Sjögren's syndrome associated with Crohn's disease successfully treated with adalimumab

REVIEW URRENT C OPINION

Osteoporosis: fracture epidemiology update 2016 Jane A. Cauley

Purpose of review The purpose of this review is to provide an update on osteoporosis epidemiology. The focus is on fractures because fractures are the most important clinical consequence of osteoporosis. Studies published over the past 18 months are identified and reviewed. Finally, the clinical impact of these new findings is discussed. Recent findings Important research in 2015–2016 include analyses of screening and rescreening in younger women and older men, risk factors for hip fractures in older men, obesity and weight loss/gain, and risk of fracture. Several dietary factors, including adherence to a Mediterranean diet and a diet rich in protein, fruits, and vegetables and maintenance of physical function with increasing age represent modifiable nonpharmacologic risk factors that improve bone health. Sarcopenia may have a more important role in fracture in men than women. Important biomarkers for fracture include low 25-hydroxyvitamin D and hemoglobin A1c. Summary Updated literature on fracture epidemiology have identified important risk factors for fracture. Keywords biomarkers, epidemiology, fracture, osteoporosis, risk factors

INTRODUCTION A new report from the 2015 World Health Organization (WHO) noted that musculoskeletal conditions including osteoporotic fractures place a heavy burden on individuals and have important health consequences in both developed and developing countries. This burden far exceeds capacity and far exceeds other noncommunicable diseases [1 ]. Of importance, this burden will increase drastically given the dramatic demographic changes leading to an increasingly aging society. Given the public health impact of musculoskeletal diseases in general and osteoporosis specifically, the purpose of this review is to update readers on the epidemiology of osteoporosis with an emphasis on fracture epidemiology. Noteworthy references are flagged in the list of references. &

WHAT’S NEW WITH SCREENING FOR OSTEOPOROSIS? The United States Prevention Services Task Force (USPSTF) recommends bone mineral density (BMD) screening for all women aged 65 years and older [2]. In younger women (age <65 years), the USPSTF recommends BMD testing for women whose 10-year predicted risk of major osteoporotic fracture is at least 9.3% using the Fracture Risk Assessment www.co-rheumatology.com

Tool (FRAX). However, Crandall et al. [3] showed that the sensitivity of this strategy was 4.7% among women aged 50–54 years, 26.5% for women aged 55–59 years, and 37.3% for women aged 60–64 years. These results suggest that clinicians trying to identify younger women for BMD testing cannot rely on current fracture risk prediction tools but must use individual patient evaluation. Two recent papers evaluated when to rescreen younger women and older men with an areal bone mineral density (aBMD) screening test. Gourlay et al. [4] studied 4068 women, aged 50–64 years, and found that the risk of major osteoporotic fracture was so low, unless they had osteoporosis on their first BMD test, they were unlikely to benefit from BMD rescreening before age 65 years. Similarly, in older men aged at least 65 years, Gourlay et al. [5] showed that men, who have an initial BMD T-score at the hip or spine less than 1.50 on their first BMD Department of Epidemiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, Pennsylvania, USA Correspondence to Dr Jane A. Cauley, DrPH, Department of Epidemiology, University of Pittsburgh, Graduate School of Public Health, 130 DeSoto Street, Crabtree A510, Pittsburgh, PA 15261, USA. Tel: +1 412 624 3057; e-mail: [email protected] Curr Opin Rheumatol 2017, 29:150–156 DOI:10.1097/BOR.0000000000000365 Volume 29  Number 2  March 2017

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Fracture epidemiology update 2016 Cauley

KEY POINTS

from a large well-characterized United States cohort of 5994 older men, the Osteoporotic Fractures in Men Study (MrOS) [9 ]. Older age (>75 years), low BMD, smoking, greater height and height loss since age 25 years, history of fracture, use of tricyclic antidepressants, history of myocardial infarction, hyperthyroidism or Parkinson’s disease, lower protein intake, and lower executive function were all independently associated with a higher risk of hip fracture. Of importance, men with BMD in the osteoporosis range and four or more of these risk factors had a 50-fold increased incidence of hip fracture compared with men with normal BMD and no risk factors. Many of these assessments can easily be incorporated into routine clinical practice and may help to identify high-risk men who may benefit from treatments. Other more novel risk factors associated with fractures include lower socioeconomic status [10,11], abdominal aortic calcification [12], decreased thigh subcutaneous fat, and lower appendicular lean mass in men; in women, only subcutaneous fat and cross-sectional area were associated with hip fractures [13]. A number of important articles have been published recently examining weight, weight change, and height in relationship to fractures. Lacombe et al. [14 ] analyzed data from the Million Women Study of 1 154 821 United Kingdom women, mean age 56 years. After a mean follow-up of 11 years, almost 45 000 women experience at least one fracture. Women with a body mass index (BMI) at least 30 kg/m2 had a 25–74% increased risk of lower leg fractures, a 53–67% increased risk of ankle fractures, and a 14–31% increased risk of humerus fractures. In contrast, obese women had a 50% lower risk of hip, 13–18% lower risk of forearm (not wrist), and a 36– 44% lower risk of wrist fractures. Women with a BMI less than 20 kg/m2 had an increased risk of femur (not neck), hip, forearm, wrist, and humerus fractures. This is the largest study to examine the association between BMI and multiple types of fractures. As acknowledged by the authors, why the association between adiposity and fractures differs by site of fracture is unknown. Possible explanations may include overall fat distribution, amount of visceral vs. subcutaneous fat because subcutaneous fat is a major source of estrogen and differences in the association between frailty and fracture type. Nevertheless, these data are important in highlighting the heterogeneous risk factors for different types of fractures. Several studies have examined the association between weight loss and fractures. Compston et al. [15] reported a significant association between unintentional weight loss (10 lbs) and fractures of the hip, spine, and clavicle in the Global Longitudinal &&

 Important research in 2015–2016 include analyses of screening and rescreening in younger women and older men, risk factors for hip fractures in older men, obesity and weight loss/gain, and risk of fracture.  Several dietary factors, including adherence to a Mediterranean diet and a diet rich in protein, fruits, and vegetables and maintenance of physical function with increasing age represent modifiable nonpharmacologic risk factors that improve bone health.  Sarcopenia may have a more important role in fracture in men than women.  Important biomarkers for fracture include low 25hydroxyvitamin D and hemoglobin A1c.

test, were unlikely to develop osteoporosis over the next 9 years and do not need retesting.

EPIDEMIOLOGY OF FRACTURES Updated hip fracture incidence rates have been recently published using Medicare data [6] but there has been no update on other types of fracture. Prior et al. [7 ] published data from the Canadian Multicentre Osteoporosis Study (CAMOS) and presented the 10-year absolute probability of fragility fractures (fractures due to a fall from a standing height or less) in men and women by age. Women aged 75–84 years had about a 24% 10-year absolute risk of fracture and men, about a 14% absolute risk over the next 10 years. In men, however, the competing risk of mortality was greater than the 10-year absolute risk of fracture. Fracture risk increased with age in both men and women but the patterns of increase were steeper in women. Of interest, hip fracture incidence did not differ in men and women aged 75–84 years. The review is clinically important by providing absolute 10-year risks of fracture in both men and women. The proportion of United States veterans who are women is projected to increase from 10.3% in 2013 to 15% in 2030. Of importance, LaFleur et al. [8] showed that women veterans had a 24% higher risk of hip fracture compared with nonveterans [hazard ratio ¼ 1.24; 95% confidence intervals (CI), 1.03–1.49] independent of established risk factors. Women veterans may represent an important high-risk group in the future. &&

RISK FACTORS FOR FRACTURE The most comprehensive study of risk factors for hip fracture in men was recently published using data

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Study of Osteoporosis in Women (N ¼ 40 179). Of importance, the increase in fracture risk was observed within 1 year of the weight loss and the increased risk was sustained 5 years after the weight loss. Crandall et al. [16 ] confirmed the association between weight loss (5%) and fractures of the upper limb, central body (hip, pelvis, spine), and hip fractures within the Women’s Health Initiative. Of interest, this article was unique in showing an increased upper limb and lower limb fractures with at least 5% weight gain, challenging the traditional clinical paradigm that weight gain is protective against fracture. The Nurses’ Health Study showed that indicators of abdominal obesity (e.g., waist circumference) were associated with an increase in hip fracture in women, independent of BMI [17]. The increased risk was, however, confined to women with low physical activity [17]. The association was not observed in a similar cohort of older men which may reflect low power in men and fewer hip fractures because 95% CIs overlapped in men and women. Abdominal obesity may be associated with an increase in fracture risk because adipose tissue is an active endocrine tissue with evidence that visceral adipose tissue releases interleukin-6 in amounts two to three times greater than subcutaneous fat [18]. In another report from the Million Women Study, every 10 cm increase in height was associated with almost a 50% increase in the risk of hip fracture [19]. Height was also associated with all fractures but the magnitude of the risk was modest. These associations may reflect a biomechanical mechanism whereby taller women experience greater forces on impact during their fall. In addition, taller women have longer hip axis lengths [20] which may place them at an increased fracture risk. &

LIFE COURSE EPIDEMIOLOGY Ben-Shlomo and Kuh [21] have defined a life course approach to chronic disease epidemiology as the ‘study of long term effects on chronic disease of physical and social exposures during gestation, childhood, adolescence, young adulthood and later adult life’. Two important life course epidemiology papers were published recently. Jerrhag et al. [22] studied distal forearm fractures in Swedish children aged 16 years or less over the period 1999–2010. The incidence of distal forearm fracture was 50% higher than during the period of 1950–1965. Over 1999–2010, the average annual increase in incidence rate was 2.2%, a significant increase in both boys and girls. These secular increases in fractures may have important implications for future fractures because childhood 152

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fracture has been shown to be associated with increased risk of fracture during adulthood [23]. A meta-analysis was recently published reviewing 10 published prospective studies of the association between parity and osteoporotic fracture risk [24]. The reports covered the period of 1966–2014 comparing 217 295 participants and more than 26 000 women with an osteoporotic fracture. Compared with nulliparous women, parous women had an 11 and 26% reduced risk of any osteoporosis and hip fracture, respectively. For each live birth, the risk of hip fracture was reduced by 12%. Potential biological mechanisms underlying a protective effect of parity on fractures may include high estrogen levels during pregnancy, increases in bone formation during pregnancy, and weight gain during pregnancy.

DIET AND OSTEOPOROTIC FRACTURES The traditional Mediterranean diet emphasizes the consumption of fruits, vegetables, fish, nuts, whole grains, and monounsaturated fats. This diet has been linked to skeletal health but the overall evidence was not convincing. Haring et al. [25 ] studied more than 90 000 women enrolled in the Women’s Health Initiative. A Mediterranean diet index score was created and ranged from 0 (none) to 9 (perfect adherence). Women with the highest Mediterranean diet score had 20% lower risk of hip fracture [hazard ratio ¼ 0.80; 95% CI (0.66–0.97)] with an absolute risk reduction of 0.29% and a number needed to treat of 342. There was, however, no association between diet score and total fractures. Two recent papers focused on specific nutrients. Among adults at least aged 50 years enrolled in CAMOS, women with protein intake less than 12% of total energy intake (TEI) and men with less than 11% TEI had a linear increased risk of osteoporotic fractures [26]. Current dietary guidelines recommend five servings of fruits and vegetables. A study of more than 75 000 from Sweden showed that men and women with zero consumption had an 88% higher risk of hip fracture than those consuming five servings per day [27]. However, more than five servings per day did not carry additional benefit. Taken together, these recent studies showing benefits of a Mediterranean diet, a protein rich diet, and a diet rich in fruits and vegetables highlight modifiable and nonpharmacologic means to improve bone health. &

TRAJECTORIES OF PHYSICAL FUNCTION AND FRACTURES Poor physical function measured at one point in time has been associated with an increased risk of Volume 29  Number 2  March 2017

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Fracture epidemiology update 2016 Cauley

fracture in many prospective studies. Trajectories of physical function have rarely been studied with respect to fractures. Barbour et al. [28 ] studied women enrolled in the Study of Osteoporotic Fractures (SOF). Time to complete five chair stands and a 6-m walk test were administered a median number of five to six times over an average of 10 years. Individual physical performance trajectory slopes were created and divided into quintiles (Q). Quintile 1 represented the greatest decline and Q5 the least decline. Q2–4 formed the referent group. Results showed that women with the greatest decline had a 21–26% and a 24–54% increased risk of nonspine fracture and hip fracture, respectively. To my knowledge, this study is the first to show that greater walking speed and chair stand speed declines were independently associated with an increased risk of hip fracture. Greater physical activity designed to improve or maintain physical performance could reduce fracture risk. &&

SARCOPENIA The term ‘sarco-osteopenia’ was coined in 2009 to emphasize that the combination of low lean mass and bone mass both contribute to fracture. Chalhoub et al. [29 ] studied 5444 men enrolled in MrOS (mean age 73.7 years) and 1114 women enrolled in SOF (mean age 77.6 years). Sarcopenia was defined as low appendicular lean mass (ALM) plus slowness and weakness. Low femoral neck BMD was defined according to the WHO definition of a T-score less than 1.0. Men with low BMD and sarcopenia [hazard ratio ¼ 3.79; 95% CI (2.65– 5.41)] and men with low BMD only [hazard ratio ¼ 1.67; 95% CI (1.45–1.93)] but not men with sarcopenia only [hazard ratio ¼ 1.14; 95% CI (0.62–2.09)] had greater risk of fracture than men with normal BMD and no sarcopenia. Women with low BMD and sarcopenia [hazard ratio ¼ 2.27; 95% CI (1.37–3.76)] and women with low BMD alone [hazard ratio ¼ 2.62; 95% CI (1.74–3.95)] but not women with only sarcopenia had greater risk of fracture than women with normal BMD and no sarcopenia. The findings from this study suggest that combined effect of sarcopenia and low BMD on fracture risk may be greater than that of each individual factor, at least in men. In women, the major risk of a fracture was due to low BMD. Sarcopenia alone was not an independent risk factor in men or women. Muscle strength and testosterone tends to decline faster in men than women with advancing age which may explain why the combination of low ALM and low BMD conferred a greater risk in men. &&

GENETICS With President Obama’s precision medicine initiative announcement in January 2016, there has been increased emphasis on the genetic predisposition to chronic disease and the identification of high-risk individuals through genetic analyses. A large-scale meta-analysis identified 63 autosomal single nucleotide polymorphisms (SNPs) associated with BMD, of which 16 were also associated with fracture risk [30]. A recent report studied the clinical utility of genetic risk scores based on the meta-analysis [31]. Results showed that when BMD is known these genetic risk scores based on these SNPs is unlikely to be sufficient for identifying high-risk individuals. Future work will need to combine the genetic analysis with functional studies to identify their role in bone biology [32].

TRABECULAR BONE SCORE Trabecular bone score (TBS) is a gray level textural index of bone microarchitecture derived from lumbar spine BMD scans. TBS has recently been encorporated in the FRAX score. An important metaanalysis was published in 2016 evaluating TBS as a fracture prediction tool and its relationship to FRAX [33 ]. The meta-analysis included 17 809 men and women from 14 prospective cohort studies. The hazard ratio per one standard deviation (SD) decrease in TBS was 1.44 (1.35, 1.53), an association that was independent of FRAX. These results support the use of TBS as an assessment of fracture risk. There is a high likelihood that TBS will be increasingly used in clinical practice. &&

BIOMARKERS FOR FRACTURES Recent papers on biomarkers for fracture are summarized in Table 1. Many papers evaluated the association between 25-hydroxyvitamin D (25(OH)D) and fractures [34,35,36 ,37]. Middleaged women in the Study of Women’s Health Across the Nation (SWAN) who had a 25(OH)D greater than 20 ng/dl premenopausally had a 46% lower risk of nontraumatic fracture over the menopausal transition [34]. There was no association between 25(OH)D and traumatic fractures. Fink et al. [35] evaluated the utility of routine laboratory tests for identifying men with osteoporosis (T-score 2.5 or less): only low 25(OH)D and high alkaline phosphatase were more likely in men with osteoporosis. Swanson et al. [37] compared 25(OH)D with 1,25(OH)D2D to establish which marker of vitamin D status was better correlated with health outcomes, and concluded that inclusion of 1,25(OH)2D did not improve the ability to predict health outcomes once

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Hip fracture

Nontraumatic fracture

N ¼ 1572 men; mean age  74 years; MrOS

N ¼ 221 men/women; 71% women; mean age ¼ 81 years

N ¼ 1238 men; mean age ¼ 74 years; MrOS

N ¼ 1755 men; mean age  75 years; MrOS

N ¼ 800 women; mean age ¼ 70 years; WHI

N ¼ 5462; 58% women; 85% White; mean age ¼ 72.8 years; CHS

N ¼ 1681 (TGF-b1); N ¼ 3266 (PIIINP); 59% women; mean age ¼ 78 years; CHS

N ¼ 2062 women; mean age  46 years; SWAN

N ¼ 4714; 59% women; mean age  74.9 years; CHS

N ¼ 2408 men/women; 25% men; mean age ¼ 72 years; NOREPOS

Fink et al. [35]

Nurmi-Luthje et al. & [36 ]

Swanson et al. [37]

Cauley et al. [38]

Ing et al. [39]

Bethel et al. [40]

Barzilay et al. [41]

Chang et al. [42]

Fink et al. [43]

Finnes et al. [44]

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N ¼ 4692 men/women; 58% women; mean age ¼ 75 years; CHS

N ¼ 1283 men/women; 51% women; mean age ¼ 75 years; LASA

Mehta et al. [46]

van Varsseveld et al. [47] All clinical fracture

Hip fracture

Hip fracture

Hip fracture

Hip fracture; composite fracture (hip, pelvis, humerus, distal forearm)

Hip fracture

Hip fracture

Clinical vertebral fracture; hip fracture; nonspine fracture

Nonvertebral fracture; hip fracture

IGF

Serum urate

HbA1c

Vitamin K1

Fetuin-A

TG baseline and change 2–5 years later

TGF-b1; PIIINP

Soluble CD14

TNFaSR1; TNFaSR2

IL-6 and IL-6sR; CRP; TNFa; TNFsR1 and 2; IL-10

25(OH)D; 1,25(OH)D

25(OH)D

25(OH)D; alkaline phosphatase

25(OH)D

Biomarker

17.6 nmol/l

6.88 ng/dl

<6% 6–<7% 7–<8% 8–<9% 9–<10% >10%

Quartiles (ng/ml) Q1: <0.46 Q2: 0.46, 0.76 Q3: 0.77, 1.25 Q4: >1.25

Per standard deviation

>300 mg/dl

Per doubling

Per standard deviation

>1739.4 pg/ml; >3509.5 pg/ml

3 proinflammatory cytokines in top quartile

Per standard deviation increase

20 ng/dl

<30 ng/ml; >129 IU/l

20 ng/dl

Cutoff –

2.24 (1.05, 4.79), P trend ¼ 0.05; 2.83 (1.34, 5.99), P trend ¼ 0.113

–

0.98 (0.88, 1.09); 0.95 (0.88, 1.02)

TG > 300: 2.5 (1.13, 5.44); increasing TG 50 mg/dl: 1.11 (1.04, 1.18)

TGF-b1: 0.78 (0.61, 0.91); PIIINP: 0.95 (0.66, 0.37)

1.09 (0.52, 2.28)

1.9 (1.1, 3.1)

1.98 (1.00, 3.96)

1.07 (0.97, 1.17); 1.00 (referent); 1.03 (0.95, 1.10); 1.08 (1.00, 1.17); 1.13 (1.03, 1.24); 1.26 (1.15, 1.37); P trend ¼ <0.001

1.32 (1.03, 1.70); 1.27 (0.99, 1.64); 1.11 (0.85, 1.43); referent; P trend ¼ 0.017

–

TGF-b1: 1.13 (0.84, 1.54); PIIINP: 0.99 (0.74, 1.32)

Overall: 1.08 (0.99, 1.19); Whites: 1.11 (1.01, 1.23)

–

Clinical vertebral fracture: 3.06 (1.66, 5.63); hi p fracture: 2.03 (1.11, 3.71); nonspine fracture: 1.31 (0.96, 1.79)

25(OH)D: Nonvertebral fracture: 1.10 (0.90, 1.13); hi p fracture: 0.69 (0.52, 0.93). 1,25(OH)2D: Nonvertebral fracture: 0.99 (0.89, 1.10); Hi p fracture: 0.74 (0.56, 1.00)

–

0.54 (0.32, 0.89)

Women

Relative risk U 0.75 (P < 0.05)

1.13 (1.05, 1.22)b; 3.05 (1.52, S6.11)b

Men

Resultsa

Bold indicates statistically significant values. CHS, Cardiovascular Health Study; CRP, C-reactive protein; HbA1c, hemoglobin A1c; IGF, insulin like growth factor 1; IL-10, interleukin 10; IL-6, interleukin 6; IL-6SR, interleukin 6 soluble receptor; LASA, Longitudinal Aging Study Amsterdam; MrOS, Osteoporosis Fractures in Men Study; NOREPOS, Norwegian Epidemiology Osteoporosis Studies; PIIINP, procollagen type III N-terminal propeptide; SWAN, Study of Women’s Health Across the Nation; TG, triglyceride; TGF-bI, transforming growth factor b; TNFa SR, TNF alpha soluble receptor; TNFa, TNF alpha; WHI, Women’s Health Initiative. a Results presented as hazard ratios (95% confidence interval) unless otherwise noted. b Prevalence ratio, 95% confidence interval.

N ¼ 20 025 men/women; 52% women; all type 2 diabetics; mean age ¼ 72 years; Taiwan

Li et al. [45 ]

&

Osteoporosis T-score <2.5

N ¼ 1744 women; mean age ¼ 48.5 years; SWAN

Cauley et al. [34] Any nontraumatic fracture

Patients

Reference

Outcome

Table 1. Summary of biomarkers and fractures: 2015–2016

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Fracture epidemiology update 2016 Cauley

a 25(OH)D level measure was available. Finally, higher 25(OH)D levels measured at the time of hip fracture was associated with improved survival after the hip fracture [36 ]. Higher individual proinflammatory cytokines have been linked to increased fracture risk in men [38] and women [39]. Of interest, men with the highest inflammatory burden had a two-fold increased risk of hip and a three-fold increased risk of clinical vertebral fracture. Soluble CD14 is also an inflammatory marker associated with osteoclasts but was unrelated to fracture overall [40]. However, there was a modest association between higher CD14 and hip fracture in Whites. Several novel biomarkers for fracture were also explored. Barzilay et al. [41] studied transforming growth factor beta one (TGF-b1) and procollagen type III N-terminal propeptide (PIIINP) in relationship to hip fracture. TGF-b1 recruits osteoclasts during bone resorption for the removal of old bone. Doubling of TGF-b1 was associated with a 22% lower risk of hip fracture in women but not men [41]. PIIINP, a marker of bone turnover, was unrelated to fracture risk [41]. High triglycerides (>300 mg/dl) at baseline and an increasing triglyceride of 50 mg/dl were both associated with an increased fracture risk, independent of many covariates including BMI and alcohol intake in the SWAN cohort [42]. These results are consistent with research linking cardiovascular disease and osteoporosis. Fetuin-A, a protein that regulates calcium mineralization, was unrelated to hip fractures [43]. Vitamin K1 is the predominant form of vitamin K in the diet and has been linked to osteoporosis. Finnes et al. [44] reported a linear trend of increasing risk of hip fracture with decreasing vitamin K1. Of interest, the effect of vitamin K1 on fracture risk was most predominant in those with low 25(OH)D [44]. Diabetes is an established risk factor for fracture but few studies have specifically studied glucose control. Li et al. [45 ] studied a large population of patients with type II diabetes from Taiwan and showed a linear increase in hip fractures with increasing hemoglobin A1c, emphasizing the need for adequate glucose control in diabetic patients. Higher serum urate levels were associated with an increased hip fracture risk in a combined sample of men and women [46]. Finally, previous studies of serum insulin like growth factor 1 (IGF-1) have been mixed. van Varsseveld et al. [47] showed a significant association between lower IGF-1 and increased risk of clinical fractures in women but not men supporting a gender difference in the effect of IGF-1 on bone health. &

&

CONCLUSION In summary, the recent literature on fracture epidemiology have yielded important information on screening and rescreening subjects with a BMD test and present up-to-date information on the 10-year absolute risk of diverse types of fractures. In depth analyses of risk factors for hip fracture in men and the association between BMI, weight change, and height have been published recently. Of interest is the differential relationship of BMI to different types of fracture and the observation that weight gain is associated with an increased risk of fracture. Use of the lifecourse approach to the epidemiology of fractures should be expanded. A recent meta-analysis showed a protective association between parity and fracture. Several modifiable risk factors have been identified including the Mediterranean diet, a diet rich in protein, fruits, and vegetables, and maintenance of physical function. Sarcopenia may play a larger role in fracture cause in men than women. Finally, several biomarkers for fracture including low 25(OH)D and HbA1c may help to identify individuals at high risk of fracture. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Briggs AM, Cross MJ, Hoy DG, et al. Musculoskeletal health conditions & represent a global threat to healthy aging: a report for the 2015 World Health Organization world report on ageing and health. Gerontologist 2016; 56 (Suppl 2):S243–S255. This article describes the global impact of musculoskeletal conditions. 2. U.S. Preventive Services Task Force. Screening for osteoporosis: US preventive services task force recommendation statement. Ann Intern Med 2011; 154:356–364. 3. Crandall CJ, Larson JC, Watts NB, et al. Comparison of fracture risk prediction by the US Preventive Services Task Force strategy and two alternative strategies in women 50–64 years old in the Women’s Health Initiative. J Clin Endocrinol Metab 2014; 99:4514–4522. 4. Gourlay ML, Overman RA, Fine JP, et al. Baseline age and time to major fracture in younger postmenopausal women. Menopause 2015; 22:589–597. 5. Gourlay ML, Overman RA, Fine JP, et al. Time to osteoporosis and major fracture in older men: the MrOS study. Am J Prev Med 2016; 50:727–736. 6. Wright NC, Curtis JR, Arora T, et al. The validity of claims-based algorithms to identify serious hypersensitivity reactions and osteonecrosis of the jaw. PLoS One 2015; 10:e0131601. 7. Prior JC, Langsetmo L, Lentle BC, et al. Ten-year incident osteoporosis&& related fractures in the population-based Canadian Multicentre Osteoporosis Study – comparing site and age-specific risks in women and men. Bone 2015; 71:237–243. These analyses provide updated 10-year absolute risk of a wide range of fracture types by age and sex. These rates primarily apply to Whites.

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Epidemiology and health-related services 8. LaFleur J, Rillamas-Sun E, Colon-Emeric CS, et al. Fracture rates and bone density among postmenopausal veteran and non-veteran women from the Women’s Health Initiative. Gerontologist 2016; 56 (Suppl 1): S78–S90. 9. Cauley JA, Cawthon PM, Peters KE, et al. Risk factors for hip fracture in older && men: the Osteoporotic Fractures in Men Study (MrOS) J Bone Miner Res 2016; 31:1810–1819. This analysis is the largest and most comprehensive study of risk factors for hip fracture in older men. Of importance, men with low BMD and four or more of these risk factors have a 50-fold increase in hip fracture compared with men with normal BMD and no risk factors. 10. Brennan SL, Holloway KL, Williams LJ, et al. The social gradient of fractures at any skeletal site in men and women: data from the Geelong Osteoporosis Study Fracture Grid. Osteoporos Int 2015; 26:1351–1359. 11. Brennan SL, Yan L, Lix LM, et al. Sex- and age-specific associations between income and incident major osteoporotic fractures in Canadian men and women: a population-based analysis. Osteoporos Int 2015; 26:59–65. 12. Szulc P. Abdominal aortic calcification: a reappraisal of epidemiological and pathophysiological data. Bone 2015; 84:25–37. 13. Malkov S, Cawthon PM, Peters KW, et al. Hip fractures risk in older men and women associated with DXA-derived measures of thigh subcutaneous fat thickness, cross-sectional muscle area, and muscle density. J Bone Miner Res 2015; 30:1414–1421. 14. Lacombe J, Cairns BJ, Green J, et al. The effects of age, adiposity, and && physical activity on the risk of seven site-specific fractures in postmenopausal women. J Bone Miner Res 2016; 31:1559–1568. This is the largest study of BMI and multiple types of fracture. High BMI (>30 kg/ m2) is associated with an increased risk of some types of fracture and a decreased risk of other types of fracture. Women with a low BMI (<20 kg/m2) had an increased risk of most fractures. 15. Compston JE, Wyman A, FitzGerald G, et al. Increase in fracture risk following unintentional weight loss in postmenopausal women: the Global Longitudinal Study of Osteoporosis in Women. J Bone Miner Res 2016; 31:1466–1472. 16. Crandall CJ, Yildiz VO, Wactawski-Wende J, et al. Postmenopausal & weight change and incidence of fracture: post hoc findings from Women’s Health Initiative Observational Study and Clinical Trials. BMJ 2015; 350:h25. Many studies have showed that weight loss is associated with an increased risk of fracture. This study is unique in also showing an increased risk of fracture associated with weight gain. 17. Meyer HE, Willett WC, Flint AJ, Feskanich D. Abdominal obesity and hip fracture: results from the Nurses’ Health Study and the Health Professionals Follow-up Study. Osteoporos Int 2016; 27:2127–2136. 18. Fain JN, Madan AK, Hiler ML, et al. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004; 145:2273–2282. 19. Armstrong ME, Kirichek O, Cairns BJ, et al. Relationship of height to sitespecific fracture risk in postmenopausal women. J Bone Miner Res 2016; 31:725–731. 20. Flicker L, Faulkner KG, Hopper JL, et al. Determinants of hip axis length in women aged 10–89 years: a twin study. Bone 1996; 18:41–45. 21. Ben-Shlomo Y, Kuh D. A life course approach to chronic disease epidemiology: conceptual models, empirical challenges and interdisciplinary perspectives. Int J Epidemiol 2002; 31:285–293. 22. Jerrhag D, Englund M, Petersson I, et al. Increasing wrist fracture rates in children may have major implications for future adult fracture burden. Acta Orthop 2016; 87:296–300. 23. Buttazzoni C, Rosengren BE, Tveit M, et al. Does a childhood fracture predict low bone mass in young adulthood? A 27-year prospective controlled study. J Bone Miner Res 2013; 28:351–359. 24. Wang Q, Huang Q, Zeng Y, et al. Parity and osteoporotic fracture risk in postmenopausal women: a dose-response meta-analysis of prospective studies. Osteoporos Int 2016; 27:319–330. 25. Haring B, Crandall CJ, Wu C, et al. Dietary patterns and fractures in & postmenopausal women: results from the Women’s Health Initiative. JAMA Intern Med 2016; 176:645–652. This large report from the Women’s Health Initiative showed that adherence to a Mediterranean diet was associated with a 20% lower risk of hip fracture, highlighting a modifiable means of improving bone health. 26. Langsetmo L, Barr SI, Berger C, et al. Associations of protein intake and protein source with bone mineral density and fracture risk: a population-based cohort study. J Nutr Health Aging 2015; 19:861–868. 27. Byberg L, Bellavia A, Orsini N, et al. Fruit and vegetable intake and risk of hip fracture: a cohort study of Swedish men and women. J Bone Miner Res 2015; 30:976–984.

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28. Barbour KE, Lui LY, McCulloch CE, et al. Trajectories of lower extremity physical performance: effects on fractures and mortality in older women. J Gerontol A Biol Sci Med Sci 2016; 71:1609–1615. Many studies have shown that poor physical performance measures are prospectively associated with a higher risk of fractures, especially, hip fracture. This study was one of the first to examine trajectories of physical function over an average of 10 years and risk of hip fracture. 29. Chalhoub D, Cawthon PM, Ensrud KE, et al. Risk of nonspine fractures in && older adults with sarcopenia, low bone mass, or both. J Am Geriatr Soc 2015; 63:1733–1740. To my knowledge, this is the first study to test the ‘sarco-osteopenia’ hypothesis that patients with both sarcopenia and osteoporosis have a greater fracture risk than those with either condition alone. Results showed this hypothesis to be true in men but not women. 30. Estrada K, Styrkarsdottir U, Evangelou E, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 2012; 44:491–501. 31. Eriksson J, Evans DS, Nielson CM, et al. Limited clinical utility of a genetic risk score for the prediction of fracture risk in elderly subjects. J Bone Miner Res 2015; 30:184–194. 32. Rivadeneira F, Makitie O. Osteoporosis and bone mass disorders: from gene pathways to treatments. Trends Endocrinol Metab 2016; 27:262–281. 33. McCloskey EV, Oden A, Harvey NC, et al. A meta-analysis of trabecular bone && score in fracture risk prediction and its relationship to FRAX. J Bone Miner Res 2016; 31:940–948. TBS is a new technique that estimates bone microarchitecture from routine lumbar spine DXA scans. This large meta-analysis demonstrates that the TBS predicts future fracture and this association is independent of FRAX. 34. Cauley JA, Greendale GA, Ruppert K, et al. Serum 25 hydroxyvitamin D, bone mineral density and fracture risk across the menopause. J Clin Endocrinol Metab 2015; 100:2046–2054. 35. Fink HA, Litwack-Harrison S, Taylor BC, et al. Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the Osteoporotic Fractures in Men (MrOS) Study. Osteoporos Int 2016; 27:331–338. 36. Nurmi-Luthje I, Luthje P, Kaukonen JP, Kataja M. Positive effects of a sufficient & pre-fracture serum vitamin D level on the long-term survival of hip fracture patients in Finland: a minimum 11-year follow-up. Drugs Aging 2015; 32:477–486. This study emphasizes the need to evaluate vitamin D status at the time of hip fractures. Patients with adequate 25(OH)D had improved survival after their hip fracture. 37. Swanson CM, Srikanth P, Lee CG, et al. Associations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with bone mineral density, bone mineral density change, and incident nonvertebral fracture. J Bone Miner Res 2015; 30:1403–1413. 38. Cauley JA, Danielson ME, Boudreau RM, et al. Inflammatory markers and incident fracture risk in older men and women: the health aging and body composition study. J Bone Miner Res 2007; 22:1088–1095. 39. Ing SW, Orchard TS, Lu B, et al. TNF receptors predict hip fracture risk in the WHI study and fatty acid intake does not modify this association. J Clin Endocrinol Metab 2015; 100:3380–3387. 40. Bethel M, Buzkova P, Fink HA, et al. Soluble CD14 and fracture risk. Osteoporos Int 2016; 27:1755–1763. 41. Barzilay JI, Buzkova P, Kizer JR, et al. Fibrosis markers, hip fracture risk, and bone density in older adults. Osteoporos Int 2016; 27:815–820. 42. Chang PY, Gold EB, Cauley JA, et al. Triglyceride levels and fracture risk in midlife women: Study of Women’s Health Across the Nation (SWAN). J Clin Endocrinol Metab 2016; 101:3297–3305. 43. Fink HA, Buzkova P, Garimella PS, et al. Association of Fetuin-A with incident fractures in community-dwelling older adults: the Cardiovascular Health Study. J Bone Miner Res 2015; 30:1394–1402. 44. Finnes TE, Lofthus CM, Meyer HE, et al. A combination of low serum concentrations of vitamins K1 and D is associated with increased risk of hip fractures in elderly Norwegians: a NOREPOS study. Osteoporos Int 2016; 27:1645–1652. 45. Li CI, Liu CS, Lin WY, et al. Glycated hemoglobin level and risk of hip fracture & in older people with type 2 diabetes: a competing risk analysis of Taiwan Diabetes Cohort Study. J Bone Miner Res 2015; 30:1338–1346. This large study of type 2 diabetics showed a linear increase in fracture risk with increasing HbA1c, emphasizing the need for adequate glucose control to prevent fractures. 46. Mehta T, Buzkova P, Sarnak MJ, et al. Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study. Metabolism 2015; 64:438–446. 47. van Varsseveld NC, Sohl E, Drent ML, Lips P. Gender-specific associations of serum insulin-like growth factor-1 with bone health and fractures in older persons. J Clin Endocrinol Metab 2015; 100:4272–4281. &&

Volume 29  Number 2  March 2017

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.