The relationship between rheumatoid arthritis (RA) and fracture risk was estimated in an international meta-analysis of individual-level data from 29 prospective cohorts. RA was associated with an increased fracture risk in men and women, and these data will be used to update FRAX®. RA is a well-documented risk factor for subsequent fracture that is incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between rheumatoid arthritis and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD) with a view to updating FRAX. The resource comprised 1,909,896 men and women, aged 20–116 years, from 29 prospective cohorts in which the prevalence of RA was 3

Screening initiatives for osteoporosis must facilitate treatment of those at elevated fracture risk. In a randomized controlled trial of 24,229 women, those in the screening group with FRAX ≥ 15

OBJECTIVES:To investigate bone mineral density (BMD), osteoporosis prevalence and SSc-specific associations of BMD in SSc patients compared with background population. METHODS:In total, 211 SSc patients (182 women, 29 men; mean age 61.3 and 62.2 years, respectively) and 505 age- and sex-matched controls from the same geographic area participated. BMD and T-score at total hip and lumbar spine was measured by dual-energy X-ray absorptiometry. Osteopenia was defined as T-score -1.0 to -2.5, and osteoporosis as T-score ≤-2.5. Associates of low BMD were identified by multiple regression analysis. RESULTS:Women with SSc had lower BMD for total hip (P < 0.001) and spine (P = 0.011), equivalent to ΔT-score -0.56 and -0.35 compared with controls. Osteopenia was present in 51.6% and 16.5% had osteoporosis (P = 0.001, compared with controls). Already in women below age 45 years, differences in hip BMD were apparent (ΔT-score -0.93, P = 0.005). In addition to expected risk factors for osteoporosis (older age, lower BMI and menopause), finger ulcers (P = 0.009) and diffuse skin involvement (P = 0.027) were associated with lower hip BMD in women. In men with SSc, more than half displayed osteopenia or osteoporosis and had numerically lower hip BMD than their age-matched counterparts. CONCLUSION:SSc patients, including men and younger women, have lower BMD than the background population. Finger ulcers and diffuse skin involvement, in addition to older age, lower BMI and being post-menopausal, are associated with lower BMD in women. The data emphasize the importance of performing bone health assessment of all SSc patients, including men and young subjects.

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.

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

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. 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). The resource comprised 906,359 women and men (66.9

CONTEXT:Contemporary patients with primary hyperparathyroidism are diagnosed with milder disease than previously. Clinical and biochemical factors predictors with an 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:Seven hundred nine patients with successful parathyroidectomy for pHPT and 2112 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 (incidence rate ratio for the highest tertile 220- mg/d 0.29, 95% confidence interval 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. CONCLUSION:Twenty-four-hour urine calcium is the most important biochemical variable to predict a decreased fracture incidence and improved bone mineral density after surgery for pHPT.

BackgroundOsteoporotic 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.MethodsThis 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.FindingsAll 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.InterpretationWhile 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.FundingINTERREG and the Region of Southern Denmark.

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. Osteosarcopenia confirmed 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 osteosarcopenia probable . Having osteosarcopenia probable significantly increased 10-year risk of hip fracture (HR adj 2.67 [1.34–5.32]), major osteoporotic fracture (HR adj 2.04 [1.27–3.27]), and mortality (HR adj 1.91 [1.21–3.04]). In contrast, LBM increased osteoporotic fracture risk (HR adj 2.08 [1.46–2.97], but not hip fracture (HR adj 1.62 [0.92–2.85]) or mortality (HR adj 0.94 [0.64–1.38]). Median time-to-hip fracture was 7.6 years (normal), 6.0 years (LBM), and 5.7 years (osteosarcopenia probable ). 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.

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.

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. 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. 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.

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.

ABSTRACT 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: β‐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: β‐coefficients 0.52–1.59; p < 0.001). Increments in baseline FI consistently associated with a change in protein expression over time (5 years, β‐range 0.05–1.35; 10 years, β‐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) (β‐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).

Post-fracture care (PFC) programs evaluate and manage patients with a minimal trauma or fragility fracture to prevent subsequent fractures. We conducted a literature review to understand current trends in PFC publications, evaluate key characteristics of PFC programs, and assess their clinical effectiveness, geographic variations, and cost-effectiveness. We performed a search for peer-reviewed articles published between January 2003 and December 2020 listed in PubMed or Google Scholar. We categorized identified articles into 4 non-mutually exclusive PFC subtopics based on keywords and abstract content: PFC Types, PFC Effectiveness/Success, PFC Geography, and PFC Economics. The literature search identified 784 eligible articles. Most articles fit into multiple PFC subtopics (PFC Types, 597; PFC Effectiveness/Success, 579; PFC Geography, 255; and PFC Economics, 98). The number of publications describing how PFC programs can improve osteoporosis treatment rates has markedly increased since 2003; however, publication gaps remain, including low numbers of publications from some countries with reported high rates of osteoporosis and/or hip fractures. Fracture liaison services and geriatric/orthogeriatric services were the most common models of PFC programs, and both were shown to be cost-effective. We identified a need to expand and refine PFC programs and to standardize patient identification and reporting on quality improvement measures. Although there is an increasing awareness of the importance of PFC programs, publication gaps remain in most countries. Improvements in established PFC programs and implementation of new PFC programs are still needed to enhance equitable patient care to prevent occurrence of subsequent fractures.