Kristina Åkesson

Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis

CONTEXT Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

Biochemical Markers of Bone Metabolism and Prediction of Fracture in Elderly Women

We studied the ability of various markers of bone turnover to predict fracture in 1040 randomly recruited 75‐year‐old women. A total of 178 of the women sustained at least one fracture during follow‐up (mean, 4.6 years). In elderly women, TRACP5b and urinary fragments of osteocalcin are promising new markers for prediction of fracture, in particular, vertebral fracture.

Subtrochanteric fractures after long-term treatment with bisphosphonates: A European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report

SummaryThis paper reviews the evidence for an association between atypical subtrochanteric fractures and long-term bisphosphonate use. Clinical case reports/reviews and case–control studies report this association, but retrospective phase III trial analyses show no increased risk. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is yet unproven.IntroductionA Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the International Osteoporosis Foundation has reviewed the evidence for a causal association between subtrochanteric fractures and long-term treatment with bisphosphonates, with the aim of identifying areas for further research and providing recommendations for physicians.MethodsA PubMed search of literature from 1994 to May 2010 was performed using key search terms, and articles pertinent to subtrochanteric fractures following bisphosphonate use were analysed.ResultsSeveral clinical case reports and case reviews report a possible association between atypical fractures at the subtrochanteric region of the femur in bisphosphonate-treated patients. Common features of these ‘atypical’ fractures include prodromal pain, occurrence with minimal/no trauma, a thickened diaphyseal cortex and transverse fracture pattern. Some small case–control studies report the same association, but a large register-based study and retrospective analyses of phase III trials of bisphosphonates do not show an increased risk of subtrochanteric fractures with bisphosphonate use. The number of atypical subtrochanteric fractures in association with bisphosphonates is an estimated one per 1,000 per year. It is recommended that physicians remain vigilant in assessing their patients treated with bisphosphonates for the treatment or prevention of osteoporosis and advise patients of the potential risks.ConclusionsBisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further research. Were the case to be proven, the risk–benefit ratio still remains favourable for use of bisphosphonates to prevent fractures.

Coordinator-based systems for secondary prevention in fragility fracture patients

The underlying causes of incident fractures—bone fragility and the tendency to fall—remain under-diagnosed and under-treated. This care gap in secondary prevention must be addressed to minimise both the debilitating consequences of subsequent fractures for patients and the associated economic burden to healthcare systems. Clinical systems aimed at ensuring appropriate management of patients following fracture have been developed around the world. A systematic review of the literature showed that 65% of systems reported include a dedicated coordinator who acts as the link between the orthopaedic team, the osteoporosis and falls services, the patient and the primary care physician. Coordinator-based systems facilitate bone mineral density testing, osteoporosis education and care in patients following a fragility fracture and have been shown to be cost-saving. Other success factors included a fracture registry and a database to monitor the care provided to the fracture patient. Implementation of such a system requires an audit of existing arrangements, creation of a network of healthcare professionals with clearly defined roles and the identification of a ‘medical champion’ to lead the project. A business case is needed to acquire the necessary funding. Incremental, achievable targets should be identified. Clinical pathways should be supported by evidence-based recommendations from national or regional guidelines. Endorsement of the proposed model within national healthcare policies and advocacy programmes can achieve alignment of the objectives of policy makers, professionals and patients. Successful transformation of care relies upon consensus amongst all participants in the multi-disciplinary team that cares for fragility fracture patients.

Preventing fractures in elderly people

Preventing fractures in elderly people is a priority, especially as it has been predicted that in 20 years almost a quarter of people in Europe will be aged over 65. This article describes the factors contributing to fracture, interventions to prevent fracture, and the various treatments.

Associations Between Homocysteine, Bone Turnover, BMD, Mortality, and Fracture Risk in Elderly Women†

Homocysteine has been suggested to be a risk factor for fracture, but the causal relationship is not clear. In 996 women from the OPRA study, high homocysteine level was associated with high bone marker levels and low BMD at baseline. During a mean 7‐year follow‐up, high homocysteine level was associated with mortality, but no clear association to fracture risk existed.

Effect of fracture on bone turnover markers: A longitudinal study comparing marker levels before and after injury in 113 elderly women

In this longitudinal, prospective, and population‐based study (n = 1044), seven BTMs were assessed before and after trauma in 113 elderly women (85 with fractures). Markers were not altered in the immediate postfracture period but were clearly elevated during fracture repair. Recent fracture should thus be taken into account when markers are used in clinical practice.

Impairment of bone turnover in elderly women with hip fracture

SummaryHip fracture is one of the most severe consequences of osteoporosis affecting aged women. However, abnormalities of bone turnover responsible for bone loss in this condition have not been clearly defined. To further evaluate the bone metabolic status of women sustaining hip fracture, we have prospectively measured serum osteocalcin as a marker of bone formation and urinary excretion of pyridinoline (Pyr) and deoxypyridinoline (D-pyr) cross-links as markers of bone collagen degradation in 174 independently living women (80 ± 8 years) within a few hours after a hip fracture. Comparison was made with 77 age-matched controls (80 ± 5 years) and 17 premenopausal women (39 ± 3 years). In addition 15 of the patients were followed with daily measurements during the first postoperative week. At the time of admission osteocalcin was 20% lower in the fractured women compared to the elderly controls (7.6 ± 3.8 vs. 9.5 ± 4.5 nglml,P = 0.001). Pyr and D-pyr were 36% and 40% higher, respectively (P = 0.0001), than in elderly controls and 85% and 76% higher than in premenopausal controls (P = 0.0001). Serum osteocalcin did not correlate with the cortisol level measured at the same time (r = 0.03, ns), nor with serum albumin and creatinine. Serum osteocalcin remained unchanged within 18 hours after fracture, whereafter it progressively decreased until the third postoperative day. No correlation was noted between the excretion of pyridinoline cross-links and the time elapsed from fracture.These data suggest that the abnormal levels of osteocalcin and pyridinolines are unrelated to traumatically induced acute changes, but reflect abnormalities of bone turnover existing prior to the fracture. Thus, hip-fracture patients have biochemical evidence of decreased bone formation and increased bone resorption when compared to age-matched controls. We suggest that these abnormalities may play a role in the decrease of the bone mass and the consequently increased bone fragility that characterize the osteoporotic hip fracture in the elderly.

Bone Turnover Markers and Prediction of Fracture: A Prospective Follow-Up Study of 1040 Elderly Women for a Mean of 9 Years

Osteoporosis is characterized by compromised bone mass and strength, predisposing to an increased risk of fracture. Increased bone metabolism has been suggested to be a risk factor for fracture. The aim of this study was to evaluate whether baseline bone turnover markers are associated with long‐term incidence of fracture in a population‐based sample of 1040 women who were 75 years old (Malmö OPRA study). Seven bone markers (S‐TRACP5b, S‐CTX‐I, S‐OC[1–49], S‐TotalOC, S‐cOC, S‐boneALP, and urinary osteocalcin) were measured at baseline and 1‐year follow‐up visit. During the mean follow‐up of 9.0 years (range 7.4–10.9), 363 women sustained at least one fracture of any type, including 116 hip fractures and 103 clinical vertebral fractures. High S‐TRACP5b and S‐CTX‐I levels were associated with increased risk of any fracture with hazard ratios [HRs (95% confidence interval)] of 1.16 (1.04–1.29) and 1.13 (1.01–1.27) per SD increase, respectively. They also were associated with increased risk of clinical vertebral fracture with HRs of 1.22 (1.01–1.48) and 1.32 (1.05–1.67), respectively. Markers were not associated with risk for hip fracture. Results were similar when we used resorption markers, including urinary osteocalcin, measured at the 1‐year visit or an average of the two measurements. The HRs were highest for any fracture in the beginning of the follow‐up period, 2.5 years from baseline. For vertebral fractures, the association was more pronounced and lasted for a longer period of time, at least for 5 years. In conclusion, elevated levels of S‐TRACP5b, S‐CTX‐I, and urinary osteocalcin are associated with increased fracture risk for up to a decade in elderly women.

Bone mineral normative data in Malmö, Sweden : comparison with reference data and hip fracture incidence in other ethnic groups

The bone mineral mass was measured in 324 residents of the city of Malmö, Sweden, by dual energy roentgen absorptiometry (DEXA) using the Lunar DPX equipment--total body, hip, and lumbar vertebrae. The bone mineral content of the wrist was also measured with single photon absorptiometry (SPA) in 88 of the individuals. Weight, height, and vertebral height, as well as body fat, lean body mass, menarcheal age, menopausal age, and hand grip strength were determined. Measurements were compared with reference bone mineral content values from the United States, Japan, and France--also hip fracture incidence was compared. All bone mineral values decreased with age. A good correlation was found between the DEXA technique of total body bone mineral and the forearm SPA values. The bone mineral content was correlated with lean body mass and weight. The Malmö bone mineral content was on the same level as in the United States, but higher than in Japan and France. The comparatively high risk of fragility fractures in the Scandinavian countries compared with most other settings cannot be explained by low bone mass.