Tineke van Geel

Contributors to Secondary Osteoporosis and Metabolic Bone Diseases in Patients Presenting with a Clinical Fracture

BACKGROUND Previously undetected contributors to secondary osteoporosis and metabolic bone diseases (SECOB) are frequently found in patients with osteoporosis, but the prevalence in patients at the time they present with a clinical fracture is unknown. METHODS All consecutive patients with a recent clinical vertebral or nonvertebral fracture, who were able and willing to be investigated (n = 626: 482 women, 144 men, age range 50-97 yr) had bone mineral density and laboratory investigations (serum calcium, inorganic phosphate, 25-hydroxyvitamin D, creatinine, intact PTH, TSH, free T(4), serum and urine protein electrophoresis, and in men also serum testosterone). RESULTS Known SECOB contributors were present in 23.0% of patients and newly diagnosed SECOB contributors in 26.5%: monoclonal proteinemia (14 of 626), renal insufficiency grade III or greater (54 of 626), primary (17 of 626) and secondary (64 of 626) hyperparathyroidism, hyperthyroidism (39 of 626), and hypogonadism in men (12 of 144). Newly diagnosed SECOBs, serum 25-hydroxyvitamin D less than 50 nmol/liter (in 63.9%), and dietary calcium intake less than 1200 mg/d (in 90.6%) were found at any age, in both sexes, after any fracture (except SECOB in men with finger and toe fractures) and at any level of bone mineral density. CONCLUSION At presentation with a fracture, 26.5% of patients have previously unknown contributors to SECOB, which are treatable or need follow-up, and more than 90% of patients have an inadequate vitamin D status and/or calcium intake. Systematic screening of patients with a recent fracture identifies those in whom potentially reversible contributors to SECOB and calcium and vitamin D deficiency are present.

Fracture Liaison Service: Impact on Subsequent Nonvertebral Fracture Incidence and Mortality

BACKGROUND A fracture liaison service model of care is widely recommended and applied, but data on its effectiveness are scarce. Therefore, the risk of subsequent nonvertebral fractures and mortality within two years after a nonvertebral fracture was analyzed in patients who presented to a hospital with a fracture liaison service and a hospital without a fracture liaison service. METHODS In 2005 to 2006, all consecutive patients with an age of fifty years or older presenting with a nonvertebral fracture were included. In the group that presented to a hospital without a fracture liaison service (the no-FLS group), only standard fracture care procedures were followed to address proper fracture-healing. In the group that presented to a hospital with a fracture liaison service (the FLS group), dual x-ray absorptiometry scans and laboratory testing were performed, and if applicable, patients were treated according to the Dutch guideline for osteoporosis. The risk for subsequent nonvertebral fracture and mortality were analyzed using multivariable Cox regression models with adjustments for age, sex, and baseline fracture location. RESULTS In total, 1412 patients presented to the fracture liaison service (73.2% were women, and the mean age was 71.1 years), and 1910 underwent standard fracture care (69.8% were women, and the mean age was 69.5 years). After adjustment for age, sex, and baseline fracture location, patients who attended the fracture liaison service had a significantly lower mortality risk (hazard ratio: 0.65; 95% confidence interval [CI]: 0.53 to 0.79) over two years of follow-up. The subsequent nonvertebral fracture risk was also significantly lower in the patients in the FLS group, but this effect was time-dependent, with a hazard ratio of 0.84 (95% CI: 0.64 to 1.10) at twelve months and 0.44 (95% CI: 0.25 to 0.79) at twenty-four months. CONCLUSIONS Patients seen at the fracture liaison service had a significantly lower mortality and subsequently a lower risk of nonvertebral fracture than those not seen at the fracture liaison service, with a reduction of 35% and 56%, respectively, over two years of follow-up. A fracture liaison service appears to be a successful approach to reduce the number of subsequent fractures and premature mortality in this cohort of patients.

Assessment of individual fracture risk: FRAX and beyond.

The World Health Organization fracture risk assessment tool (FRAX) and the Garvan fracture risk calculator are both widely available tools for individualized fracture risk prediction in daily practice. The FRAX model is implemented in several guidelines and most widely used at present. However, clinicians should take into account the differences between the models, especially with regard to the effect of the number of falls, number and clustering of previous fractures, and the number of clinical risk factors on the outcome of predicted fracture risk. Further development will be needed for optimal integration of bone- and fall-related risks, clustering of fractures, and dosing of risk factors to validate the models in different populations and to validate the ability to select patients who will achieve fracture risk reduction with anti-osteoporosis therapy. FRAX may be used as the primary model, and in patients with recurrent fractures and falls the use of the Garvan model may be of additional value.

Measures of bioavailable serum testosterone and estradiol and their relationships with muscle mass, muscle strength and bone mineral density in postmenopausal women: a cross-sectional study

OBJECTIVE The physiologic role of circulating endogenous testosterone and estrogen concentrations in relation to lean body mass (LBM) and muscle strength is not as well documented in postmenopausal women as in elderly men. DESIGN Three hundred and twenty-nine healthy postmenopausal women were randomly selected from a general practice population-based sample aged between 55 and 85 years. METHODS Total testosterone and estrogen (TT and TE) and sex hormone-binding globulin (SHBG) were determined and estimates of bioavailable testosterone (free androgen index (TT/SHBG, FAI), calculated free testosterone (cFT), and estrogen (TE/SHBG, ESR) were calculated. Examinations included bone mineral density (BMD) of the spine and femoral neck (FN), LBM, maximum quadriceps extension strength (MES) and maximum handgrip strength (MGS), timed up-and-go test (TUGT), osteocalcin (OC), and urinary deoxy-pyridinoline/creatinine (DPyr). Correlations were assessed using Pearsons correlation coefficient (r). RESULTS With advancing age, LBM, MES, MGS, BMD, and ESR significantly declined (range r: -0.356 to -0.141) and TUGT, and DPyr significantly increased (range r: 0.135 to 0.282 (P<0.05)). After age-adjustment, LBM, MES, and BMD in spine and FN were significantly related to bioavailable testosterone (range r: 0.146 to 0.193, for cFT, and 0.157 to 0.224, for FAI) and to ESR (range r: 0.162 to 0.273). OC and DPyr were significantly inversely related to ESR (r: -0.154 and -0.144 respectively). CONCLUSIONS Age-related loss of LBM, MES and BMD in postmenopausal women is partly dependent on the presence of endogenous bioavailable testosterone and estrogen.

Timing of Subsequent Fractures after an Initial Fracture

A prior fracture is a well-documented risk factor for a subsequent fracture and it doubles the risk of subsequent fractures. Few studies have investigated the time that elapses between the initial and subsequent fracture. These studies show that the subsequent fracture risk is not constant, but fluctuates over time. The risk of subsequent vertebral, hip, and nonvertebral non-hip fractures is highest immediately after initial hip, clinical, and radiographic vertebral fractures and nonvertebral fractures and declines afterward, regardless of gender, age, and initial fracture location. These studies indicate the need for early action after an initial fracture with medical interventions that have an effect within a short term to reduce the preventable risks of subsequent fractures.

Individualizing fracture risk prediction.

Low bone mineral density (BMD) and clinical factors (CRF) have been identified as factors associated with an increased relative risk of fractures. From this observation and for clinical decision making, the concept of prediction of the individual absolute risk of fractures has emerged. It refers to the individuals risk for fractures over a certain time period, e.g. the next 5 and 10 years. Two individualized fracture risk calculation tools that are increasingly used and are available on the web are the FRAX algorithm and the Garvan fracture risk calculator. These tools integrate BMD and CRFs for fracture risk calculation in the individual patient in daily practice. Although both tools include straightforward risk factors, such as age, sex, previous fractures, body weight and BMD, they differ in several aspects, such as the inclusion of other CRFs, fall risks and number of previous fractures. Both models still need to be validated in different populations before they can be generalized to other populations, since the background risk for fractures is population specific. Further studies will be needed to validate their contribution in selecting patients who will achieve fracture risk reduction with anti-osteoporosis therapy.

Progressively Increasing Fracture Risk With Advancing Age After Initial Incident Fragility Fracture: The Tromso Study

The risk of subsequent fracture is increased after initial fractures; however, proper understanding of its magnitude is lacking. This population‐based study examines the subsequent fracture risk in women and men by age and type of initial incident fracture. All incident nonvertebral fractures between 1994 and 2009 were registered in 27,158 participants in the Tromsø Study, Norway. The analysis included 3108 subjects with an initial incident fracture after the age of 49 years. Subsequent fracture (n = 664) risk was expressed as rate ratios (RR) and absolute proportions irrespective of death. The rates of both initial and subsequent fractures increased with age, the latter with the steepest curve. Compared with initial incident fracture rate of 30.8 per 1000 in women and 12.9 per 1000 in men, the overall age‐adjusted RR of subsequent fracture was 1.3 (95% CI, 1.2–1.5) in women, and 2.0 (95% CI, 1.6–2.4) in men. Although the RRs decreased with age, the absolute proportions of those with initial fracture who suffered a subsequent fracture increased with age; from 9% to 30% in women and from 10% to 26% in men, between the age groups 50–59 to 80+ years. The type of subsequent fracture varied by age from mostly minor fractures in the youngest to hip or other major fractures in the oldest age groups, irrespective of type and severity of initial fracture. In women and men, 45% and 38% of the subsequent hip or other major fractures, respectively, were preceded by initial minor fractures. The risk of subsequent fracture is high in all age groups. At older age, severe subsequent fracture types follow both clinically severe and minor initial incident fractures. Any fragility fracture in the elderly reflects the need for specific osteoporosis management to reduce further fracture risk.

Increased fracture risk in patients with type 2 diabetes mellitus: An overview of the underlying mechanisms and the usefulness of imaging modalities and fracture risk assessment tools

Type 2 diabetes mellitus has recently been linked to an increased fracture risk. Since bone mass seems to be normal to elevated in patient with type 2 diabetes, the increased fracture risk is thought to be due to both an increased falling frequency and decreased bone quality. The increased falling frequency is mainly a result of complications of the disease such as a retinopathy and polyneuropathy. Bone quality is affected through changes in bone shape, bone micro-architecture, and in material properties such as bone mineralization and the quality of collagen. Commonly used methods for predicting fracture risk such as dual energy X-ray absorptiometry and fracture risk assessment tools are helpful in patients with type 2 diabetes mellitus, but underestimate the absolute fracture risk for a given score. New imaging modalities such as high resolution peripheral quantitative computed tomography are promising for giving insight in the complex etiology underlying the fragility of the diabetic bone, as they can give more insight into the microarchitecture and geometry of the bone. We present an overview of the contributing mechanisms to the increased fracture risk and the usefulness of imaging modalities and risk assessment tools in predicting fracture risk in patients with type 2 diabetes.

Development of a simple prognostic nomogram for individualising 5-year and 10-year absolute risks of fracture: a population-based prospective study among postmenopausal women

Objectives Previous fracture prediction models have been based on the assumption of a stable risk of subsequent fractures over time. The aim of the present work was to develop a nomogram for prediction of 5-year and 10-year individualised absolute fracture risks for postmenopausal women taking into account the time relation between fractures. Methods A population-based prospective study was performed in 23 general practice centres located in the southern part of The Netherlands. At baseline (1992–1994), 4203 postmenopausal women between 50 and 80 years participated and 2372 of them also participated 10 years later. Baseline measurements included lumbar spine bone mineral density (BMD) and clinical risk factor evaluation. The incidence of fractures was ascertained. Bayesian model averaging and Coxs proportional hazards model were used. Results After enrolment, 382 (16.1%) women had a clinical fracture. Fracture risk was associated with advancing age (HR 1.09 per SD (5 years); 95% CI 1.01 to 1.17), lumbar spine BMD (HR 1.23 per −1 SD; 95% CI 1.10 to 1.37) and a prior fracture, with HR 3.27 (95% CI 2.50 to 4.30) for a recent prior fracture (≤5 years previously) and HR 1.97 (95% CI 1.43 to 2.71) for a non-recent prior fracture after menopause (>5 years previously). Women with a recent prior fracture had 66% higher risk of an incident fracture than those with a non-recent prior fracture (HR 1.66; 95% CI 1.15 to 2.40). Conclusions The nomogram developed can help doctors to inform patients more effectively and thus better manage patient care by providing an individualised fracture risk taking into account the time relationship for fractures.

Risk factors for clinical fractures among postmenopausal women: a 10-year prospective study

Objective. Only scarce data are available on the long-term absolute risk (AR) of all clinical fractures, taking into account the time when they occurred. Therefore, we assessed during a 10-year follow-up the risk factors associated with the occurrence of any first or second clinical fracture. Study design. This was a population-based study in 10 general practice centres. The sample comprised 2372 postmenopausal women, aged between 50 and 80 years at baseline, who completed a questionnaire about the incidence of radiographically confirmed fractures and fracture risks, analysed by multiple Cox regression. Main outcome measure. AR for any clinical fracture. Results. During the 10-year follow-up, 380 women (16%) had a fracture. A first fracture occurred in 267 women (11%). Osteoporosis at the lumbar spine (T-score <−2.5; hazard ratio (HR) 1.8, 95% confidence interval (CI) 1.4–2.3) and age over 60 years (HR1.4, 95% CI 1.1–1.8) were the only risk factors retained in the Cox analysis. The AR in the lowest-risk group was 10%, and it was 23% in the highest-risk group. A second fracture occurred in 113 women during follow-up (5%). The time when a fracture occurred was the only risk factor retained in the Cox analysis. The AR for a second fracture was 41% in the five years after any first fracture before baseline and 25% if the first fracture had occurred earlier (HR 1.8, 95% CI 1.3–2.7). Conclusion. In postmenopausal women, over a 10-year follow-up, the AR of a second clinical fracture is highest in the five years after any first clinical fracture. The AR for a first clinical fracture is lower and depends on osteoporosis and age.