Showing papers in "Osteoporosis International in 2002"

The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis.

Abstract: Studies of oral corticosteroid dose and loss of bone mineral density have reported inconsistent results. In this meta-analysis, we used information from 66 papers on bone density and 23 papers on fractures to examine the effects of oral corticosteroids on bone mineral density and risk of fracture. Strong correlations were found between cumulative dose and loss of bone mineral density and between daily dose and risk of fracture. The risk of fracture was found to increase rapidly after the start of oral corticosteroid therapy (within 3 to 6 months) and decrease after stopping therapy. The risk remained independent of underlying disease, age and gender. We conclude that oral corticosteroid treatment using more than 5 mg (of prednisolone or equivalent) daily leads to a reduction in bone mineral density and a rapid increase in the risk of fracture during the treatment period. Early use of preventive measures against corticosteroid-induced osteoporosis is recommended.

Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study.

Abstract: Vitamin D insufficiency and low calcium intake contribute to increase parathyroid function and bone fragility in elderly people. Calcium and vitamin D supplements can reverse secondary hyperparathyroidism thus preventing hip fractures, as proved by Decalyos I. Decalyos II is a 2-year, multicenter, randomized, double-masked, placebo-controlled confirmatory study. The intention-to-treat population consisted of 583 ambulatory institutionalized women (mean age 85.2 years, SD = 7.1) randomized to the calcium–vitamin D3 fixed combination group (n= 199); the calcium plus vitamin D3 separate combination group (n= 190) and the placebo group (n= 194). Fixed and separate combination groups received the same daily amount of calcium (1200 mg) and vitamin D3 (800 IU), which had similar pharmacodynamic effects. Both types of calcium-vitamin D3 regimens increased serum 25-hydroxyvitamin D and decreased serum intact parathyroid hormone to a similar extent, with levels returning within the normal range after 6 months. In a subgroup of 114 patients, femoral neck bone mineral density (BMD) decreased in the placebo group (mean =–2.36% per year, SD = 4.92), while remaining unchanged in women treated with calcium-vitamin D3 (mean = 0.29% per year, SD = 8.63). The difference between the two groups was 2.65% (95% CI =–0.44, 5.75%) with a trend in favor of the active treatment group. No significant difference between groups was found for changes in distal radius BMD and quantitative ultrasonic parameters at the os calcis. The relative risk (RR) of HF in the placebo group compared with the active treatment group was 1.69 (95% CI = 0.96, 3.0), which is similar to that found in Decalyos I (RR = 1.7; 95% CI = 1.0, 2.8). Thus, these data are in agreement with those of Decalyos I and indicate that calcium and vitamin D3 in combination reverse senile secondary hyperparathyroidism and reduce both hip bone loss and the risk of hip fracture in elderly institutionalized women.

Biomechanics of bone: determinants of skeletal fragility and bone quality.

Abstract: Bone fragility can be defined by biomechanical parameters, including ultimate force (a measure of strength), ultimate displacement (reciprocal of brittleness) and work to failure (energy absorption). Bone fragility is influenced by bone size, shape, architecture and tissue 'quality'. Many osteoporosis treatments build bone mass but also change tissue quality. Antiresorptive therapies, such as bisphosphonates, substantially reduce bone turnover, impairing microdamage repair and causing increased bone mineralization, which can increase the brittleness of bone. Anabolic therapies, such as parathyroid hormone (PTH-(1-84)) or teriparatide (PTH-( 1-34)), increase bone turnover and porosity, which offset some of the positive effects on bone strength. Osteoporosis therapies may also affect bone architecture by causing the redistribution of bone structure. Restructuring of bone during treatment may change bone fragility, even in the absence of drug effects on bone mineral density (BMD). This effect may explain why some drugs can affect fracture incidence disproportionately to changes in BMD. For instance, in a recent clinical trial, PTH-(1-34) therapy caused a dose-related increase in spinal BMD without any dose-dependent effect on the observed decrease in spinal fracture incidence. This apparent disassociation between spinal BMD and bone fragility is probably due to effects of PTH-(1-34) on bone architecture within vertebral bodies. While it has been shown that BMD is highly heritable, bone mineral distribution and architecture are also under strong genetic influence. Recent findings suggest that different genes regulate trabecular and cortical structures within lumbar vertebrae, producing a wide range of bone architectural designs. These findings suggest that there is no single optimal bone architecture; instead many different architectural solutions produce adequate bone strength.

Vitamin D and Muscle Function

Abstract: The aim of this review is to summarize current knowledge on the relation between vitamin D and muscle function. Molecular mechanisms of vitamin D action on muscle tissue have been known for many years and include genomic and non-genomic effects. Genomic effects are initiated by binding of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) to its nuclear receptor, which results in changes in gene transcription of messenger RNA and subsequent protein synthesis. Non-genomic effects of vitamin D are rapid and mediated through a membrane-bound vitamin D receptor (VDR). Genetic variations in the VDR and the importance of VDR polymorphisms in the development of osteoporosis are still a matter of controversy and debate. Most recently, VDR polymorphisms have been described to affect muscle function. The skin has an enormous capacity for vitamin D production and supplies the body with 80–100% of its requirements of vitamin D. Age, latitude, time of day, season of the year and pigmentation can dramatically affect the production of vitamin D in the skin. Hypovitaminosis D is a common feature in elderly people living in northern latitudes and skin coverage has been established as an important factor leading to vitamin D deficiency. A serum 25-hydroxyvitamin D level below 50 nmol/l has been associated with increased body sway and a level below 30 nmol/l with decreased muscle strength. Changes in gait, difficulties in rising from a chair, inability to ascend stairs and diffuse muscle pain are the main clinical symptoms in osteomalacic myopathy. Calcium and vitamin D supplements together might improve neuromuscular function in elderly persons who are deficient in calcium and vitamin D. Thus 800 IU of cholecalciferol in combination with 1200 mg of elemental calcium reduces hip fractures and other non-vertebral fractures and should generally be recommended in individuals who are deficient in calcium and vitamin D. Given the strong interdependency of vitamin D deficiency, low serum calcium and high levels of parathyroid hormone, however, it is difficult to identify exact mechanisms of action.

Mechanical strain and bone cell function: A review

Abstract: Bones are able to withstand functional loads without either breaking or sustaining extensive damage because they have evolved the capacity to adapt their architecture in relation to changes in their habitual loading environment [1–3]. Reduced loading due to long-term bed rest, cast immobilization, or microgravity conditions induces significant bone loss and mineral changes [4–6], which only begin to be recovered following the reintroduction of normal activity. It is assumed, therefore, that the functional input required to stimulate and maintain normal bone architecture is the loading environment encountered during normal activity. Although most fractures occur as a result of the loads engendered during accidents such as falls or collisions, these loads (since they are encountered only at the time of fracture) cannot be used as a controlling input for bone cells to adapt bone strength. It is most likely therefore that bone cells respond directly or indirectly to the local strains engendered in their vicinity by the loads of normal functional activity. These strains are the product of the bones’ external loads and their structural properties and so contain all the information necessary to be the controlling input for adaptive bone modeling and remodeling. Frost [7] likened strain-adaptive remodeling to a domestic thermostat (or ‘mechanostat’) that is ‘off’ under circumstances of normal physiologic strain and ‘on’ in response to strain magnitudes outside normal physiologic thresholds. This is an attractive analogy but inevitably limited in its applicability. Just as the precise input and mechanism by which loading is transduced into cellular control of bone remodeling is unknown, so are bone’s objectives (the on/off points) in terms of strain. A number of studies have shown that bone’s adaptive (re)modeling behavior is more complex than on/off formation/resorption responses to strain magnitude. For instance, static strains do not engender adaptive responses [8,9] whereas dynamic strains which change at high physiologic rates (as in impact loading) engender greater adaptive responses than those which change more slowly [10–13]. The on/off points therefore relate to a strain-related stimulus rather than a particular strain value [9]. The inference, derived from animal experiments, that bone cells respond preferentially to a subset of their mechanical environment dominated by high strains changing at fast rates and presented in unusual distributions, has been substantiated by exercise studies in humans. Thus high impact activities such as squash, tennis, and badminton, for example, are more osteogenic, than running, cycling, swimming, or ice hockey [14]. These human exercise studies also support the data from animal studies that local loading induces local site specific changes in bone architecture [15–17]. In tennis players and baseball pitchers, for example, humeral hypertropy occurs only in the playing arm in which the stimulatory loading is actually experienced [16,18]. Conversely, protection from strain-related stimuli causes a localized reduction in bone mass. External fixation, for example, causes an increase in the diameter of the medullary cavity and reduced bone mineral content [4,19,20]. Even with generalized decreases in skeletal loading, as occurs during space flight, bone loss occurs in a non-uniform manner, with the distal leg bones experiencing the highest bone loss [21,22]. This has been hypothesized to occur because of the absence of normal high frequency heel strike activity under microgravity conditions [23]. It seems, therefore, that Osteoporos Int (2002) 13:688–70

A New Approach to the Development of Assessment Guidelines for Osteoporosis

Abstract: The diagnosis of osteoporosis is made from the measurement of BMD. DXA at the hip is the appropriate diagnostic site. Current clinical guidelines follow the principle that BMD measurements are indicated in individuals with risk factors for fracture and that treatment is recommended in those with a BMD below a critical value. In some countries reimbursement for the costs of treatment depend upon such thresholds for BMD. In Europe the critical value corresponds to a T-score of-2.5 SD, whereas in the USA less stringent criteria are used. It is evident, however, that fracture risk at any given T-score varies markedly according to age and other risk factors. This has led to the view that interventions should be targeted to those at high risk, irrespective of a fixed BMD threshold. In this sense, BMD is utlized as a risk assessment, since in many instances intervention thresholds will be less stringent than the diagnostic threshold. Thus, intervention thresholds need to differ from diagnostic thresholds and be based on fracture probabilities. A 10-year fracture probability appears to be an appropriate time frame. There are a number of problems to be overcome in the development of assessment guidelines. They need to take account of not only the risk of hip fracture but also that of other fractures which contribute significantly to morbidity, particularly in younger individuals. A promising approach is to weight fracture probabilities according to the disutility incurred compared with hip fracture probability. Account also needs to be taken of the large geographic variation in fracture probabilities worldwide. A further challenge for the future will be to identify risk factors that predict fracture with high validity in different regions of the world and their independent contributions, so that models of risk prediction can be constructed and ultimately validated in independent cohorts.

Changes in bone mineral density with age in men and women: a longitudinal study.

Abstract: We performed a prospective study to evaluate the normal changes in bone mineral density (BMD) in the forearm, hip, spine and total body, and to study the agreement between changes in BMD estimated from cross-sectional data and the actual longitudinal changes. Six hundred and twenty subjects (398 women, 222 men; age 20–89 years) without diseases or medication known to affect bone metabolism undertook baseline evaluations, and 525 (336 women, 189 men) completed the study. BMD was measured twice 2 years apart by dual-energy X-ray absorptiometry. From cross-sectional evaluations the only premenopausal bone loss (<0.003 g/cm2/year) was found in the hip. In women after menopause and in men an age-related bone loss (0.002–0.006 g/cm2/year) was found at all sites. The data from the longitudinal evaluation showed a small bone loss in women before menopause at the hip and lumbar spine (<0.4%/year (<0.004 g/cm2/year)); this bone loss nearly tripled in the early postmenopausal years (<10 years since menopause), and thereafter decreased to the premenopausal rate for the hip, and to zero for the lumbar spine. The most pronounced bone loss after menopause occurred in the forearm (1.2 %/year (0.006 g/cm2/year)), and it remained constant throughout life. In men there was a small longitudinal bone loss in the hip throughout life, and a small bone loss in the distal forearm after the age of 50 years. In all groups, except for the early postmenopausal women, we found a small increase in total body BMD with age. When comparing the changes in BMD estimated from cross-sectional data with the longitudinal changes, only the hip and forearm generally displayed agreement, whereas the changes in the total body and spine generally were incongruous. In conclusion, the hip and forearm appear to be the sites with the best agreement between the cross-sectional estimated and the longitudinal age-related changes in BMD.

Does a fracture at one site predict later fractures at other sites? A British cohort study.

Abstract: The extent to which a fracture at one skeletal site predicts further fractures at other sites remains uncertain. We addressed this issue using information from the UK General Practice Research Database, which contains the medical records of general practitioners; our study population consisted of all patients aged 20 years or older with an incident fracture during 1988 to 1998. We identified 222 369 subjects (119 317 women, 103 052 men) who had sustained at least one fracture during follow-up. There was a 2- to 3-fold increase in the risk of subsequent fractures at different skeletal sites. A patient with a radius/ulna fracture had a standardized incidence ratio (SIR) of 3.0 (95% confidence interval 2.9-3.1) for fractures at a different skeletal site; for initial vertebral fracture, this ratio was 2.9 (2.8-3.1) and for initial femur/hip fracture it was 2.6 (2.5-2.7). The SIRs were generally higher among men than women. Men aged 65-74 years with a radius/ulna fracture or vertebral fracture had substantially higher rates of subsequent femur/hip fractures than expected; SIRs were 6.0 (3.4-9.9) and 13.4 (7.3-22.5). Corresponding SIRs among women of similar age were 3.3 (2.8-3.9) and 5.8 (4.1-8.1), respectively. Men and women aged 65 years or older with a vertebral fracture had a 5-year risk of femur/hip fracture of 6.7% and 13.3%, respectively. Our results indicate that fractures at any site are strong risk factors for subsequent fractures, among both elderly men and women.

Direct medical costs attributable to osteoporotic fractures.

Abstract: Osteoporotic fractures are a major cause of morbidity in the elderly, the most rapidly growing segment of our population. We characterized the incremental direct medical costs following such fractures in a population-based cohort of men and women in Olmsted County, Minnesota. Cases included all County residents 50 years of age and older with an incident fracture due to minimal or moderate trauma between January 1, 1989 and January 1, 1992. For each case, a control of the same age (± 1 year) and sex who was attended in the local medical system in the same year was identified. Total incremental costs (cases – controls) in the year after fracture were estimated. Unit costs for each health service/procedure were obtained through the Mayo Cost Data Warehouse, which provides a standardized, inflation-adjusted estimate reflecting the national average cost of providing the service. Regression analysis was used to identify factors associated with incremental costs. There were 1263 case/control pairs; their average age was 73.8 years and 78% were female. Median total direct medical costs were $761 and $625, respectively, for cases and nonfracture controls in the year prior to fracture, and $3884 and $712, respectively, in the year following fracture. The highest median incremental costs were for distal femur ($11 756) and hip fractures ($11 241), whereas the lowest were for rib fractures ($213). Although hip fractures resulted in more incremental cost than any other fracture type, this amounted to only 37% of the total incremental cost of all moderate-trauma fractures combined. Regression analyses revealed that age, prior year costs and type of fracture were significant predictors of incremental costs (p<0.03 for all comparisons). The incremental costs of osteoporotic fractures are therefore substantial. Whereas hip fractures contributed disproportionately, they accounted for only one-third of the total incremental cost of fractures in our cohort. The use of incremental costs in economic analyses will provide a more accurate reflection of the true cost-effectiveness of osteoporosis prevention.

Incidence of limb fracture across Europe: Results from the European prospective osteoporosis study (EPOS)

Abstract: The aim of this population-based prospective study was to determine the incidence of limb fracture by site and gender in different regions of Europe. Men and women aged 50-79 years were recruited from population registers in 31 European centers. Subjects were invited to attend for an interviewer-administered questionnaire and lateral spinal radiographs. Subjects were subsequently followed up using an annual postal questionnaire which included questions concerning the occurrence of new fractures. Self-reported fractures were confirmed where possible by radiograph, attending physician or subject interview. There were 6451 men and 6936 women followed for a median of 3.0 years. During this time there were 140 incident limb fractures in men and 391 in women. The age-adjusted incidence of any limb fracture was 7.3/1000 person-years [pyrs] in men and 19 per 1000 pyrs in women, equivalent to a 2.5 times excess in women. Among women, the incidence of hip, humerus and distal forearm fracture, though not 'other' limb fracture, increased with age, while in men only the incidence of hip and humerus fracture increased with age. Among women, there was evidence of significant variation in the occurrence of hip, distal forearm and humerus fractures across Europe, with incidence rates higher in Scandinavia than in other European regions, though for distal forearm fracture the incidence in east Europe was similar to that observed in Scandinavia. Among men, there was no evidence of significant geographic variation in the occurrence of these fractures. This is the first large population-based study to characterize the incidence of limb fracture in men and women over 50 years of age across Europe. There are substantial differences in the descriptive epidemiology of limb fracture by region and gender.

How many children remain fracture-free during growth? a longitudinal study of children and adolescents participating in the Dunedin Multidisciplinary Health and Development Study.

Abstract: While much is known regarding the incidence and pattern of fractures during growth, information is sparse as to how many children fracture repeatedly and how many remain fracture-free during growth. The Dunedin Multidisciplinary Health and Development Study, a birth cohort, whose members were questioned regularly throughout growth (at ages 5, 7, 9, 11, 13, 15 and 18 years) concerning injuries including fractures, has provided a unique opportunity to answer these questions. Life-table analysis showed that approximately half the children remained fracture-free throughout growth [girls 60.1%, (95% CI 54.7–65.0) and boys 49.3% (95% CI 44.0–54.4)]. Data on fracture history, for participants seen at every phase, was available for 601 members through to the age of 18 years (61.1% of the cohort seen at age 5 years). Two hundred and ninety-one of these 601 participants reported 498 fractures, with 172 sustaining a single fracture, and 119 more than one fracture (15.8% girls and 23.4% boys). The most common site of fracture was the wrist/forearm (24.1% of all fractures). We conclude that although bone fractures are a common adverse event in childhood, half of all children remain fracture-free throughout growth.

Mandibular radiomorphometric indices in the diagnosis of reduced skeletal bone mineral density.

Abstract: Diagnosis of osteoporosis allows the delivery of preventive and therapeutic intervention and is usually achieved using bone densitometric techniques. One referral criterion for densitometry is osteopenia on radiographs. The aim of this study was to measure the validity of mandibular cortical indices measured on panoramic radiographs in the diagnosis of reduced skeletal bone density. Seventy-four women underwent bone densitometry of the femoral neck, lumbar spine and the forearm. Fifty-five patients (74%) were classified as having a reduced bone density (T-score ≤–1). Twenty-seven patients had a T-score of <–2.5 observed at one or more of the three measurement sites. A panoramic radiograph was taken of each patient and two observers made measurements of cortical thickness at the mental foramen (mental index, MI), antegonion (antegonial index, AI) and gonion (gonial index, GI) regions. Logistic regression and receiver operating characteristic (ROC) curve analyses were used to measure the validity of cortical indices in the diagnosis of reduced bone mineral density. Only MI contributed significantly to a diagnosis of low skeletal bone mineral density (T-score ≤–1). The 95% limits of agreement between observers in measurement of MI were 1.32 to +1.32 mm. When data for both observers were combined, the area under the ROC curve was 0.733 (SE = 0.072; 95% confidence interval = 0.618 to 0.83), indicating moderate accuracy. A diagnostic threshold for MI of 3 mm (or less) is suggested as the most appropriate threshold for referral for bone densitometry. However, the study provided only limited support for the use of panoramic radiomorphometric indices in diagnosing low skeletal bone mineral density. They might, questionably, be used as part of a method of osteoporosis risk assessment.

Survival and potential years of life lost after hip fracture in men and age-matched women.

Abstract: Hip fracture is associated with a higher mortality rate in men than in women. However, mean age of men and women with hip fracture differs markedly. Thus, some of the differences in the clinical pattern and outcome between genders could be related to different ages. To avoid the influence of age on gender-specific outcome, we analyzed prefracture conditions and hip fracture outcome in a cohort of men and of age-matched women. Risk factors for low bone mass were recorded in 106 men (mean age +/- SD, 80.3 +/- 9.3 years) and 264 age-matched women (mean age 81.4 +/- 8.0) with hip fracture. We compared mortality rate, survival, years of potential life lost and modification of housing conditions. These outcomes were prospectively assessed during an average 3.6 years follow-up (up to 7 years). Men with hip fracture differed from age-matched hip-fractured women by a higher alcohol and tobacco consumption, a greater frequency of living in couple, and by less prevalent fractures. Mortality rate after hip fracture was significantly higher in men (RR = 1.74, 95% CI 1.34-2.24). Since mortality is higher in the general male population, we compared reduction in life expectancy taking into account the gender-specific mortality rate. The excess mortality in each age-group of hip-fractured patients, which was measured during the whole follow-up period, and is an estimate of death attributable to fracture, did not differ between genders. Reduction in life expectancy due to hip fracture was similar in both genders (5.9 +/- 4.5 and 5.8 +/- 4.8 years, in men and women, respectively; NS), but the proportion of the years of life lost was higher in men (70 +/- 33%) than in women (59 +/- 42%, p < 0.01). It was concluded that for the same age, mortality rate after hip fracture was higher in men than in women. Although the reduction in life expectancy was similar in both genders, the proportion of the years of life lost was higher in men, suggesting a worse impact of hip fracture on survival in men, even after consideration of the higher mortality rate in the general male population.

Correlates of osteoprotegerin levels in women and men.

Abstract: Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kB ligand (RANK-L) OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD) Thus, we measured serum OPG levels in an age-stratified, random sample of men (n= 346 age range, 23–90 years) and women (n= 304; age range 21–93 years) and related them to sex steroid levels, bone turnover markers and BMD Serum OPG levels increased with age in both men (R= 039, p<0001) and women (R= 018, p<001) Premenopausal women had higher OPG levels than men under age 50 years (171 ± 6 pg/ml vs 134 ± 6 pg/ml, respectively, p<0001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 ± 7 pg/ml vs 188 ± 7 pg/ml, respectively, p= 0179) OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R=–027, p<0001), but no associations were present with either estrogen or testosterone levels in the women In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency

Processing and analysis of in vivo high-resolution MR images of trabecular bone for longitudinal studies: reproducibility of structural measures and micro-finite element analysis derived mechanical properties.

Abstract: The authors have developed a system for the characterization of trabecular bone structure from high-resolution MR images. It features largely automated coil inhomogeneity correction, trabecular bone region segmentation, serial image registration, bone/marrow binarization, and structural calculation steps. The system addresses problems of efficiency and inter- and intra-operator variability inherent in previous analyses. The system is evaluated on repetitive scans of 8 volunteers for both two-dimensional (2D) apparent structure calculations and three-dimensional (3D) mechanical calculations using micro-finite element analysis. Coil correction methods based on a priori knowledge of the coil sensitivity and on low-pass filtering of the high-resolution mages are compared and found to perform similarly. Image alignment is found to cause small but significant changes in some structural parameters. Overall the automated system provides on the order of a 3-fold decrease in trained operator time over previous manual methods. Reproducibility is found to be dependent on image quality for most parameters. For 7 subjects with good image quality, reproducibility of 2–4% is found for 2D structural parameters, while 3D mechanical parameters vary by 4–9%, with percent standardized coefficients of variation in the ranges of 15–34% and 20–38% respectively.

Biochemical indices of bone turnover and the assessment of fracture probability.

Abstract: O. Johnell, A. Odén, C. De Laet, P. Garnero, P. D. Delmas and J. A. Kanis Department of Orthopaedics, Malmö General Hospital, Malmö, Sweden; Consulting Statistician, Gothernberg, Sweden; Institute for Public Health, Erasmus MC, Rotterdam, The Netherlands; INSERM Research Unit 403, Hôpital E. Herriot, Lyon, France; and WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK

In vivo assessment of architecture and micro-finite element analysis derived indices of mechanical properties of trabecular bone in the radius.

Abstract: Measurement of microstructural parameters of trabecular bone noninvasively in vivo is possible with high-resolution magnetic resonance (MR) imaging. These measurements may prove useful in the determination of bone strength and fracture risk, but must be related to other measures of bone properties. In this study in vivo MR imaging was used to derive trabecular bone structure measures and combined with micro-finite element analysis (microFE) to determine the effects of trabecular bone microarchitecture on bone mechanical properties in the distal radius. The subjects were studied in two groups: (I) postmenopausal women with normal bone mineral density (BMD) (n = 22, mean age 58 +/- 7 years) and (II) postmenopausal women with spine or femur BMD -1 SD to -2.5 SD below young normal (n = 37, mean age 62 +/- 11 years). MR images of the distal radius were obtained at 1.5 T, and measures such as apparent trabecular bone volume fraction (App BV/TV), spacing, number and thickness (App TbSp, TbN, TbTh) were derived in regions of interest extending from the joint line to the radial shaft. The high-resolution images were also used in a micro-finite element model to derive the directional Young's moduli (E1, E2 and E3), shear moduli (G12, G23 and G13) and anisotropy ratios such as E1/E3. BMD at the distal radius, lumbar spine and hip were assessed using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed by serum osteocalcin and bone resorption by serum type I collagen C-terminal telopeptide breakdown products (serum CTX) and urinary CTX biochemical markers. The trabecular architecture displayed considerable anisotropy. Measures of BMD such as the ultradistal radial BMD were lower in the osteopenic group (p<0.01). Biochemical markers between the two groups were comparable in value and showed no significant difference between the two groups. App BV/TV, TbTh and TbN were higher, and App TbSp lower, in the normal group than the osteopenic group. All three directional measures of elastic and shear moduli were lower in the osteopenic group compared with the normal group. Anisotropy of trabecular bone microarchitecture, as measured by the ratios of the mean intercept length (MIL) values (MIL1/MIL3, etc.), and the anisotropy in elastic modulus (E1/E3, etc.), were greater in the osteopenic group compared with the normal group. The correlations between the measures of architecture and moduli are higher than those between elastic moduli and BMD. Stepwise multiple regression analysis showed that while App BV/TV is highly correlated with the mechanical properties, additional structural measures do contribute to the improved prediction of the mechanical measures. This study demonstrates the feasibility and potential of using MR imaging with microFE modeling in vivo in the study of osteoporosis.

An osteoporosis clinical pathway for the medical management of patients with low-trauma fracture.

Abstract: Patients with an osteoporotic fracture have at least a 2-fold risk for additional fracture and should benefit from targeted diagnostic and treatment procedures for osteoporosis. To address this issue, we set up an osteoporosis clinical pathway (OCP) for the medical management of patients with low-trauma fracture. Following acute management of the fracture by the orthopedic team, patients are enrolled in the pathway, which is based on an interaction between the OCP multidisciplinary team, orthopedic surgeons and/or primary care physicians. After collection of patient data, suggestions for additional diagnostic examinations with their interpretation, and treatment proposals are made. Patients and their families are also invited to attend a multidisciplinary interactive educational program on physical therapy, lifestyle habits and nutrition. During a 36-month period, 385 patients (311 women, 74 men; mean age +/- SD: 73.0 +/- 13.5 years; hip fracture 45%, ankle/tibia 24%, proximal humerus 8.6%, spine 5.5%, pelvis 3.9%, distal forearm 3.6%, other sites 17.4%) were enrolled in the OCP. An osteoporosis awareness questionnaire administered within 10 days of fracture showed that 73% of patients believed that their fracture was not related to the disease. Dual-energy X-ray absorptiometry, performed in 63% of patients, showed that 86% had low bone mass or osteoporosis. Specific antiosteoporotic therapy was proposed for 33% of patients in addition to calcium and vitamin D supplements, the latter suggested for 93%. A survey performed in 216 patients 6 months later, indicated that 63% of the suggested treatments had been prescribed and that 67% of this group were continuing treatment. Such a clinical pathway for the medical management of low-trauma fracture can help to identify patients with osteoporosis in a high-risk population, provide support to the orthopedic surgeon and/or the primary care physician for diagnostic and treatment procedures, and should significantly contribute to increase awareness of the disease in patients and their families.

Proximal femur geometry to detect and distinguish femoral neck fractures from trochanteric fractures in postmenopausal women

Abstract: Some proximal femur geometry (PFG) parameters, measured by dual-energy X-ray absorptiometry (DXA), have been reported to discriminate subjects with hip fracture. Relatively few studies have tested their ability to discriminate femoral neck fractures from those of the trochanter. To this end we performed a cross-sectional study in a population of 547 menopausal women over 69 years of age with femoral neck fractures (n = 88), trochanteric fractures (n = 93) or controls (n = 366). Hip axis length (HAL), neck-shaft angle (NSA), femoral neck diameter (FND) and femoral shaft diameter (FSD) were measured by DXA, as well as the bone mineral density (BMD) of the nonfractured hip at the femoral neck, trochanter and Ward's triangle. In fractured subjects, BMD was lower at each measurement site. HAL was longer and NSA wider in those with femoral neck fractures. With logistic regression the age-adjusted odds ratio (OR) for a 1 standard deviation (SD) decrease in BMD was significantly associated at each measurement site with femoral neck fracture (femoral neck BMD: OR 1.9, 95% confidence interval (95% CI): 1.4-2.5; trochanter BMD: OR 1.6, 95% CI 1.2-2.0; Ward's triangle BMD: OR 1.7, 95% CI 1.3-2.2) and trochanteric fracture (femoral neck BMD: OR 2.6, 95% CI 1.9-3.6; trochanter BMD: OR 3.0, 95% CI 2.2-4.1; Ward's triangle BMD: OR 1.8, 95% CI 1.4-2.3). Age-adjusted OR for 1 SD increases in NSA (OR 2.2, 95% CI 1.7-2.8) and HAL (OR 1.3, 95% CI 1.1-1.6) was significantly associated with the fracture risk only for femoral neck fracture. In the best predictive model the strongest predictors were site-matched BMD for both fracture types and NSA for neck fracture. Trochanteric BMD had the greatest area (0.78, standard error (SE) 0.02) under the receiver operating characteristic curve in trochanteric fractures, whereas for NSA (0.72, SE 0.03) this area was greatest in femoral neck fractures. These results confirm the association of BMD with proximal femur fracture and support the evidence that PFG plays a significant role only in neck fracture prediction, since NSA is the best predictive parameter among those tested.

Changes in hip fracture epidemiology: redistribution between ages, genders and fracture types.

Abstract: After several reports of increasing hip fracture incidence some studies have suggested a trend-break. In a previous study of hip fractures we forecast a 70% increase in the total number of fractures from 1985 up to year 2000. We therefore studied the incidence trend for the last 15 years and supply a new prognosis up to year 2010. We recorded all incident hip fractures treated in the county of Ostergotland, Sweden (≈ 400 000 inhabitants) 1982–96. A total of 11 517 hip fractures in men and women aged 50 years and above were included in the study after cross-validation between a computerized register of radiologic investigations and the hospital records. The projected number of fractures up to year 2010 was estimated by a Poisson regression model, considering both age and year of fracture in every single year 1982–96 for the respective fracture type and gender, and applied to the projected population. The annual number of hip fractures increased by 39% in men and 25% in women during the study period. Amongst men, the age-adjusted incidence of cervical fractures increased from 188 to 220/100 000 and of trochanteric fractures from 138 to 170/100 000. In women the incidence of cervical fractures decreased from 462/100 000 to 418/100 000 and of trochanteric fractures from 407/100 000 to 361/100 000. Cervical/trochanteric fracture incidence rate ratio leveled off, and also the female/male fracture rate ratio declined. A prognosis assuming that the incidence development will continue as during 1982–96, and a population in agreement with the forecast, predicts that the total age- and sex-adjusted number of hip fractures will decrease by 11% up to year 2010 compared with 1996. In women and men, however, a decrease of 19% and an increase of 7% respectively were projected. If the age- and sex-specific incidence remains at the same level as at the end of the study period, no significant change in the total numbers will occur. A trend-break was thus found in hip fracture incidence for women but not for men. Whether this is due to therapeutic and/or preventive measures in women is unknown. According to the most probable scenario a substantial increase in male trochanteric fractures (36%) is expected up to 2010, while all other hip fractures in both genders will decrease by 4–32% resulting in a total reduction of 11%.

Improving risk assessment: hip geometry, bone mineral distribution and bone strength in hip fracture cases and controls. The EPOS study. European Prospective Osteoporosis Study

Abstract: Hip geometry and bone mineral density (BMD) have previously been shown to relate independently to hip fracture risk. Our objective was to determine by how much hip geometric data improved the identification of hip fracture. Lunar pencil beam scans of the proximal femur were obtained. Geometric and densitometric values from 800 female controls aged 60 years or more (from population samples which were participants in the European Prospective Osteoporosis Study, EPOS) were compared with data from 68 female hip fracture patients aged over 60 years who were scanned within 4 weeks of a contralateral hip fracture. We used Lunar DPX ‘beta’ versions of hip strength analysis (HSA) and hip axis length (HAL) applied to DPX(L) data. Compressive stress (Cstress), calculated by the HSA software to occur as a result of a typical fall on the greater trochanter, HAL, body mass index (BMI: weight/(height)2) and age were considered alongside femoral neck BMD (FN-BMD, g/cm2) as potential predictors of fracture. Logistic regression was used to generate predictors of fracture initially from FN-BMD. Next age, Cstress (as the most discriminating HSA-derived parameter), HAL and BMI were added to the model as potentially independent predictors. It was not necessary to include both HAL and Cstress in the logistic models, so the entire data set was examined without excluding the subjects missing HAL measurements. Cstress combined with age and BMI provided significantly better prediction of fracture than FN-BMD used alone as is current practice, judged by comparing areas under receiver operating characteristic (ROC) curves (p<0.001, deLong’s test). At a specificity of 80%, sensitivity in identification was improved from 66% to 81%. Identifying women at high risk of hip fracture is thus likely to be substantially enhanced by combining bone density with age, simple anthropometry and data on the structural geometry of the hip. HSA might prove to be a valuable enhancement of DXA densitometry in clinical practice and its use could justify a more pro-active approach to identifying women at high risk of hip fracture in the community.

Evaluation of Osteoporosis Treatment in Seniors after Hip Fracture

Abstract: A retrospective chart review was carried out on all consecutive patients over 65 years of age admitted to a tertiary care teaching hospital with a diagnosis of a new hip fracture. A further chart review occurred after discharge from post-surgery rehabilitation. The primary objective was to evaluate the prevalence of osteoporosis diagnosis and treatment in both phases of the study. Secondary objectives included evaluation of the mortality rates, length of stay, prevalence of osteoporosis investigation, and prevalence of osteoporosis diagnosis based on the clinical subspecialty involved. There were 311 patients evaluated in the initial phase, and 226 after rehabilitation. The mortality rate was 5.8% (10% for men, 4% for women; p<0.005) in the acute care hospital and 9.3% (8% men, 10% women) during rehabilitation. Previous hip fracture occurred in 17.4%, and 1.5% were readmitted during the study period with fracture of the opposite hip. Osteoporosis was diagnosed in the acute care hospital on admission in 11.9% and on discharge in 15.4%. In the rehabilitation hospital it was diagnosed in 9.7% on admission and 11.2% on discharge (p = NS). Osteoporosis treatment (including calcium or vitamin D therapy) was instituted in 13% on admission to acute care and in 9.7% at the time of discharge. For the rehabilitation hospital, treatment occurred in 12.8% on admission and 10.2% on discharge. The diagnosis of osteoporosis significantly increased the prevalence of treatment (p<0.001). Use of specific agents (hormone replacement therapy, bisphosphonates or calcitonin) occurred in <6% of all patients. Osteoporosis is under-diagnosed and under-treated in this group of elderly hip fracture patients. It is associated with significant mortality and morbidity and every effort should be made to prevent future fractures. Physicians in the “front line” of hip fracture treatment are missing this key aspect of management in their patients. Education of these physicians, as well as the public, may be the key to addressing this care gap.

Acceptance and compliance with external hip protectors: a systematic review of the literature.

Abstract: Hip fractures may be prevented by the use of external hip protectors, but compliance is often poor. Therefore, the objective of this study was to assess the determinants of compliance with hip protectors by systematically reviewing the literature. A literature search was performed in PubMed, Embase and the Cochrane Library. Primary acceptance with hip protectors ranged from 37% to 72% (median 68%); compliance varied between 20% and 92% (median 56%). However, in most studies it was not very clear how compliance was defined (e.g., average wearing time on active days and during waking hours, number of user-days per all available follow-up days, percentage falls with hip protector) and how it was measured. To provide more insight in the compliance percentages, the different methods of defining and measuring compliance were presented for the selected studies, when provided. Because of the heterogeneity in study design of the selected studies and the lack of quantitative data in most studies, results regarding the determinants of compliance could not be statistically pooled. Instead a qualitative summary of the determinants of compliance was given. The reasons most frequently mentioned for not wearing hip protectors, were: not being comfortable (too tight/poor fit); the extra effort (and time) needed to wear the device; urinary incontinence; and physical difficulties/illnesses. In conclusion, compliance is a very complex, but important issue in hip protector research and implementation. Based on the experiences of elderly people who wear the hip protectors, adjustments should be made to the protector and the underwear, while maintaining the force attenuation capacity. Furthermore, methods to improve the compliance should be developed, and their effectiveness tested.

Use of Clinical Risk Factors in Elderly Women with Low Bone Mineral Density to Identify Women at Higher Risk of Hip Fracture: The EPIDOS Prospective Study

Abstract: Elderly women with very low bone mineral density (BMD) ( T-score

The Anabolic Effects of Parathyroid Hormone

Abstract: Several generations ago, the catabolic effects of parathyroid hormone (PTH) on the skeleton gave rise to the description of primary hyperparathyroidism as a disease of ‘bones, stones and groans’ [1,2]. The skeleton is still universally affected in severe primary hyperparathyroidism. Classical radiographic features include degranulation of the skull (so-called salt and pepper appearance), distal tapering of the clavicles, subperiosteal bone resorption of the phalanges, brown tumors and bone cysts. Both cancellous and cortical elements of the skeleton are affected with the spine (primarily cancellous bone) and the distal radius (primarily cortical bone) showing such catabolic consequences. It is this classic presentation of primary hyperparathyroidism that has given rise to the idea that PTH is bad for bones. In this review we will summarize information from an increasingly compelling set of animal and human data indicating that under certain circumstances, PTH is good for bones.

Hip Fracture Risk and Proximal Femur Geometry from DXA Scans

Abstract: In this retrospective study of hip fracture risk evaluation from hip dual-energy X-ray absorptiometry (DXA) scans, our objectives were to determine which part of the femoral neck length contributes most to the fracture risk and to define a geometric parameter better than hip axis length (HAL) for discriminating hip fracture patients. Forty-nine Caucasian women with a nontraumatic femoral neck fracture were matched on age to 49 normal women and on both age and femoral neck bone mineral density (BMD) to 49 unfractured women. In addition to BMD, geometric parameters including neck-shaft angle, neck width and several HAL segments were evaluated by discriminant analysis to determine which was the best hip fracture discriminator. Neck-shaft angle had a limited influence on the hip fracture risk. Age-related bone loss was associated with a neck width increase in unfractured and fractured patients. HAL was significantly longer in fractured patients and was a significant discriminator between fractured patients and normal controls. HAL was not significant as a discriminator between fractured and low-BMD unfractured patients. The intertrochanter-head center distance (from the intertrochanteric line to the femoral head center) coincides with the femoral lever arm and includes no segments that adapt to BMD changes, such as the greater trochanter-intertrochanter distance. Among all tested lengths, this segment was the part of HAL that discriminated best between fractured and low-BMD unfractured patients. A longer intertrochanter-head center distance increased the risk of femoral neck fracture among low-BMD patients. Including automatic measurement of this segment in standard DXA protocols may prove useful in identifying patients at high risk for hip fracture. At present, HAL remains the easier neck length to measure, but automatic evaluation of the intertrochanter-head center distance must be a goal for future image analysis development.

Prevention of early postmenopausal bone loss by strontium ranelate: the randomized, two-year, double-masked, dose-ranging, placebo-controlled PREVOS trial

Abstract: Early postmenopausal women (n = 160) were randomised to receive placebo or strontium ranelate (SR) 125 mg/day, 500 mg/day or 1 g/day for 2 years (40 participants per group). All participants received calcium 500 mg/day. The primary efficacy parameter was the percent variation in lumbar bone mineral density (BMD), measured using dual-energy X-ray absorptiometry. Secondary efficacy criteria included hip BMD and biochemical markers of bone turnover. At month 24, SR 1 g/day significantly increased lumbar BMD compared with placebo [mean (SD) +5.53% (5.12); p<0.001] for measured values and [mean (SD) +1.41% (5.33%); p<0.05] for values adjusted for bone strontium content. The annual increase for adjusted values was +0.66% compared with −0.5% with placebo, with an overall beneficial effect after 2 years of about 2.4% with SR 1 g/day relative to placebo. There were no other significant between-group differences in adjusted lumbar BMD. Femoral neck and total hip BMD were also significantly increased at month 24 with SR 1 g/day compared with placebo [mean (SD): +2.46% (4.78) and +3.21% (4.68), respectively; both p<0.001)]. SR 1 g/day significantly increased bone alkaline phosphatase at all time points (p<0.05) compared with baseline and between-group analysis showed a significant increase, compared with placebo, at month 18 (p = 0.048). No effect on markers of bone resorption was observed. SR was as well tolerated as placebo. The minimum does at which SR is effective in preventing bone loss in early postmenopausal non-osteoporotic women is therefore 1 g/day.

Digital X-ray radiogrammetry predicts hip, wrist and vertebral fracture risk in elderly women: a prospective analysis from the study of osteoporotic fractures.

Abstract: Digital X-ray radiogrammetry (DXR) is a technique that uses automated image analysis of standard hand radiographs to estimate bone mineral density (DXR-BMD). Previous studies have shown that DXR-BMD measurements have high precision, are strongly correlated with forearm BMD and are lower in individuals with prevalent fractures. To determine whether DXR-BMD measurements predict wrist, hip and vertebral fracture risk we conducted a case–cohort study within a prospective study of 9704 community-dwelling elderly women (the Study of Osteoporotic Fractures). We compared DXR-BMD, and BMD of the radius (proximal and distal), calcaneus, femoral neck and posteroanterior lumbar spine in women who subsequently suffered a wrist (n= 192), hip (n= 195), or vertebral fracture (n= 193) with randomly selected controls from the same cohort (n= 392–398). DXR-BMD was estimated from hand radiographs acquired at the baseline visit. The radiographs were digitized and the Pronosco X-posure System was used to compute DXR-BMD from the second through fourth metacarpals. Wrist fractures were confirmed by radiographic reports and hip fractures were confirmed by radiographs. Vertebral fractures were defined using morphometric analysis of lateral spine radiographs acquired at baseline and an average of 3.7 years later. Age-adjusted odds ratio (OR, vertebral fracture) or relative hazard (RH, wrist and hip fracture) for a 1 SD decrease in BMD were computed. All BMD measurements were similar for prediction of wrist (RH = 1.5–2.1) and vertebral fracture (OR = 1.8–2.5). Femoral neck BMD best predicted hip fracture (RH = 3.0), while the relative hazards for all other BMD measurements were similar (RH = 1.5–1.9). These prospective data indicate that DXR-BMD performs as well as other peripheral BMD measurements for prediction of wrist, hip and vertebral fractures. Therefore, DXR-BMD may be useful for prediction of fracture risk in clinical settings where hip BMD is not available.

New model-independent measures of trabecular bone structure applied to in vivo high-resolution MR images.

Abstract: Complementing measurements of bone mass with measurements of the architectural status of trabecular bone is expected to improve predictions of fracture risk in osteoporotic patients and improve the assessment of response to drug therapy. With high-resolution MRI the trabecular network can be imaged with 156×156×500 mm3 voxels, sufficient to depict individual trabeculae, albeit with inaccurate thickness. In this work, distance transformation techniques were applied to the three-dimensional image of the distal radius of postmenopausal patients. Structural indices such as trabecular number (app.Tb.N), thickness (app.Tb.Th) and separation (app.Tb.Sp) were determined without model assumptions. A new metric index, the apparent intra-individual distribution of separations (app.Tb.Sp.SD), is introduced. The reproducibility of the MR procedure and structure assessment was determined on volunteers, and the coefficient of variation was found to be 2.7–4.6% for the mean values of structural indices and 7.7% for app.Tb.Sp.SD. The distance transformation methods were then applied to two groups of patients: one of postmenopausal women without vertebral fracture and one of postmenopausal women with at least one vertebral fracture. It was found that app.Tb.Sp.SD discriminates fracture subjects from non-fracture patients as well as dual-energy X-ray absorptiometry (DXA) measurements of the radius and the spine, but not as well as DXA of the hip. Using receiver operating characteristic analysis, the area under the curve (AUC) values were 0.67 for app.Tb.Sp.SD, 0.72 for DXA radius, 0.67 for DXA spine and 0.81 for DXA of the hip. A combination of MR indices reached an AUC of 0.75. Age-adjusted odds ratio ranged from 1.85 to 2.03 for app.Tb.N, app.Tb.Sp and app.Tb.Sp.SD (p<0.003). We conclude that in vivo high-resolution MRI not only has the potential of imaging trabecular bone, but in combination with novel metrics may offer new insight into the structural changes occurring in postmenopausal women.

A systematic review of health state utility values for osteoporosis-related conditions.

Abstract: An important weakness of economic models in the field of osteoporosis has been the dependence on assumptions or expert judgements rather than empirical estimates for the utility values of key health events associated with osteoporosis such as hip, vertebral, wrist fracture and established osteoporosis. This paper seeks to identify the best available utility estimates for health states associated with osteoporosis and make recommendations about their use. It is based on a systematic search of the main literature databases. Studies meeting inclusion criteria have been reviewed in terms of the appropriateness of the valuation technique, the validity of the descriptive system (if one was used), the number and type of respondents, and overall quality of the study. Twenty three estimates of health state values (HSVs) were found across the four conditions from five studies. These empirical estimates were found to differ significantly from the commonly used assumptions in economic evaluation, but with a wide variation between estimates for the same state (0.32 to 0.80 for vertebral fracture states). This variation can be partly explained by the valuation technique, health state description and the background and perspective of respondent, and leaves scope for considerable discretion that could be abused. There are also problems in using values obtained from the study populations to those in economic models and the difficulty of predicting health state values in those who avoid a fracture. The review recommends a set of health state values as part of a “reference case” for use in economic models. Due to the paucity of good quality of estimates in this area, further recommendations are made regarding the design of future studies to collect HSVs relevant to economic models.