Bo Abrahamsen

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person‐years. However, long‐term use may be associated with higher risk (∼100 per 100,000 person‐years). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

Excess mortality following hip fracture: a systematic epidemiological review.

Summary This systematic literature review has shown that patients experiencing hip fracture after low-impact trauma are at considerable excess risk for death compared with nonhip fracture/community control populations. The increased mortality risk may persist for several years thereafter, highlighting the need for interventions to reduce this risk.Patients experiencing hip fracture after low-impact trauma are at considerable risk for subsequent osteoporotic fractures and premature death. We conducted a systematic review of the literature to identify all studies that reported unadjusted and excess mortality rates for hip fracture. Although a lack of consistent study design precluded any formal meta-analysis or pooled analysis of the data, we have shown that hip fracture is associated with excess mortality (over and above mortality rates in nonhip fracture/community control populations) during the first year after fracture ranging from 8.4% to 36%. In the identified studies, individuals experienced an increased relative risk for mortality following hip fracture that was at least double that for the age-matched control population, became less pronounced with advancing age, was higher among men than women regardless of age, was highest in the days and weeks following the index fracture, and remained elevated for months and perhaps even years following the index fracture. These observations show that patients are at increased risk for premature death for many years after a fragility-related hip fracture and highlight the need to identify those patients who are candidates for interventions to reduce their risk.

Subtrochanteric and Diaphyseal Femur Fractures in Patients Treated With Alendronate: A Register-Based National Cohort Study†‡

Alendronate (aln) is a potent bisphosphonate with a prolonged duration of action. Recent reports have found long‐term aln use to be common in patients with subtrochanteric or proximal diaphyseal femur fracture, raising concerns that these fractures could be a consequence of excessive suppression of bone turnover. Two national observational register‐based studies were performed: (1) cross‐sectional study (N = 11,944) comparing age distribution, exposure, and trauma mechanisms between different types of proximal femur fractures and (2) matched cohort study in patients with prior nonhip fractures (N = 5187 + 10,374), testing the hypothesis that the increase in the risk of subsequent atypical femur fractures exceeded the increase in typical hip fractures. We also sought evidence of a dose‐response relationship, where high adherence to or long‐term use of aln led to more atypical femur fractures. We found that 7% of patients with atypical fractures were aln exposed, and the same was found for typical hip fractures. In the cohort study, the HR for subtrochanteric/diaphyseal fracture with aln was 1.46 (0.91–2.35, p = 0·12) compared with 1.45 (1.21–1.74, p < 0·001) for hip fracture after adjustment for comorbidity and co‐medications. The risk was reduced by high adherence, and the ratio between hip and subtrochanteric/diaphyseal femur fractures was identical in aln‐treated patients and the control cohort even in the limited number of patients who received long‐term treatment. Subtrochanteric/diaphyseal femur fractures share the epidemiology and treatment response of classical hip fractures and are best classified as osteoporotic fractures.

Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe

Objectives To identify participants’ characteristics that influence the anti-fracture efficacy of vitamin D or vitamin D plus calcium with respect to any fracture, hip fracture, and clinical vertebral fracture and to assess the influence of dosing regimens and co-administration of calcium. Design Individual patient data analysis using pooled data from randomised trials. Data sources Seven major randomised trials of vitamin D with calcium or vitamin D alone, yielding a total of 68 517 participants (mean age 69.9 years, range 47-107 years, 14.7% men). Study selection Studies included were randomised studies with at least one intervention arm in which vitamin D was given, fracture as an outcome, and at least 1000 participants. Data synthesis Logistic regression analysis was used to identify significant interaction terms, followed by Cox’s proportional hazards models incorporating age, sex, fracture history, and hormone therapy and bisphosphonate use. Results Trials using vitamin D with calcium showed a reduced overall risk of fracture (hazard ratio 0.92, 95% confidence interval 0.86 to 0.99, P=0.025) and hip fracture (all studies: 0.84, 0.70 to 1.01, P=0.07; studies using 10 μg of vitamin D given with calcium: 0.74, 0.60 to 0.91, P=0.005). For vitamin D alone in daily doses of 10 μg or 20 μg, no significant effects were found. No interaction was found between fracture history and treatment response, nor any interaction with age, sex, or hormone replacement therapy. Conclusion This individual patient data analysis indicates that vitamin D given alone in doses of 10-20 μg is not effective in preventing fractures. By contrast, calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures.

Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival

INTRODUCTION osteoporosis is a common disease, and the incidence of osteoporotic fractures is expected to rise with the growing elderly population. Immediately following, and probably several years after a hip fracture, patients, both men and women, have a higher risk of dying compared to the general population regardless of age. The aim of this study was to assess excess mortality following hip fracture and, if possible, identify reasons for the difference between mortality for the two genders. METHODS this is a nationwide register-based cohort study presenting data from the National Hospital Discharge Register on mortality, comorbidity and medication for all Danish patients (more than 41,000 persons) experiencing a hip fracture between 1 January 1999 and 31 December 2002. Follow-up period was until 31 December 2005. RESULTS we found a substantially higher mortality among male hip fracture patients than female hip fracture patients despite men being 4 years younger at the time of fracture. Both male and female hip fracture patients were found to have an excess mortality rate compared to the general population. The cumulative mortality at 12 months among hip fracture patients compared to the general population was 37.1% (9.9%) in men and 26.4% (9.3%) in women. In the first year, the risk of death significantly increased for women with increasing age (hazard ratio, HR: 1.06, 95% confidence interval, CI: 1.06-1.07), the number of comedications (HR 1.04, 95% CI 1.03-1.05) and the presence of specific Charlson index components and medications described below. For men, age (HR 1.07, 95% CI 1.07-1.08), number of comedications (HR 1.06, 95% CI 1.04-1.07) and presence of different specific Charlson index components and medications increased the risk. Long-term survival analyses revealed that excess mortality for men compared with women remained strongly significant (HR 1.70, 95% CI 1.65-1.75, P < 0.001), even when controlled for age, fracture site, the number of medications, exposure to drug classes A, C, D, G, J, M, N, P, S and for chronic comorbidities. CONCLUSION excess mortality among male patients cannot be explained by controlling for known comorbidity and medications. Besides gender, we found higher age and multimorbidity to be related to an increased risk of dying within the first year after fracture; acute complications might be one of the explanations. This study emphasises the need for particular rigorous postoperative diagnostic evaluation and treatment of comorbid conditions in the male hip fracture patient.

Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials

INTRODUCTION Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium. SUBJECTS AND METHODS Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies. RESULTS The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06). CONCLUSION Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.

Cumulative Alendronate Dose and the Long-Term Absolute Risk of Subtrochanteric and Diaphyseal Femur Fractures: A Register-Based National Cohort Analysis

CONTEXT Bisphosphonates are the mainstay of anti-osteoporotic treatment and are commonly used for a longer duration than in the placebo-controlled trials. A link to development of atypical subtrochanteric or diaphyseal fragility fractures of the femur has been proposed, and these fractures are currently the subject of a U.S. Food and Drug Administration review. OBJECTIVE Our objective was to examine the risk of subtrochanteric/diaphyseal femur fractures in long term users of alendronate. DESIGN We conducted an age- and gender-matched cohort study using national healthcare data. PATIENTS Patients were alendronate users, without previous hip fracture, who began treatment between January 1, 1996, and December 31, 2005 (n=39,567) and untreated controls, (n=158,268). MAIN OUTCOME MEASURES Subtrochanteric or diaphyseal femur fractures were evaluated. RESULTS Subtrochanteric and diaphyseal fractures occurred at a rate of 13 per 10,000 patient-years in untreated women and 31 per 10,000 patient-years in women receiving alendronate [adjusted hazard ratio (HR)=1.88; 95% confidence interval (CI)=1.62-2.17]. Rates for men were six and 31 per 10,000 patient-years, respectively (HR=3.98; 95% CI=2.62-6.05). The HR for hip fracture was 1.37 (95% CI=1.30-1.46)) in women and 2.47 (95% CI=2.07-2.95) in men. Risks of subtrochanteric/diaphyseal fracture were similar in patients who had received 9 yr of treatment (highest quartile) and patients who had stopped therapy after the equivalent of 3 months of treatment (lowest quartile). CONCLUSIONS Alendronate-treated patients are at higher risk of hip and subtrochanteric/diaphyseal fracture than matched control subjects. However, large cumulative doses of alendronate were not associated with a greater absolute risk of subtrochanteric/diaphyseal fractures than small cumulative doses, suggesting that these fractures could be due to osteoporosis rather than to alendronate.

Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women — results of the Danish Osteoporosis Prevention Study

OBJECTIVES To study the fracture reducing potential of hormonal replacement therapy (HRT) in recent postmenopausal women in a primary preventive scenario. METHODS Prospective controlled comprehensive cohort trial: 2016 healthy women aged 45-58 years, from three to 24 months past last menstrual bleeding were recruited from a random sample of the background population. Mean age was 50. 8+/-2.8 years, and the number of person years followed was 9335.3. There were two main study arms: a randomised arm (randomised to HRT; n=502, or not; n=504) and a non-randomised arm (on HRT; n=221, or not; n=789 by own choice). First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women. RESULTS After five years, a total of 156 fractures were sustained by 140 women. There were 51 forearm fractures in 51 women. By intention-to-treat analysis (n=2016), overall fracture risk was borderline statistically significantly reduced (RR=0.73, 95% CI: 0.50-1.05), and forearm fracture risk was significantly reduced (RR=0.45, 95% CI: 0.22-0.90) with HRT. Restricting the analysis to women who had adhered to their initial allocation of either HRT (n=395) or no HRT (n=977) showed a significant reduction in both the overall fracture risk (RR=0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR=0.24, 95% CI: 0.09-0.69). Compliance with HRT was 65% after five years. CONCLUSIONS It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention.

Declining incidence of hip fractures and the extent of use of anti-osteoporotic therapy in Denmark 1997–2006

SummaryThe incidence of hip fractures in Denmark declined by about 20% from 1997 to 2006 in both men and women aged 60 and over. The decrease in hip fracture rates was much too large to be explained by the extent of anti-osteoporotic medication used in the country.IntroductionThe purpose of this study is to clarify (1) if hip fracture rates decline in Denmark despite low treatment rates and (2) if changes in age-specific rates could be explained by anti-osteoporotic medications.MethodsNational registers were used to obtain incidence rates for hip fractures in men and women aged 60+ and aggregated national data on number of users of anti-osteoporotic medications for 1997–2006. The potential contribution of anti-osteoporotic treatment to prevented hip fractures was estimated.ResultsIncidence rates declined by 20% in men and 22% in women. Use of specific anti-osteoporotic medications had increased from 1.8% in 60+-year-old women and 0.2% in 60+-year-old men to 7.3% and 1.3%, respectively. The decrease risk in men was nearly the same as in women, despite a six times lower treatment prevalence. The number of prevented hip fractures that could be attributed to therapy was 1.3% in men and 3.7% in women.ConclusionsThe decrease in hip fractures is much too large to be explained by the extent of anti-osteoporotic medication. Interestingly, the decrease in fracture rates also applied to men, despite much lower treatment rates. Potential explanations include smoking habits, obesity, national home visit programmes, improved general health and vitamin D supplementation.

Cross calibration of QDR-2000 and QDR-1000 dual-energy X-ray densitometers for bone mineral and soft-tissue measurements

Replacement of dual energy X-ray densitometry (DXA) equipment may be necessary in many labs with time, or new equipment may be added. In this context we compared patient scans between a Hologic QDR-1000W and a QDR-2000 (n = 29-43, depending on anatomic region) and between QDR-2000 single beam (SB) and fan beam (FB) modes (n = 40-62) as a quality control measure. A total of 83 subjects (79 females and four males) with a wide range of bone mineral densities (BMD) were studied. There was a linear relationship between results with the QDR-1000W and QDR-2000 in SB mode, and between SB and FB mode on the QDR-2000, but the magnitude of the coefficients and constants differed for the different anatomic regions. In SB mode the QDR-2000 underestimated whole body and forearm BMD by 3% relative to the QDR-1000W, even after cross calibration using a spine phantom. Femoral total BMD was slightly, but not significantly, underestimated. Thus, additional postanalysis correction had to be applied to forearm and whole-body scans. In FB with the QDR-2000, spine and whole-body BMD was underestimated by 3%, but femur total and neck BMD was overestimated by 2.2 and 2.8%, respectively, compared with SB scans on the same device. Soft-tissue composition with FB (enhanced analysis protocol) on the QDR-2000 differed greatly from that obtained using SB (standard protocol). Lean tissue mass was 4 kg lower and fat mass 4 kg higher in FB mode.(ABSTRACT TRUNCATED AT 250 WORDS)