-adjusted HR 1.33 per SD, 95 % CI 1.09; 1.63) and there was an inverse association between BMD Z-scores over time and fractures. CONCLUSION: Patients with RA had higher risk of fractures than controls. Fracture risk was related to BMD at baseline and over time in patients with RA. In addition, worse disability (measured by HAQ) over time was associated with higher risk of fractures.

24-hour Urine Calcium Predicts Reduced Fracture Incidence and Improved BMD After Surgery for Primary Hyperparathyroidism.

CONTEXT: Contemporary patients with primary hyperparathyroidism are diagnosed with milder disease than previously. Clinical and biochemical factors predictors with impact on fracture incidence and bone mineral density after surgery have not been firmly established. OBJECTIVE: To investigate predictors of fracture incidence and bone mineral density preoperatively and after surgery for primary hyperparathyroidism (pHPT). DESIGN: Prospectively collected surgical cohort with matched population controls. Data were cross-linked with the Swedish National Patient Register, the Prescribed Drug Register, and the Cause of Death Register. SETTING: Tertiary referral center. PATIENTS OR OTHER PARTICIPANTS: 709 patients with successful parathyroidectomy for pHPT, and 2,112 controls matched on sex, age, and municipality were included in the study. MAIN OUTCOME MEASURES: Fracture incidence, absolute change and ≥2.77% increase in bone mineral density of femoral neck, L2-L4 and distal third of radius at 1-year follow-up. RESULTS: Patients with pHPT had an increased fracture incidence before surgery but not after pHPT surgery. Fracture incidence after surgery was inversely related to preoperative 24-hour urine calcium (IRR for the highest tertile 220- mg/d 0.29, CI 95% 0.11-0.73). Serum and 24-hour urine calcium, parathyroid hormone, osteocalcin and adenoma weight were all associated with bone mineral density recovery after surgery. CONCLUSIONS: 24-hour urine calcium is the most important biochemical variable to predict a decreased fracture incidence and improved bone mineral density after surgery for pHPT.

Ten-year follow-up of fracture risk in a systematic population-based screening program: the risk-stratified osteoporosis strategy evaluation (ROSE) randomised trial.

Background: Osteoporotic fractures pose a growing public health concern. Osteoporosis is underdiagnosed and undertreated, highlighting the necessity of systematic screening programs. We aimed to evaluate the effectiveness of a two-step population-based osteoporotic screening program. Methods: This ten-year follow-up of the Risk-stratified Osteoporosis Strategy Evaluation (ROSE) randomized trial tested the effectiveness of a screening program utilizing the Fracture Risk Assessment Tool (FRAX) for major osteoporotic fractures (MOF) to select women for dual-energy x-ray absorptiometry (DXA) scan following standard osteoporosis treatment. Women residing in the Region of Southern Denmark, aged 65-80, were randomised (single masked) into a screening or a control group by a computer program prior to inclusion and subsequently approached with a mailed questionnaire. Based on the questionnaire data, women in the screening group with a FRAX value ≥15% were invited for DXA scanning. The primary outcome was MOF derived from nationwide registers. ClinicalTrials.gov: NCT01388244, status: Completed. Findings: All randomised women were included February 4, 2010-January 8, 2011, the same day as approached to participate. During follow-up, 7355 MOFs were observed. No differences in incidences of MOF were identified, comparing the 17,072 women in the screening group with the 17,157 controls in the intention-to-treat analysis (IRR 1.01, 0.95; 1.06). However, per-protocol, women DXA-scanned exhibited a 14% lower incidence of MOF (IRR 0.86, 0.78; 0.94) than controls with a FRAX value ≥15%. Similar trends were observed for hip fractures, all fractures, and mortality. Interpretation: While the ROSE program had no overall effect on osteoporotic fracture incidence or mortality it showed a preventive effect for women at moderate to high risk who underwent DXA scans. Hence the overall effect might have been diluted by those who were not at an intervention level threshold risk or those who did not show up for DXA. Using self-administered questionnaires as screening tools may be inefficient for systematic screening due to the low and differential screening uptake. Funding: INTERREG and the Region of Southern Denmark.

Pro-Inflammatory Proteins Associated with Frailty and Its Progression-A Longitudinal Study in Community-Dwelling Women.

The complex pathophysiology underlying biological aging creates challenges for identifying biomarkers associated with frailty. This longitudinal, nontargeted proteomics study aimed to identify proteins associated with frailty, particularly the change from nonfrail to frail. The population-based Osteoporosis Prospective Risk Assessment cohort includes women all of whom are 75 years old at inclusion (n = 1044) and reassessed at 80 years (n = 715) and 85 years (n = 382). A deficits in health frailty index (FI) and 92 plasma proteins (Olink CVD-II panel) were available at all ages. The identical age facilitated differentiating chronological and biological aging. Bidirectional analyses, performed cross-sectionally and longitudinally, used regression models controlled for false discovery rate (FDR), across 5- and 10-year time windows and longitudinal mixed models. Frailty outcomes were frailty index, frailty status (frail defined as FI ≥ 0.25), change in frailty index, and change in frailty status, together with protein expression or change in protein expression. Elevated levels of 32 proteins were positively associated with the FI, cross-sectionally at all ages (range: ß-coefficients 0.22-2.06; FDR 0.021-0.024), of which 18 were also associated with frailty status (range: odds ratios 1.40-5.77; FDR 0.022-0.016). Based on the accrued data, eight core proteins (CD4, FGF23, Gal-9, PAR-1, REN, TNFRSF10A TNFRSF11A, and TNFRSF10B) are proposed. A one-unit change in the FI was additively associated with increased protein expression over 5 and 10 years (range: ß-coefficients 0.52-1.59; p < 0.001). Increments in baseline FI consistently associated with a change in protein expression over time (5 years, ß-range 0.05-1.35; 10 years, ß-range 0.51-1.48; all p < 0.001). A one-unit increase in protein expression was also associated with an increased probability of being frail (FI ≥ 0.25) (ß-range: 0.14-0.61). Mirroring the multisystem deterioration that typifies frailty, the proteins and their associated biological pathways reflect pathologies, including the renal system, skeletal homeostasis, and TRAIL-activated apoptotic signaling. The core proteins are compelling candidates for understanding the development and progression of frailty with advancing age, including the intrinsic musculoskeletal component. © 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).

Differential expression of the inflammatory ciita gene may be accompanied by altered bone properties in intact sex steroid-deficient female rats.

OBJECTIVE: The class II transactivator (CIITA), encoded by the CIITA gene, controls expression of immune response regulators, which affect bone homeostasis. Previously, we investigated a functional CIITA polymorphism in elderly women. Women carrying the allele associated with lower CIITA levels displayed higher bone mineral density (BMD), but also higher bone loss. The present exploratory study in a rat model sought to investigate effects of differential expression of Ciita on bone structural integrity and strength. Two strains DA (normal-to-high expression) and DA.VRA4 (lower expression) underwent ovariectomy (OVX) or sham-surgery at ~ 14-weeks of age (DA OVX n = 8, sham n = 4; DA.VRA4 OVX n = 10, sham n = 2). After 16-weeks, femoral BMD and bone mineral content (BMC) were measured and morphometry and biomechanical testing performed. RESULTS: In DA.VRA4 rats, BMD/BMC, cross-sectional area and biomechanical properties were lower. Ciita expression was accompanied by OVX-induced changes to cross-sectional area and femoral shaft strength; DA rats had lower maximum load-to-fracture. Thus, while lower Ciita expression associated with lower bone mass, OVX induced changes to structural and mechanical bone properties were less pronounced. CONCLUSION: The data tentatively suggests association between Ciita expression and structural and mechanical bone properties, and a possible role in bone changes resulting from estrogen deficiency.

Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.