In this meta-analysis of international cohorts, current smoking is confirmed as a significant BMD-independent predictor of future fracture with a stronger relationship in men than in women. A causative and reversible effect of smoking on fracture risk is suggested by past smoking having a significantly lower risk than current smoking. In this meta-analysis of international cohorts, the aim was to examine the relationship of current and past smoking with fracture risk to provide an update for future iterations of the FRAX tool. The risk of fracture associated with current and past smoking was estimated using an extended Poisson model applied separately to each of 58 prospective international cohort studies. Covariates included current time since start of follow up, current age, and in an additional model, BMD at the femoral neck. The results of the different studies were merged by using inverse-variance weighted β-coefficients. This analysis included a total of 1,691,024 participants (61.2

The relationship between bone mineral density (BMD) at the forearm and fracture risk was determined in a meta-analysis of primary data from 11 cohort studies of 35,121 men and women. Low forearm BMD was a significant predictor of fracture risk, independently of FRAX®. The aim of this study was to quantify the relationship between forearm BMD, FRAX and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk. We studied 35,121 men and women from 11 predominantly population-based cohorts followed for an average of 11.1 years and a total of 388,654 person-years. The association between forearm BMD, FRAX probabilities (calculated without femoral neck BMD), and the risk of fracture was examined using an extension of the Poisson regression model in each cohort by sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD difference in BMD). The different studies were merged using weighted coefficients. The GR of forearm BMD for major osteoporotic fracture was 1.41 (95

The relationship between bone mineral density (BMD) at the femoral neck and fracture risk was determined in a meta-analysis of primary data of 307205 men and women from 53 cohort studies. Low BMD was an important predictor of fracture risk, particularly for hip fracture. This study aimed to quantify the relationship between DXA-measured femoral neck BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value on fracture risk, with a view to updating FRAX®. We studied 307,205 men and women from within 53 predominately population-based cohorts followed up for an average of 8.7 years and a total of 2,683,185 person-years. The association of BMD and fracture risk was examined using a Poisson model in each cohort separately by sex. Results were expressed as a gradient of risk (GR, hazard ratio/standard deviation decrease in BMD). The different studies were then merged using weighted coefficients. Most hip fractures arose in men and women with low bone mass or osteoporosis at baseline (73 = 0.12 for women and p = 0.89 for men). A significant decrease in GR for hip fracture was observed with increasing duration of follow-up, but the magnitude of the effect was modest compared with the effect of age. For other fracture outcomes, including non-hip major osteoporotic fracture, the gradient of risk was lower than for hip fracture. Femoral neck BMD is a risk factor for fracture of substantial importance, particularly for future hip fracture. The lower magnitude of association at older age is consistent with other non-skeletal factors contributing to hip fracture risk with advancing age. Its validation on an international basis supports its use in case finding strategies. Its use should, however, take account of the variations in predictive value of BMD with age, sex, length of follow-up, and BMD.

In the largest meta-analysis of international cohorts to date, a family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. Parental and sibling histories of fracture carry the same significance for future fracture, including the impact of family hip fracture on future hip fracture risk. PURPOSE:We have undertaken a meta-analysis of international prospective cohorts to quantify the relationship between a family history of fracture and future fracture incidence. METHODS:The analysis dataset comprised 350,542 men and women from 42 cohorts in 29 countries followed for 2.8 million person-years. We investigated the relationship between family history of hip fracture or any fracture and the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture (MOF), and hip fracture alone using an extended Poisson model in each cohort. Models were adjusted for current age, sex, BMD, and follow-up time. RESULTS:As no difference in influence of family history of fracture was seen between genders, results are presented for men and women combined. A parental history of hip fracture was associated with a higher risk of incident fracture across all fracture outcome categories, with a stronger relationship with future hip fracture (hazard ratios (HR, 95% CI) for hip and MOF 1.37, 1.23-1.52 and 1.19, 1.12-1.27, respectively). Associations were slightly reduced but remained significant when additionally adjusted for BMD and did not vary by baseline offspring age, follow-up time, or parent affected. In a more limited analysis, parental history of any fracture or a sibling history of hip or any fracture showed similar associations to those observed with parental history of hip fracture. CONCLUSIONS:A family history of fracture is confirmed as a significant BMD-independent predictor of future fracture risk. While parental hip fracture appears the strongest factor for future hip fracture, a family history of other fractures might be appropriate for inclusion in future iterations of the FRAX tool.

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

It is unclear whether thyroid hormone levels are associated with the risk of mortality, cardiovascular disease (CVD) events, or cancer in men with normal TSH. We analyzed if serum free T4 (FT4) or TSH is associated with the risk of mortality, incident CVD events, or cancer in Swedish men. Elderly men (n = 1801; mean age 75 years) in the Gothenburg and Malmö subcohorts of the prospective, population-based Osteoporotic Fractures in Men Study-Sweden study were followed for median 12.2 years regarding all-cause mortality [1207 (67%) died] and for median 5.1 years regarding incident CVD events (n = 338) and cancer (n = 249). The statistical analyses included Cox proportional hazards regression with adjustment for covariates including prevalent atrial fibrillation (AF). Serum FT4 (per SD increase) was associated with increased risk of mortality [men with normal TSH: fully adjusted hazard ratio (HR) 1.23, 95% confidence interval (CI): 1.11-1.35] and incident CVD events (HR 1.25, 95% CI: 1.05-1.48) but not with the risk of cancer. The association between FT4 and CVD events was mainly due to increased risk of cerebrovascular (CBV) events (HR 1.56, 95% CI: 1.24-1.96). Finally, TSH was not associated with the risk of mortality, CVD events, or cancer. FT4, but not TSH, is a predictor of mortality risk in elderly men. The association between FT4 and elevated risk of CVD events was mostly due to increased risk of CBV events, which remained significant also after adjustment for prevalent AF.

Purpose:To describe the prevalence of neck pain (NP) and low back pain (LBP) of varying severity in older community-dwelling men, identify associated factors, and evaluate whether prevalent NP/LBP are risk factors for experiencing pain 5 years later. Patients and Methods:MrOS Sweden is a prospective observational study that included 3014 community-dwelling men aged 69-81 years, of whom 1962 attended a 5-year follow-up. NP/LBP were assessed based on 1-year prevalence (yes/no), pain severity (none, mild, moderate, severe), and the presence of radicular pain with or without motor deficits (yes/no), at both baseline and follow-up. Results:At baseline, the 1-year prevalence for having either NP, LBP, or both was 55%. The 1-year prevalence for NP was 29% and for LBP 45%. Among men with NP, 18% reported severe pain, while 17% of men with LBP reported severe pain. Men with NP at baseline had a relative risk (RR) of 4.0 (95% CI: 3.4-4.6) for reporting NP 5 years later, compared to men without NP at baseline. Men with severe NP had an RR of 10.7 (95% CI: 7.5-15.1) for reporting severe NP 5 years later, compared to men without severe NP at baseline. The corresponding RRs for LBP were 2.8 (95% CI: 2.5-3.1) and 6.5 (95% CI: 4.9-8.6). Poor self-rated health and dizziness were associated with NP/LBP at both time points, while smoking was associated with lower risk of NP. Conclusion:More than half of community-dwelling men aged 69-81 experience pain in the spinal region during a year (nearly one-third NP and just below half LBP). The majority experience only mild to moderate pain. Baseline pain, especially severe pain, strongly predicts pain 5 years later, and associated factors may help identify high-risk groups suitable for targeted interventions.

The aim of this international meta-analysis was to quantify the predictive value of BMI for incident fracture and relationship of this risk with age, sex, follow-up time, and BMD. A total of 1 667 922 men and women from 32 countries (63 cohorts), followed for a total of 16.0 million person-years were studied. 293 325 had FN BMD measured (2.2 million person-years follow-up). An extended Poisson model in each cohort was used to investigate relationships between WHO-defined BMI categories (Underweight: <18.5 kg/m2; Normal: 18.5-24.9 kg/m2; Overweight: 25.0-29.9 kg/m2; Obese I: 30.0-34.9 kg/m2; Obese II: ≥35.0 kg/m2) and risk of incident osteoporotic, major osteoporotic and hip fracture (HF). Inverse-variance weighted β-coefficients were used to merge the cohort-specific results. For the subset with BMD available, in models adjusted for age and follow-up time, the hazard ratio (95% CI) for HF comparing underweight with normal weight was 2.35 (2.10-2.60) in women and for men was 2.45 (1.90-3.17). Hip fracture risk was lower in overweight and obese categories compared to normal weight [obese II vs normal: women 0.66 (0.55-0.80); men 0.91 (0.66-1.26)]. Further adjustment for FN BMD T-score attenuated the increased risk associated with underweight [underweight vs normal: women 1.69 (1.47-1.96); men 1.46 (1.00-2.13)]. In these models, the protective effects of overweight and obesity were attenuated, and in both sexes, the direction of association reversed to higher fracture risk in Obese II category [Obese II vs Normal: women 1.24 (0.97-1.58); men 1.70 (1.06-2.75)]. Results were similar for other fracture outcomes. Underweight is a risk factor for fracture in both men and women regardless of adjustment for BMD. However, while overweight/obesity appeared protective in base models, they became risk factors after additional adjustment for FN BMD, particularly in the Obese II category. This effect in the highest BMI categories was of greater magnitude in men than women. These results will inform the second iteration of FRAX®.

In this retrospective population cohort comprising 36,864 adult lymphoma patients, an increased risk of MOF, including hip fractures, was observed within 18 months of lymphoma diagnosis compared with the Swedish population and especially increased in the 51–60-year age group. To explore the risk of osteoporotic fractures in lymphoma patients compared with that in the general Swedish population. Fracture risk was evaluated in a retrospective cohort comprising lymphoma patients (aged ≥ 18 years) diagnosed between 2000 and 2018 (n = 36,864), as recorded in the Swedish Lymphoma Register, and a matched cohort from the general population (n = 368,082). The risk of major osteoporotic fracture (MOF) overall (n = 1009, 60

The link between antibodies and bone mass is debated. Activated IgG, which interacts directly with Fc gamma receptors, stimulates osteoclastogenesis in vitro, and local injection in immune-activated mice leads to bone loss. Multiple myeloma patients with high serum IgG levels have induced osteoclast activation and display bone loss. In addition, bone loss has been linked to serum autoantibodies in autoimmune diseases, including anti-citrullinated protein antibodies (ACPA) in individuals with rheumatoid arthritis (RA). Whether serum IgG or autoantibodies regulate bone mass under healthy conditions is poorly studied. In elderly men, neither serum levels of polyclonal IgG nor autoantibody were associated with areal bone mineral density in the MrOS Sweden study. Repetitive systemic injections of high-dose polyclonal IgG complexes in mice did not exert any discernible impact on bone mineral density. However, repetitive local intra-articular injection of the same IgG complexes led to a localized reduction of trabecular bone density. These results indicate antibodies may only impact bone density when close to the bone, such as within the synovial joint.

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

In this retrospective cohort study of adult stem cell transplanted patients (n = 8463), a significant increased risk of both MOF and hip fractures was seen compared with the Swedish population and occurred in mean more than 2 years after stem cell transplantation. To explore the risk for osteoporotic fracture in patients who have undergone hematopoietic stem cell transplantation (HSCT) compared with the Swedish population. The risk of osteoporotic fractures was determined in a retrospective population cohort study of adult (≥ 18 years) Swedish patients (n = 8463), who were transplanted with HSCT 1997–2016 and compared with all adults living in Sweden during the same period. In the total study group (n = 8463), 90 hip fractures (1.1

Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ -2.5, whereas 53% had T-scores between -1.0 and -2.5 and 37% had T-scores ≥-1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

Overt and subclinical hyperthyroidism are associated with an increased fracture risk, but whether thyroid hormones are associated with fracture risk in individuals with normal thyroid-stimulating hormone (TSH) has mostly been investigated in women. Therefore, we investigated if serum levels of free thyroxine (FT4) or TSH are associated with fracture risk in Swedish men. We followed (median 12.2 yr) elderly men (n = 1825; mean age 75, range 69-81 yr) participating in the Gothenburg and Malmo subcohorts of the prospective, population-based MrOS-Sweden study. The statistical analyses included Cox proportional hazards regression. Men receiving levothyroxine treatment were excluded. In our total cohort, serum FT4 (per SD increase) was associated with increased risk of major osteoporotic fractures (MOFs; n = 479; fully adjusted hazard ratio [HR] 1.14, 95% CI, 1.05-1.24) and hip fractures (n = 207; HR 1.18, 95% CI, 1.04-1.33). Also, in men with normal TSH (n = 1658), FT4 (per SD increase) was significantly associated with increased risk of MOF and hip fractures. Furthermore, men in the highest FT4 quartile had a 1.5-fold increase in hip fracture risk compared with men in the three lower FT4 quartiles, both in the total population and in men with normal TSH (fully adjusted: HR 1.45, 95% CI, 1.04-2.02 and HR 1.51, 95% CI, 1.07-2.12, respectively). In contrast, the risk of MOF was not statistically different in the highest FT4 quartile compared with the three lower FT4 quartiles. Finally, serum TSH was not associated with fracture risk after full adjustment for covariates. In conclusion, serum FT4, but not serum TSH, is a predictor of hip fracture risk in elderly Swedish men. Additionally, there was an association between FT4 (per SD increase) and the risk of MOF. Thyroid hormone excess (hyperthyroidism) is associated with increased fracture risk. However, whether thyroid hormones are associated with fracture risk in individuals with normal thyroid-stimulating hormone (TSH), which regulates free thyroxine (FT4), has mostly been investigated in women. Therefore, we investigated if FT4 or TSH levels are associated with fracture risk in Swedish men. We followed (median 12.2 yr) 1825 elderly men (mean age 75 yr) in the population-based MrOS-Sweden study. During the follow-up, 479 men suffered from a major osteoporotic fracture (MOF) and 207 men sustained a hip fracture. In our total cohort as well as in men with normal TSH, serum FT4 (per SD increase) was associated with increased risk of MOF and hip fractures. Furthermore, men in the highest FT4 quartile had a 1.5-fold increase in hip fracture risk compared with men in the three lower FT4 quartiles, both in the total population and in men with normal TSH. In contrast, the risk of MOF was similar in the highest FT4 quartile compared with the three lower quartiles. Finally, serum TSH was not associated with fracture risk. In conclusion, serum FT4, but not serum TSH, is a predictor of hip fracture risk in elderly Swedish men.

BACKGROUND:Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE:To clarify associations of sex hormones with these outcomes. DATA SOURCES:Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION:Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION:Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS:Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS:Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION:Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE:Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited. We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors. Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4–6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell’s Concordance Index (C-index). Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6

Background and purpose: Scheuermann’s disease is characterized by kyphosis and frequently mild back pain. As the level of kyphosis may progress over time, also the level of pain may increase. We evaluated the prevalence of Scheuermann’s disease, and their pain, in Swedish elderly men.Patients and methods: The Osteoporotic Fractures in Men (MrOS) Study Sweden (n = 3,014) is a population-based prospective observational study of community-living men aged 69–81 years. At baseline, participants answered a questionnaire including history of neck/back pain during the preceding year and characteristics of any pain (severity, sciatica, and neurological deficits). Lateral thoracic/lumbar spine radiographs were taken of 1,453 men. We included the 1,417 men with readable radiographs. Scheuermann’s disease was defined as 3 or more consecutive vertebrae with > 5° wedging with no other explanation for the deformity.Results: 92 of the 1,417 men (6.5%, 95% confidence interval 5.3–7.9) had Scheuermann’s disease. 31% of men with and 31% without Scheuermann’s disease reported neck pain (P = 0.90) and 51% with and 55% without the disease reported back pain (P = 0.4). Among men with Scheuermann’s disease and back pain, none reported severe pain, 57% moderate, and 43% mild, compared with 7%, 50%, and 44% in those without Scheuermann’s disease (P = 0.2). In those with Scheuermann’s disease 63% reported no sciatica, 15% sciatica without neurological deficits, and 22% sciatica with neurological deficits, compared with 56%, 16%, and 28% in those without the disease (P = 0.6).Conclusion: The prevalence of Scheuermann’s disease in elderly Swedish men is between 5.3% and 7.9%. The condition seems at this age not to be associated with neck or back pain.

Introduction: The European Working Group on Sarcopenia in Older People (EWGSOP) published a revised definition of sarcopenia in 2018. There are few incidence studies of sarcopenia following the latest definition. Objective: To study prevalence, incidence proportion and incidence rate of sarcopenia in a simple random sample of older Swedish men using the EWGSOP2 definition. Methods: Men aged 69-81 were invited to participate in the Osteoporotic Fractures in Men (MrOs) Sweden study. Of 2,004 included participants, 1,266 participants (mean age 75.1, SD 3.1 years) completed baseline and 5-year follow-up measurements. We assessed muscle strength by measuring grip strength and chair stands test, lean mass by dual energy X-ray absorptiometry and physical performance by gait speed at baseline and follow-up. Sarcopenia prevalence and incidence were calculated according to the EWGSOP2 definition.Results: Sarcopenia prevalence increased from 5.6% at baseline to 12.0% at follow-up. During the mean 5.2year follow-up period, 9.1% developed sarcopenia (incidence proportion), corresponding to an incidence rate of 1.8 per 100 person-years at risk while 39.4% of the participants with sarcopenia at baseline participating in follow-up reversed to no longer having confirmed sarcopenia at 5-year follow-up.Conclusion: The prevalence of sarcopenia defined along EWGSOP2 criteria doubled within 5 years in older men, and more than a third of the study participants with sarcopenia at baseline did not have sarcopenia at follow-up. We conclude that sarcopenia is not a static condition.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)