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issn:0937-941
1.  Vertebroplasty and Kyphoplasty Are Associated with an Increased Risk of Secondary Vertebral Compression Fractures A Population-based Cohort Study 
Introduction
Predominantly uncontrolled studies suggest that there may be a greater risk of subsequent vertebral compression fractures (VCFs) associated with vertebroplasty and kyphoplasty. To further understand the risk of VCFs, we conducted a population-based retrospective cohort study using data from a large regional health insurer.
Materials and Methods
Administrative claims procedure codes were used to identify a treatment group of patients receiving either a vertebroplasty or kyphoplasty (treatment group) and a comparison group of patients with a primary diagnosis of VCF who did not receive treatment during the same time period. The main outcomes of interest, validated by two independent medical record reviewers and adjudicated by a physician panel, were any new VCFs within: 1) 90-days; 2) 360-days; and 3) at adjacent vertebral levels. Multivariable logistic regression examined the association of vertebroplasty/kyphoplasty with new VCFs.
Results
Among 48 treatment (51% vertebroplasty, 49% kyphoplasty) and 164 comparison patients, treated patients had a significantly greater risk of secondary VCFs than comparison patients for fractures within 90 days of the procedure or comparison group time point (adjusted odds ratio (OR) = 6.3; 95% confidence interval (CI) 1.7 – 23.0) and within 360 days (adjusted OR = 3.1; 95% CI:1.1 – 8.4). Vertebroplasty and kyphoplasty were associated with a significantly greater rate of adjacent-level fractures as well.
Conclusions
Patients who had undergone vertebroplasty and kyphoplasty had a greater risk of new VCFs compared to patients with prior VCFs who did not undergo either procedure.
doi:10.1007/s00198-008-0745-5
PMCID: PMC4089886  PMID: 18797812
2.  Multimodal Intervention to Improve Osteoporosis Care in Home Health Settings: Results from a Cluster Randomized Trial 
Purpose
To test an evidence-implementation intervention to improve the quality of care in the home health care setting for patients at high risk for fractures.
Methods
We conducted a cluster randomized trial of a multimodal intervention targeted at home care for high-risk patients (prior fracture or physician-diagnosed osteoporosis) receiving care in a statewide home health agency in Alabama. Offices throughout the state were randomized to receive the intervention or to usual care. The primary outcome was the proportion of high-risk home health patients treated with osteoporosis medications. A t-test of difference in proportions was conducted between intervention and control arms and constituted the primary analysis. Secondary analyses included logistic regression estimating the effect of individual patients being treated in an intervention arm office on the likelihood of a patient receiving osteoporosis medications. A follow-on analysis examined the effect of an automated alert built into the electronic medical record that prompted the home health care nurses to deploy the intervention for high risk patients using a pre-post design.
Results
Among the offices in the intervention arm the average proportion of eligible patients receiving osteoporosis medications post-intervention was 19.1%, compared with 15.7% in the usual care arm (difference in proportions 3.4%, 95% CI: −2.6 −9.5%). The overall rates of osteoporosis medication use increased from 14.8% prior to activation of the automated alert to 17.6% afterward, a non-significant difference.
Conclusions
The home health intervention did not result in a significant improvement in use of osteoporosis medications in high risk patients.
doi:10.1007/s00198-013-2340-7
PMCID: PMC4089895  PMID: 23536256
Osteoporosis; Home Care Services; Quality Improvement; Secondary Prevention
3.  Disease-specific perception of fracture risk and incident fracture rates: GLOW cohort study 
Purpose
Accurate patient risk perception of adverse health events promotes greater autonomy over, and motivation towards, health-related lifestyles. We compared self-perceived fracture risk and 3-year incident fracture rates in postmenopausal women with a range of morbidities in the Global Longitudinal study of Osteoporosis in Women (GLOW).
Methods
GLOW is an international cohort study involving 723 physician practices across 10 countries (Europe, North America, Australasia). 60,393 women aged ≥55 years completed baseline questionnaires detailing medical history and self-perceived fracture risk. Annual follow-up determined self-reported incident fractures.
Results
In total 2,945/43,832 (6.8%) sustained an incident fracture over 3 years. All morbidities were associated with increased fracture rates, particularly Parkinson’s disease (hazard ratio [HR]; 95% confidence interval [CI], 3.89; 2.78–5.44), multiple sclerosis (2.70; 1.90–3.83), cerebrovascular events (2.02; 1.67–2.46), and rheumatoid arthritis (2.15; 1.53–3.04) (all p<0.001). Most individuals perceived their fracture risk as similar to (46%) or lower than (36%) women of the same age.
While increased self-perceived fracture risk was strongly associated with incident fracture rates, only 29% experiencing a fracture perceived their risk as increased. Under-appreciation of fracture risk occurred for all morbidities, including neurological disease, where women with low self-perceived fracture risk had a fracture HR 2.39 (CI 1.74–3.29) compared with women without morbidities.
Conclusions
Postmenopausal women with morbidities tend to under-appreciate their risk, including in the context of neurological diseases, where fracture rates were highest in this cohort. This has important implications for health education, particularly among women with Parkinson’s disease, multiple sclerosis, or cerebrovascular disease.
doi:10.1007/s00198-013-2438-y
PMCID: PMC3867337  PMID: 23884437
Fracture risk; Self-perception; Postmenopausal; Parkinson’s disease; Multiple sclerosis; Cerebrovascular event
4.  Fracture prevention in patients with cognitive impairment presenting with a hip fracture: secondary analysis of data from the HORIZON Recurrent Fracture Randomised Controlled Trial 
PURPOSE
Patients with cognitive impairment (CI) are at high risk of fracture but often denied osteoporosis therapy. We tested whether the effects of zoledronic acid (Zol) on re-fracture and mortality differed in patients presenting with a hip fracture by cognitive status.
METHODS
We used data from the HORIZON Recurrent Fracture Trial, of yearly intravenous 5mg Zol vs. placebo in patients presenting with a hip fracture. Primary outcome was new fracture and secondary outcome mortality.
Short Portable Mental Status Questionnaire (SPMSQ) with a cut-point of >2 was used to identify CI. Fine-Gray models for competing events were fitted to study the effect of Zol on re-fracture and Cox regression for death. A multiplicative term was introduced to study a potential interaction between treatment and cognitive status on outcomes.
RESULTS
1,966/2,127 (92.4%) patients had baseline SPMSQ measured. 350 (17.8%) had CI, balanced between treatment arms. In the placebo arm, there was similar fracture incidence between those with and without CI (15.4% vs. 12.3%, p=0.26). There was no significant interaction for the effect of CI on Zol and re-fracture (p=0.66)). CI was associated with higher 1-year mortality (12.6% vs. 4.3%, p<0.001) and the interaction was bordering significance (interaction p=0.066). Zol prolonged survival only in patients with normal cognitive status (HR 0.56 [95%CI 0.40-0.80]) and not in those with CI (HR 0.90 [95%CI 0.59-1.38]).
CONCLUSIONS
While these results require confirmation, the findings support the use of bisphosphonates in patients with both osteoporotic fracture and CI expected to live for more than 6 months.
doi:10.1007/s00198-013-2420-8
PMCID: PMC3867338  PMID: 23812596
Fractures, Bone; Mortality; Zoledronic Acid; Dementia; Epidemiology
5.  Serotonin-norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption 
Purpose
Antidepressants have been associated with increased bone loss and fractures in older adults in observational studies, but the mechanism is unclear. We examined the effects of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, on biomarkers of bone turnover in a prospective treatment study of late-life depression.
Methods
76 individuals aged 60 and older with current major depressive disorder received a 12-week course of venlafaxine XR 150-300mg daily. We measured serum C-terminal cross-linking telopeptide of type I collagen (β-CTX) and N-terminal propeptide of type I procollagen (P1NP), measures of bone resorption and formation, respectively, before and after treatment. We then analyzed the change in β-CTX and P1NP within each participant. Venlafaxine levels were measured at the end of the study. We assessed depression severity at baseline and remission status after treatment.
Results
After 12 weeks of venlafaxine, β-CTX increased significantly, whereas P1NP did not significantly change. The increase in β-CTX was significant only in participants whose depression did not remit (increase of 10% in non-remitters versus 4% in remitters). Change in β-CTX was not correlated with serum levels of venlafaxine or norvenlafaxine.
Conclusion
Our findings suggest that the primary effect of serotonergic antidepressants is to increase bone resorption. However, such an increase in bone resorption seemed to depend on whether or not participants’ depression remitted. Our results are in agreement with prior observational studies reporting increased bone loss in older adults taking serotonergic antidepressants. These negative effects on bone homeostasis could potentially contribute to increased fracture risk in older adults.
doi:10.1007/s00198-012-2170-z
PMCID: PMC4066460  PMID: 23358607
6.  Anatomical distribution of vertebral fractures: comparison of pediatric and adult spines 
Introduction
We hypothesized that the anatomical distribution of vertebral fractures (VF) would be different in children compared with adults.
Methods
We compared the distribution of VF defined using the Genant semi-quantitative method (GSQ method) in adults (N=221; 545 fractures) and in children early in the course of glucocorticoid therapy (N = 44; 94 fractures).
Results
The average age in the adult cohort was 62.9 years (SD, 13.4 yrs), 26% were male, the mean lumbar spine Z-score was −1.0 (SD, 1.5), and the corresponding T-score was −2.4 (SD, 1.4). The pediatric cohort median age was 7.7 years (range, 2.1–16.6 years), the mean lumbar spine Z-score was −1.7 (SD, 1.5), 52% were male, and disease categories were acute lymphoblastic leukemia (66%), rheumatological conditions (21%), and nephrotic syndrome (14%). The VF distribution was biphasic in both populations, but the peaks differed in location. In adults, the peaks were at T7/T8 and at T12/L1. In children, the focus was higher in the thoracic spine, at T6/T7, and lower in the lumbar spine, at L1/L2. When children were assessed in two age-defined sub-groups, a biphasic VF distribution was seen in both, but the upward shift of the thoracic focus to T6 was observed only in the older group, with the highest rates of fracture present between ages 7 and 10 years.
Conclusions
These results suggest that the anatomical distribution of VF differs between children and adults, perhaps relating to the different shape of the immature spine, notably the changing ratio of kyphosis to lordosis.
doi:10.1007/s00198-011-1837-1
PMCID: PMC4067402  PMID: 22109742 CAMSID: cams4411
Biomechanics; Corticosteroid osteoporosis; Osteoporosis; Pediatrics; Radiology; Vertebral fracture
7.  Skeletal effects of zoledronic acid in an animal model of chronic kidney disease 
Summary
Bisphosphonates reduce skeletal loss and fracture risk, but their use has been limited in patients with chronic kidney disease. This study shows skeletal benefits of zoledronic acid in an animal model of chronic kidney disease.
Introduction
Bisphosphonates are routinely used to reduce fractures but limited data exists concerning their efficacy in non-dialysis chronic kidney disease. The goal of this study was to test the hypothesis that zoledronic acid produces similar skeletal effects in normal animals and those with kidney disease.
Methods
At 25 weeks of age, normal rats were treated with a single dose of saline vehicle or 100 µg/kg of zoledronic acid while animals with kidney disease (approximately 30 % of normal kidney function) were treated with vehicle, low dose (20 µg/kg), or high dose (100 µg/kg) zoledronic acid, or calcium gluconate (3 % in the drinking water). Skeletal properties were assessed 5 weeks later using micro-computed tomography, dynamic histomorphometry, and mechanical testing.
Results
Animals with kidney disease had significantly higher trabecular bone remodeling compared to normal animals. Zoledronic acid significantly suppressed remodeling in both normal and diseased animals yet the remodeling response to zoledronic acid was no different in normal and animals with kidney disease. Animals with kidney disease had significantly lower cortical bone biomechanical properties; these were partially normalized by treatment.
Conclusions
Based on these results, we conclude that zoledronic acid produces similar amounts of remodeling suppression in animals with high turnover kidney disease as it does in normal animals, and has positive effects on select biomechanical properties that are similar in normal animals and those with chronic kidney disease.
doi:10.1007/s00198-012-2103-x
PMCID: PMC4063946  PMID: 22907737
Anti-remodeling agents; Bisphosphonate; Bone mechanics; Remodeling suppression
8.  Genetic and environmental influences on bone mineral density in pre- and post-menopausal women 
Genetic factors influencing acquisition of peak bone mass account for a substantial proportion of the variation in bone mineral density (BMD), although the extent to which genes also contribute to variation in bone loss is debatable. Few prospective studies of related individuals have been carried out to address this issue. To gain insights into the nature of the genetic factors contributing to variation in BMD, we studied 570 women from large Amish families. We evaluated and compared the genetic contributions to BMD in pre- and post-menopausal women, with the rationale that genetic variation in pre-menopausal women is due primarily to genetic determinants of peak bone mass, while genetic variation in post-menopausal women is due to the combined genetic effects of peak bone mass and bone loss. Bone mineral density was measured at one point in time at the hip and spine by dual energy X-ray absorptiometry (DXA). We used variance decomposition procedures to partition variation in BMD into genetic and environmental effects common to both groups and to pre- and post-menopausal women separately. Total variation in BMD was higher in post- compared to pre-menopausal women. Genes accounted for 58–88% of the total variation in BMD in pre-menopausal women compared to 37–54% of the total variation in post-menopausal women. In absolute terms, however, the genetic variance was approximately similar between the two groups because the environmental variance was 3 1/2- to 4-fold larger in the post-menopausal group. The genetic correlation in total hip BMD was 0.81 between pre- and post-menopausal women and differed significantly from one, consistent with the presence of at least some non-overlapping genetic effects in the two groups for BMD at this site. Overall, these analyses suggest that many, but not all, of the genetic factors influencing variation in BMD are common to both pre- and post-menopausal women.
doi:10.1007/s00198-005-1948-7
PMCID: PMC4049290  PMID: 15997421
Bone loss; Bone mineral density; Genetics; Heritability; Peak bone mass; Variance
9.  Bone turnover and body weight relationships differ in normal-weight compared with heavier postmenopausal women 
Low body weight is associated with increased risk for fractures, whereas higher body weight has been shown to be protective against osteoporosis. This study evaluated whether body weight plays a role regulating bone turnover and mass in normal-weight (body mass index (BMI) <25 kg/m2), overweight (BMI 25–29.9 kg/ m2) and obese (BMI ≥ 30 kg/m2) postmenopausal women who were either receiving hormone replacement therapy [HRT(+)] or not [HRT(−)] (total of six groups). Body weight, BMI, total body bone mineral content (TBBMC), and markers of bone formation (serum osteocalcin) and bone resorption (urinary pyridinoline (PYD) and deoxypyridinoline) were retrospectively analyzed in 210 postmenopausal women. The mean age was 67±6 years, with mean body weight of 70.8±14.2 kg, ranging from 45.0 to 115.5 kg. Body weight was positively correlated with TBBMC (r=0.50, p<0.0001). There was a lower TBBMC and higher bone formation rate in normal-weight than obese HRT(−) women, but in women taking HRT there were no differences between BMI categories. In addition, in normal-weight HRT(−) women only, PYD and body weight showed a negative correlation (r=−0.39, p=0.01). Among normal-weight, but not overweight or obese subjects, we observed higher TBBMC and lower bone turnover in the HRT(+) compared with the HRT(−) group. Regression models explained 36% of the variance in TBBMC, mainly through body weight. Additional models could only explain 11–15% of the variance in bone turnover. Taken together, these data suggest that among normal-weight but not obese postmenopausal women, higher bone turnover is associated with lower bone mass, and that only normal-weight women show a different bone turnover profile with HRT treatment. Body weight should be considered an important factor in bone metabolism with relevant clinical implications.
doi:10.1007/s00198-002-1324-9
PMCID: PMC4042209  PMID: 12730781
Bone formation; Bone resorption; Bone mass; Body weight; Hormone replacement therapy
10.  Fear of falling, fracture history and comorbidities are associated with health-related quality of life among European and US women with osteoporosis in a large international study 
Purpose
Health-related quality of life (HRQoL) is impaired in women treated for postmenopausal osteoporosis (PMO). The objective of this study was to examine the relationship between clinical characteristics, comorbidities, medical history, patient demographics and HRQoL in women with PMO.
Methods
Baseline data were obtained and combined from two large and similar multinational observational studies: Prospective Observational Scientific Study Investigating Bone Loss Experience in Europe (POSSIBLE EU®)and in the US (POSSIBLE US™) including postmenopausal women in primary care settings initiating, switching or who had been on bone loss treatment for some time. HRQoL measured by health utility scores (EQ-5D™) were available for 7,897 women (94% of study participants). The relationship between HRQoL and baseline clinical characteristics, medical history and patient demographics was assessed using parsimonious, multivariable, mixed-model analyses.
Results
Median health utility score was 0.80 (interquartile range 0.69–1.00). In multivariable analyses, young age, low body mass index, previous vertebral fracture, increased number of comorbidities, high fear of falling and depression were associated with reduced HRQoL. Regression-based model estimates showed that previous vertebral fracture was associated with lower health utility scores by 0.08 (10.3%) and demonstrated the impact of multiple comorbidities and of fear of falling on HRQoL.
Conclusions
In this large observational study of women with PMO, there was substantial inter-individual variability in HRQoL. An increased number of comorbidities, fear of falling and previous vertebral fracture were associated with significant reductions in HRQoL.
doi:10.1007/s00198-013-2408-4
PMCID: PMC3818139  PMID: 23754200
Osteoporosis; Postmenopausal; Health-related quality of life; Falls; Fracture; Observational study
11.  Predicting EQ-5D-US and SF-6D societal health state values from the Osteoporosis Assessment Questionnaire 
Summary
Linear regression was applied to data from 275 persons with osteoporosis-related fracture to estimate EQ-5D-US and SF-6D health state values from the Osteoporosis Assessment Questionnaire. The models explained 56% and 58% of the variance in scores, respectively, and root mean square error values (0.096 and 0.085) indicated adequate prediction for use when actual values are unavailable.
Introduction
This study was conducted to provide models that predict EQ-5D-US and SF-6D societal health state values from the Osteoporosis Assessment Questionnaire (OPAQ).
Methods
OPAQ, EQ-5D, and SF-6D data from individuals at two centers with prior osteoporosis-related fracture were used. Fractures were classified by type as hip/hip-like, spine/spine-like, or wrist/wrist-like. Spearman rank correlations between preference-based system (EQ-5D and SF-6D) dimensions and OPAQ subscales were estimated. Linear regression was used to estimate preference-based system health state values based on OPAQ subscales. We assessed models including age, sex, and fracture type and chose the model with the best performance based on the root mean square error (RMSE) estimate.
Results
Among the 275 participants (198 women), with mean age of 68 years (range 50–94), the distribution of fracture types included 10% hip/5% hip-like, 18% spine/11% spine-like, and 24% wrist/18% wrist-like. The final regression model for EQ-5D-US included three OPAQ attributes (physical function, emotional status, and symptoms), predicted 56% of the variance in EQ-5D-US scores, and had a RMSE of 0.096. The final model for SF-6D, which included all four OPAQ dimensions, predicted 58% of the variance in SF-6D scores and had a RMSE of 0.085.
Conclusions
Two models were developed to estimate EQ-5D-US and SF-6D health state values from OPAQ and demonstrated adequate prediction for use when actual values are not available.
doi:10.1007/s00198-011-1619-9
PMCID: PMC4017660  PMID: 21484360
Cost-utility analysis; Economic evaluation; Health state values; Osteoporosis; Societal preferences
12.  Hormonal and dietary influences on true fractional calcium absorption in women: role of obesity 
Summary
The goal in this study was to examine the hormonal and dietary predictors of true fractional Ca absorption (TFCA) in adult women and to determine whether TFCA differs due to body weight. Results showed that TFCA is higher in obese individuals and dietary fat, estradiol, and 1,25-dihydroxy vitamin D are the most significant positive predictors of TFCA in adult women.
Introduction
Calcium absorption is an important determinant of calcium balance and is influenced by several factors. Previous studies have identified that age, intake of protein, fat and fiber, and hormones such as 1, 25-dihyroxyvitamin D (1,25(OH)2D3) influence absorption. The determinants of TFCA using the double isotope method, the gold standard estimate of absorption, have not been examined previously in adult women nor has the role of obesity been addressed.
Methods
In this study, we examined the hormonal and dietary predictors of TFCA in adult women with a wide range of age, body weights, and nutrient intake. TFCA was measured using dual stable isotope (42Ca and 43Ca) technique. Serum was analyzed for bone-regulating hormones, and dietary information was obtained through food records. The independent dietary factors and hormonal predictors (25-hydroxyvitamin D, 1,25(OH)2D3, parathyroid hormone, and estradiol) of TFCA were analyzed using multiple regression analysis.
Results
Two hundred twenty-nine women aged 54±11 years old (24–75 years) and with BMI of 31±7.0 kg/m2 were eligible and were categorized into tertiles of body mass index (BMI) into leaner, overweight, and obese. In the entire group of women, total fat intake, estradiol, and 1,25 (OH)2D3 are significant positive predictors (p<0.05). As expected, age is a significant negative predictor of TFCA (R2=26%). TFCA is higher in obese women compared to non-obese women (p<0.05).
Conclusion
Together, these data show that dietary fat is the most significant positive predictor of TFCA which may have implications for dietary intake for non-obese individuals who are more likely to have lower and potentially compromised Ca absorption.
doi:10.1007/s00198-012-1901-5
PMCID: PMC4016952  PMID: 22282301
Dietary fat; Estradiol; Obesity; Premenopausal/postmenopausal women; True fractional Ca absorption; Vitamin D
13.  National Bone Health Alliance Bone Turnover Marker Project: current practices and the need for US harmonization, standardization, and common reference ranges 
Summary
This position paper reviews how the National Bone Health Alliance (NBHA) will execute a project to help assure health professionals of the clinical utility of bone turnover markers; the current clinical approaches concerning osteoporosis and the status and use of bone turnover markers in the USA; the rationale for focusing this effort around two specific bone turnover markers; the need to standardize bone marker sample collection procedures, reference ranges, and bone turnover marker assays in clinical laboratories; and the importance of harmonization for future research of bone turnover markers.
Introduction
Osteoporosis is a major global health problem, with the prevalence and incidence of osteoporosis for at-risk populations estimated to be 44 million Americans. The potential of bone markers as an additional tool for health care professionals to improve patient outcomes and impact morbidity and mortality is crucial in providing better health care and addressing rising health care costs. This need to advance the field of bone turnover markers has been recognized by a number of organizations, including the International Osteoporosis Foundation (IOF), National Osteoporosis Foundation, International Federation of Clinical Chemistry, and Laboratory Medicine (IFCC), and the NBHA.
Methods
This position paper elucidates how this project will standardize bone turnover marker sample collection procedures in the USA, establish a USA reference range for one bone formation (serum procollagen type I N propeptide, s-PINP) and one bone resorption (serum C-terminal telopeptide of type I collagen, s-CTX) marker, and standardize bone turnover marker assays used in clinical laboratories. This effort will allow clinicians from the USA to have confidence in their use of bone turnover markers to help monitor osteoporosis treatment and assess future fracture risk. This project builds on the recommendations of the IOF/IFCC Bone Marker Standards Working Group by developing USA reference standards for s-PINP and s-CTX, the markers identified as most promising for use as reference markers.
Results
The goals of this project will be realized through the NBHA and will include its governmental, academic, for-profit, and non-profit sector stakeholders as well as major academic and commercial laboratories. Upon completion, a parallel effort will be pursued to make bone turnover marker measurements reliable and accepted by all health care professionals for facilitating treatment decisions and ultimately be reimbursed by all health insurance payers.
Conclusions
Successful completion of this project will help assure health professionals from the USA of the clinical utility of bone turnover markers and ties in with the parallel effort of the IOF/IFCC to develop worldwide bone turnover reference ranges.
doi:10.1007/s00198-012-2049-z
PMCID: PMC4011662  PMID: 22797491
Bone turnover markers; Position paper
14.  Long-term mortality following fractures at different skeletal sites: a population-based cohort study 
Summary
Adjusting for age, sex, and precipitating cause, the relative risk of death was increased following fractures at most skeletal sites.
Introduction
This study aims to determine long-term survival following fractures due to any cause at each skeletal site.
Methods
In a historical cohort study, 2,901 Olmsted County, MN, USA, residents ≥35 years old who experienced any fracture in 1989–1991 were followed passively for up to 22 years for death from any cause. Standardized mortality ratios (SMRs) compared observed to expected deaths.
Results
During 38,818 person-years of follow-up, 1,420 deaths were observed when 1,191 were expected (SMR, 1.2; 95 % CI, 1.1–1.3). The overall SMR was greatest soon after fracture, especially among the men, but remained elevated for over a decade thereafter. Adjusting for age and sex, relative death rates were greater for pathological fractures and less for severe trauma fractures compared to the fractures due to no more than moderate trauma. In the latter group, long-term mortality was increased following fractures at many skeletal sites. After further adjustment for precipitating cause, overall SMRs were elevated not only following fractures at the traditional major osteoporotic sites (i.e., distal forearm, proximal humerus, thoracic/lumbar vertebrae, and proximal femur) combined (SMR, 1.2; 95 % CI, 1.1–1.3) but also following all other fracture types combined (SMR 1.2; 95 % CI, 1.1–1.4), excluding the hand and foot fractures not associated with any increased mortality.
Conclusions
The persistence of increased mortality long after the occurrence of a fracture has generally been attributed to underlying comorbidity, but this needs to be defined in much greater detail if specific opportunities are to be identified for reducing the excess deaths observed.
doi:10.1007/s00198-012-2225-1
PMCID: PMC3630278  PMID: 23212281
Cohort study; Epidemiology; Fractures; Population-based; Survival
15.  Impact + resistance training improves bone health and body composition in prematurely menopausal breast cancer survivors: a randomized controlled trial 
Summary
Our randomized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for >1 year.
Introduction
Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors (BCS). We investigated whether impact + resistance training could improve bone mineral density (BMD), reduce bone turnover, build muscle, and decrease fat mass in BCS with premature menopause.
Methods
We conducted a randomized controlled trial in 71 BCS (mean age, 46.5 years) within 5 years of treatment-related menopause. Women were randomly assigned to one of two groups: (1) impact + resistance training (prevent osteoporosis with impact + resistance (POWIR)) or (2) exercise placebo (FLEX) 3×/week for 1 year. Outcomes were hip and spine BMD (in grams per square centimeter) and body composition (percent body fat (%BF) and lean and fat mass (in kilograms)) by DXA and bone turnover markers (serum osteocalcin (in nanograms per milliliter) and urinary deoxypryrodinoline (in nanomoles per milliliter).
Results
There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample. In analyses restricted to BCS who were menopausal for ≥1 year, POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX (femoral neck—POWIR, 0.004±0.093 g/cm2 vs. FLEX, −0.010±0.089 g/cm2; p<0.01; spine—POWIR, −0.003±0.114 g/cm2 vs. FLEX, −0.020±0.110 g/cm2; p=0.03). POWIR prevented increases in %BF (POWIR, 0.01 % vs. FLEX, 1.3 %; p<0.04). Women with attendance to POWIR at ≥64 % had better improvements in %BF than women attending less often (p<0.03).
Conclusion
Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS.
doi:10.1007/s00198-012-2143-2
PMCID: PMC3856427  PMID: 22996743
Chemotherapy; Neoplasm; Obesity; Osteoporosis; Physical activity
16.  High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep 
Osteoporosis International  2014;25:1891-1903.
Summary
Chronic environmental fluoride exposure under calcium stress causes fragility fractures due to osteoporosis and bone quality deterioration, at least in sheep. Proof of skeletal fluorosis, presenting without increased bone density, calls for a review of fracture incidence in areas with fluoridated groundwater, including an analysis of patients with low bone mass.
Introduction
Understanding the skeletal effects of environmental fluoride exposure especially under calcium stress remains an unmet need of critical importance. Therefore, we studied the skeletal phenotype of sheep chronically exposed to highly fluoridated water in the Kalahari Desert, where livestock is known to present with fragility fractures.
Methods
Dorper ewes from two flocks in Namibia were studied. Chemical analyses of water, blood and urine were executed for both cohorts. Skeletal phenotyping comprised micro-computer tomography (μCT), histological, histomorphometric, biomechanical, quantitative backscattered electron imaging (qBEI) and energy-dispersive X-ray (EDX) analysis. Analysis was performed in direct comparison with undecalcified human iliac crest bone biopsies of patients with fluoride-induced osteopathy.
Results
The fluoride content of water, blood and urine was significantly elevated in the Kalahari group compared to the control. Surprisingly, a significant decrease in both cortical and trabecular bones was found in sheep chronically exposed to fluoride. Furthermore, osteoid parameters and the degree and heterogeneity of mineralization were increased. The latter findings are reminiscent of those found in osteoporotic patients with treatment-induced fluorosis. Mechanical testing revealed a significant decrease in the bending strength, concurrent with the clinical observation of fragility fractures in sheep within an area of environmental fluoride exposure.
Conclusions
Our data suggest that fluoride exposure with concomitant calcium deficit (i) may aggravate bone loss via reductions in mineralized trabecular and cortical bone mass and (ii) can cause fragility fractures and (iii) that the prevalence of skeletal fluorosis especially due to groundwater exposure should be reviewed in many areas of the world as low bone mass alone does not exclude fluorosis.
doi:10.1007/s00198-014-2707-4
PMCID: PMC4048471  PMID: 24777741
Fluoride; Fluorosis; Fragility fracture; Osteoporosis
17.  Skeletal Findings in Children Recently Initiating Glucocorticoids for the Treatment of Nephrotic Syndrome 
Introduction
Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationship among glucocorticoid exposure, lumbar spine areal BMD (LS BMD) and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome.
Methods
Lateral thoracolumbar spine radiography and lumbar spine bone mineral density (LS BMD) were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semi-quantitative grading was used as the primary method for vertebral morphometry; the Algorithm-Based Qualitative (ABQ) method was used for secondary vertebral deformity analysis.
Results
Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant Grade 1 deformity each. All deformities were mild anterior wedging (2 at each of T6, T7 and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; 2 children at T6 and 2 at T8). Two of the children with ABQ signs also had a Genant Grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure.
Conclusions
Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study.
doi:10.1007/s00198-011-1621-2
PMCID: PMC4000256  PMID: 21494860 CAMSID: cams4233
children; nephrotic syndrome; glucocorticoids; bone mineral density; vertebral deformities
18.  Longitudinal changes in calcaneal quantitative ultrasound measures during childhood 
Summary
This longitudinal study examined how calcaneal quantitative ultrasound (QUS) measures change during childhood while taking into account skeletal maturation, body mass index (BMI), and physical activity. The study reported sex differences in QUS growth curves and an inverse relationship between BMI and speed of sound (SOS) measures.
Introduction
The aim of this study was to examine how calcaneal QUS parameters change over time during childhood and to determine what factors influence these changes.
Methods
The study sample consisted of a total of 192 Caucasian children participating in the Fels Longitudinal Study. A total of 548 calcaneal broadband ultrasound attenuation (BUA) and SOS observations were obtained between the ages of 7.6 and 18 years. The best fitting growth curves were determined using statistical methods for linear mixed effect models.
Results
There are significant sex differences in the pattern of change in QUS parameters (p<0.05). The relationship between QUS measures and skeletal age is best described by a cubic growth curve in boys and a linear pattern among girls. Boys experience their most rapid growth in BUA and SOS in early and late adolescence, while girls experience constant growth throughout childhood. Adiposity levels were significantly associated with the changes in SOS among boys (p<0.001) and girls (p<0.01), indicating that children with higher BMI are likely to have lower SOS over time compared to children with lower BMI. For girls, physical activity levels showed positive associations with changes in QUS measures (p<0.05).
Conclusion
This study documents significant sex differences in the pattern of change in QUS measures over childhood and adolescence. Our study also shows significant influences of adiposity and physical activity on the pattern of change in QUS measures during childhood.
doi:10.1007/s00198-010-1458-0
PMCID: PMC3988661  PMID: 20976593
Calcaneal quantitative ultrasound; Children; Longitudinal study; Skeletal health
19.  Osteoporosis Assessment Questionnaire-Physical Function (OPAQ-PF): a psychometrically validated osteoporosis-targeted patient reported outcome measure of daily activities of physical function 
Osteoporosis International  2014;25:1775-1784.
Summary
The purpose of this study was to evaluate the measurement properties of the Osteoporosis Assessment Questionnaire-Physical Functioning (OPAQ-PF). Based on this study, the OPAQ-PF has confirmed unidimensionality and acceptable reliability, construct validity, and sensitivity to change in a recent fracture/no recent fracture osteoporosis sample.
Methods
Dimensionality was established through exploratory and confirmatory factor analysis. Patients completed three patient reported outcome (PRO) measures and four performance-based measures (PBMs) at baseline to enable an evaluation of construct validity. Patients without a recent fracture completed the OPAQ-PF 2 weeks after baseline to enable an evaluation of test–retest reliability. Ability to detect change and interpretation of change were investigated following completion of the OPAQ-PF 12 and 24 weeks postbaseline by patients with a recent fracture.
Results
A prospective psychometric validation study in 144 postmenopausal women, with moderate to severe osteoporosis, 37 of whom had experienced a recent fragility fracture (<6 weeks). Unidimensionality was established for the OPAQ-PF by factor analysis. The OPAQ-PF had good internal consistency (α = 0.974) and test–retest reliability (mean intraclass correlation coefficient (ICC) 0.993. The OPAQ-PF differentiated between patients with/without recent fracture, and by severity of osteoarthritis; it correlated strongly with hypothesized-related scales and PBMs (r > 0.3, p < 0.001). Ability to detect change was established with high correlations between changes in OPAQ-PF score and changes in global concept scores in recent fracture patients (r ≥ 0.6, 24-week change). Effect size of change on OPAQ-PF score increased by level of global change (p < 0.001). Anchor-based methods identified an OPAQ-PF change of 10 at an individual patient level and 20 at a group level as meaningful to patients.
Conclusions
The OPAQ-PF has confirmed unidimensionality and acceptable reliability, construct validity, and sensitivity to change in a recent fracture/no recent fracture osteoporosis sample.
doi:10.1007/s00198-014-2695-4
PMCID: PMC4023015  PMID: 24737386
OPAQ-PF; Osteoporosis; Outcomes assessment; Patient reported outcomes; Physical function; Psychometrics
20.  A comparison of DXA and CT based methods for estimating the strength of the femoral neck in post-menopausal women 
Purpose
Simple 2-dimensional (2D) analyses of bone strength can be done with dual energy x-ray absorptiometry (DXA) data and applied to large data sets. We compared 2D analyses to 3-dimensional (3D) finite element analyses (FEA) based on quantitative computed tomography (QCT) data.
Methods
213 women participating in the Study of Women’s Health across the Nation (SWAN) received hip DXA and QCT scans. DXA BMD and femoral neck diameter and axis length were used to estimate geometry for composite bending (BSI) and compressive strength (CSI) indices. These and comparable indices computed by Hip Structure Analysis (HSA) on the same DXA data were compared to indices using QCT geometry. Simple 2D engineering simulations of a fall impacting on the greater trochanter were generated using HSA and QCT femoral neck geometry; these estimates were benchmarked to a 3D FEA of fall impact.
Results
DXA-derived CSI and BSI computed from BMD and by HSA correlated well with each other (R= 0.92 and 0.70) and with QCT-derived indices (R= 0.83–0.85 and 0.65–0.72). The 2D strength estimate using HSA geometry correlated well with that from QCT (R=0.76) and with the 3D FEA estimate (R=0.56).
Conclusions
Femoral neck geometry computed by HSA from DXA data corresponds well enough to that from QCT for an analysis of load stress in the larger SWAN data set. Geometry derived from BMD data performed nearly as well. Proximal femur breaking strength estimated from 2D DXA data is not as well correlated with that derived by a 3D FEA using QCT data.
doi:10.1007/s00198-012-2066-y
PMCID: PMC3606278  PMID: 22810918
Hip Structure Analysis; DXA; QCT; Bone Mineral Density; Fracture; Women
21.  Micro-finite element analysis applied to high-resolution MRI reveals improved bone mechanical competence in the distal femur of female pre-professional dancers 
Summary
Micro-finite element analysis applied to high-resolution (0.234-mm length scale) MRI reveals greater whole and cancellous bone stiffness, but not greater cortical bone stiffness, in the distal femur of female dancers compared to controls. Greater whole bone stiffness appears to be mediated by cancellous, rather than cortical bone adaptation.
Introduction
The purpose of this study was to compare bone mechanical competence (stiffness) in the distal femur of female dancers compared to healthy, relatively inactive female controls.
Methods
This study had institutional review board approval. We recruited nine female modern dancers (25.7± 5.8 years, 1.63±0.06 m, 57.1±4.6 kg) and ten relatively inactive, healthy female controls matched for age, height, and weight (32.1±4.8 years, 1.6±0.04 m, 55.8±5.9 kg). We scanned the distal femur using a 7-T MRI scanner and a three-dimensional fast low-angle shot sequence (TR/TE= 31 ms/5.1 ms, 0.234 mm×0.234 mm×1 mm, 80 slices). We applied micro-finite element analysis to 10-mm-thick volumes of interest at the distal femoral diaphysis, metaphysis, and epiphysis to compute stiffness and cross-sectional area of whole, cortical, and cancellous bone, as well as cortical thickness. We applied two-tailed t-tests and ANCOVA to compare groups.
Results
Dancers demonstrated greater whole and cancellous bone stiffness and cross-sectional area at all locations (p< 0.05). Cortical bone stiffness, cross-sectional area, and thickness did not differ between groups (>0.08). At all locations, the percent of intact whole bone stiffness for cortical bone alone was lower in dancers (p<0.05). Adjustment for cancellous bone cross-sectional area eliminated significant differences in whole bone stiffness between groups (p>0.07), but adjustment for cortical bone cross-sectional area did not (p<0.03).
Conclusions
Modern dancers have greater whole and cancellous bone stiffness in the distal femur compared to controls. Elevated whole bone stiffness in dancers may be mediated via cancellous, rather than cortical bone adaptation.
doi:10.1007/s00198-012-2105-8
PMCID: PMC3719856  PMID: 22893356
7 Tesla; Bone microarchitecture; Dancers; Micro-finite element analysis; MRI; Ultra high field
22.  Performance of FRAX in a Cohort of Community Dwelling, Ambulatory Older Men: The Osteoporotic Fractures in Men (MrOS) Study 
FRAX has been extensively studied in women, but there are few studies of its performance in men. We evaluated its performance in older men who participated in the Osteoporotic Fractures in Men Study (MrOS).
FRAX estimates for 10-year hip fracture and major osteoporotic fracture (MOF; hip, clinical spine, forearm, and shoulder) were calculated from data obtained from MrOS participants and compared to observed 10-year fracture cumulative incidence calculated using product limit estimate methods, accounting for competing mortality risk.
5,891 men were followed for an average of 8.4 years. Without BMD in the FRAX model, the mean 10-year predicted fracture probabilities for hip and MOF were 3.5% and 8.9%, respectively; addition of BMD to the calculations reduced these estimates to 2.3% and 7.6%. Using FRAX without BMD, predicted quintile probabilities closely estimated cumulative incidence of hip fracture (range of observed to predicted ratios 0.9-1.1). However, with BMD in the FRAX calculation, observed to predicted hip fracture probabilities were not close to unity and varied markedly across quintiles of predicted probability. For MOF, FRAX without BMD overestimated observed cumulative incidence (range of observed to predicted ratios 0.7-0.9) and addition of BMD did not improve this discrepancy (range of observed to predicted ratios 0.7-1.1). Addition of BMD to the calculation had mixed effects on the discriminatory performance of FRAX, depending on the analysis tool applied.
Among this cohort of community dwelling older men, the FRAX risk calculator without BMD was well calibrated to hip fracture but less well to MOF.
doi:10.1007/s00198-012-2215-3
PMCID: PMC3767034  PMID: 23179575
fracture; prediction; men; risk assessment
23.  An investigation of the association between omega 3 FA and bone mineral density among older adults: results from the National Health and Nutrition Examination Survey years 2005–2008 
Summary
The relation of omega 3 fatty acids (n-3 FA) with bone mineral density (BMD) was assessed among adults >60 years; NHANES data (2005–2008). The association of dietary n-3 FA with measures of hip BMD was equivocal, but n-3 FA supplement use was significantly associated with higher spine BMD—a finding that deserves further study.
Introduction
Associations between polyunsaturated fatty acids and bone mineral density are not well understood.
Purpose
To evaluate the cross-sectional relation between dietary omega 3 fatty acid intake (specifically docosahexaenoic acid, eicosapentaenoic acid, and octadecatetraenoic) and BMD at the hip and spine among older adults.
Methods
Omega 3 FA intake (g/day) was assessed from two 24-h recalls using the National Health and Nutrition Examination Survey (NHANES, in 2005–2008); and omega 3 FA supplement use (yes/no) via questionnaire. Multivariable regression models were developed to explain variance in femoral neck, total femur, and lumbar spine BMD among 2,125 men and women over 60 years.
Results
Mean age was 70 years. In adjusted models, dietary omega 3 FA were marginally associated with greater femoral neck BMD (p =0.0505), but not with total femur BMD (p =0.95) or lumbar spine BMD (p =0.74). Omega 3 supplement use was significantly positively associated with lumbar spine BMD (p =0.005) but not with femoral neck or total femur BMD.
Conclusions
Dietary intakes of omega 3 FA were marginally associated with femoral neck BMD; however, omega 3 supplement use was significantly associated with higher lumbar spine BMD in older adults. These results emphasize the need for assessment of total omega 3 intakes (diet and supplements) to provide a greater range of intake and a more accurate picture of the relation between omega 3 FA and BMD.
doi:10.1007/s00198-013-2501-8
PMCID: PMC3969769  PMID: 24121998
Bone mineral density; NHANES; Omega-3 fatty acids; Polyunsaturated fatty acids
24.  The muscle-bone unit of peripheral and central skeletal sites in children and young adults 
Purpose
To describe changes and gender differences in the muscle-bone unit at different skeletal sites during pubertal development.
Methods
442 children aged 5-18 years were studied. Measurements of bone mineral content (BMC), lean mass (LM) and fat mass of the whole body (WB), legs, arms and lumbar spine were obtained from dual energy X-ray absorptiometry. Peripheral quantitative computed tomography was used to measure BMC of the radius diaphysis and cross-sectional muscle area (CSMA) of the mid-forearm. These measurements were used to describe differences between, and within, genders at each pubertal stage in BMC accrual relative to muscle, both before and after adjustment for height, regional fat and muscle at central and peripheral skeletal sites.
Results
In males there were significant increases in adjusted WB and leg BMC at the end of pubertal development. Unadjusted and adjusted lumbar spine BMC increased at the onset of, and at the end, of puberty. Radius BMC increased at most pubertal stages. In females, there were increases in unadjusted and adjusted whole body BMC at late puberty, in leg BMC at the onset of puberty, and at pubertal stage four. Unadjusted arm BMC increased at most pubertal stages; however, after adjustment an increase occurred at pubertal stage four. Both adjusted and unadjusted lumbar spine BMC increased at pubertal stage four. Unadjusted radius BMC increased at most pubertal stages. Females had greater BMC at all skeletal sites, compared to males, except at the radius, where adjusted BMC was greater in males at pubertal stage four.
Conclusions
Males and females accrue more BMC in relation to lean mass at multiple skeletal sites as puberty proceeds. Females accrue more BMC in relation to lean mass, in comparison to males, at most skeletal sites.
doi:10.1007/s00198-010-1216-3
PMCID: PMC3966020  PMID: 20333357
muscle-bone unit; puberty; child; musculoskeletal development; dual energy X-ray absorptiometry; Tomography, X-ray computed
25.  Fracture risk assessment after BMD examination: whose job is it, anyway? 
Osteoporosis International  2014;25:1445-1453.
Summary
Fracture risk assessments on bone mineral density reports guide family physicians’ treatment decisions but are subject to inaccuracy. Qualitative analysis of interviews with 22 family physicians illustrates their pervasive questioning of reported assessment accuracy and independent assumption of responsibility for assessment. Assumption of responsibility is common despite duplicating specialists’ work.
Introduction
Fracture risk is the basis for recommendations of treatment for osteoporosis, but assessments on bone mineral density (BMD) reports are subject to known inaccuracies. This creates a complex situation for referring physicians, who must rely on assessments to inform treatment decisions. This study was designed to broadly understand physicians’ current experiences with and preferences for BMD reporting; the present analysis focuses on their interpretation and use of the fracture risk assessments on reports, specifically
Methods
A qualitative, thematic analysis of one-on-one interviews with 22 family physicians in Ontario, Canada was performed.
Results
The first major theme identified in interview data reflects questioning by family physicians of reported fracture risk assessments’ accuracy. Several major subthemes related to this included questioning of: 1) accuracy in raw bone mineral density measures (e.g., g/cm2); 2) accurate inclusion of modifying risk factors; and 3) the fracture risk assessment methodology employed. A second major theme identified was family physicians’ independent assumption of responsibility for risk assessment and its interpretation. Many participants reported that they computed risk assessments in their practice to ensure accuracy, even when provided with assessments on reports.
Conclusions
Results indicate family physicians question accuracy of risk assessments on BMD reports and often assume responsibility both for revising and relating assessments to treatment recommendations. This assumption of responsibility is common despite the fact that it may duplicate the efforts of reading physicians. Better capture of risk information on BMD referrals, quality control standards for images and standardization of risk reporting may help attenuate some inefficiency.
doi:10.1007/s00198-014-2661-1
PMCID: PMC3988517  PMID: 24610580
Bone mineral density; Fracture risk assessment; Osteoporosis; Qualitative research; Radiology; Reporting

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