Jan Dequeker

Effect of Oral Alendronate on Bone Mineral Density and the Incidence of Fractures in Postmenopausal Osteoporosis

BACKGROUND Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. METHODS We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. RESULTS The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (+/- SE) differences in bone mineral density between the women receiving 10 mg of alendronate daily and those receiving placebo were 8.8 +/- 0.4 percent in the spine, 5.9 +/- 0.5 percent in the femoral neck, 7.8 +/- 0.6 percent in the trochanter, and 2.5 +/- 0.3 percent in the total body (P < 0.001 for all comparisons). The 5-mg dose was less effective than the 10-mg dose, and the regimen of 20 mg followed by 5 mg was similar in efficacy to the 10-mg dose. Overall, treatment with alendronate was associated with a 48 percent reduction in the proportion of women with new vertebral fractures (3.2 percent, vs. 6.2 percent in the placebo group; P = 0.03), a decreased progression of vertebral deformities (33 percent, vs. 41 percent in the placebo group; P = 0.028), and a reduced loss of height (P = 0.005) and was well tolerated. CONCLUSIONS Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebral deformities, and height loss in postmenopausal women with osteoporosis.

Direct three-dimensional morphometric analysis of human cancellous bone : microstructural data from spine, femur, iliac crest and calcaneus

The appearance of cancellous bone architecture is different for various skeletal sites and various disease states. During aging and disease, plates are perforated and connecting rods are dissolved. There is a continuous shift from one structural type to the other. So traditional histomorphometric procedures, which are based on a fixed model type, will lead to questionable results. The introduction of three‐dimensional (3D) measuring techniques in bone research makes it possible to capture the actual architecture of cancellous bone without assumptions of the structure type. This requires, however, new methods that make direct use of the 3D information. Within the framework of a BIOMED I project of the European Union, we analyzed a total of 260 human bone biopsies taken from five different skeletal sites (femoral head, vertebral bodies L2 and L4, iliac crest, and calcaneus) from 52 donors. The samples were measured three‐dimensionally with a microcomputed tomography scanner and subsequently evaluated with both traditional indirect histomorphometric methods and newly developed direct ones. The results show significant differences between the methods and in their relation to the bone volume fraction. Based on the direct 3D analysis of human bone biopsies, it appears that samples with a lower bone mass are primarily characterized by a smaller plate‐to‐rod ratio, and to a lesser extent by thinner trabecular elements.

Incidence of vertebral fracture in europe: results from the European Prospective Osteoporosis Study (EPOS).

Vertebral fracture is one of the major adverse clinical consequences of osteoporosis; however, there are few data concerning the incidence of vertebral fracture in population samples of men and women. The aim of this study was to determine the incidence of vertebral fracture in European men and women. A total of 14,011 men and women aged 50 years and over were recruited from population‐based registers in 29 European centers and had an interviewer‐administered questionnaire and lateral spinal radiographs performed. The response rate for participation in the study was approximately 50%. Repeat spinal radiographs were performed a mean of 3.8 years following the baseline film. All films were evaluated morphometrically. The definition of a morphometric fracture was a vertebra in which there was evidence of a 20% (+4 mm) or more reduction in anterior, middle, or posterior vertebral height between films—plus the additional requirement that a vertebra satisfy criteria for a prevalent deformity (using the McCloskey‐Kanis method) in the follow‐up film. There were 3174 men, mean age 63.1 years, and 3614 women, mean age 62.2 years, with paired duplicate spinal radiographs (48% of those originally recruited to the baseline survey). The age standardized incidence of morphometric fracture was 10.7/1000 person years (pyr) in women and 5.7/1000 pyr in men. The age‐standardized incidence of vertebral fracture as assessed qualitatively by the radiologist was broadly similar—12.1/1000 pyr and 6.8/1000 pyr, respectively. The incidence increased markedly with age in both men and women. There was some evidence of geographic variation in fracture occurrence; rates were higher in Sweden than elsewhere in Europe. This is the first large population‐based study to ascertain the incidence of vertebral fracture in men and women over 50 years of age across Europe. The data confirm the frequent occurrence of the disorder in men as well as in women and the rise in incidence with age.

Risk Factors for Hip Fracture in Men from Southern Europe: The MEDOS Study

Abstract: The aims of this study were to identify risk factors for hip fracture in men aged 50 years or more. We identified 730 men with hip fracture from 14 centers from Portugal, Spain, France, Italy, Greece and Turkey during the course of a prospective study of hip fracture incidence and 1132 age-stratified controls selected from the neighborhood or population registers. The questionnaire examined aspects of work, physical activity past and present, diseases and drugs, height, weight, indices of co-morbidity and consumption of tobacco, alcohol, calcium, coffee and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), low sunlight exposure, a low degree of recreational physical activity, low consumption of milk and cheese, and a poor mental score. Co-morbidity including sleep disturbances, loss of weight, impaired mental status and poor appetite were also significant risk factors. Previous stroke with hemiplegia, prior fragility fractures, senile dementia, alcoholism and gastrectomy were associated with significant risk, whereas osteoarthrosis, nephrolithiasis and myocardial infarction were associated with lower risks. Taking medications was not associated with a difference in risk apart from a protective effect with the use of analgesics independent of co-existing osteoarthrosis and an increased risk with the use of anti-epileptic agents. Of the potentially ‘reversible’ risk factors, BMI, leisure exercise, exposure to sunlight and consumption of tea and alcohol and tobacco remained independent risk factors after multivariate analysis, accounting for 54% of hip fractures. Excluding BMI, 46% of fractures could be explained on the basis of the risk factors sought. Of the remaining factors low exposure to sunlight and decreased physical activity accounted for the highest attributable risks (14% and 9% respectively). The use of risk factors to predict hip fractures had relatively low sensitivity and specificity (59.6% and 61.0% respectively). We conclude that lifestyle factors are associated with significant differences in the risk of hip fracture. Potentially remediable factors including a low degree of physical exercise and a low BMI account for a large component of the total risk.

The variable incidence of hip fracture in southern Europe: the MEDOS Study.

We assessed the incidence of hip fracture and ecological correlates in residents of 14 communities in six countries of Southern Europe. Hip fracture cases were recorded prospectively in defined catchment areas over a 1-year interval. A retrospective questionnaire was used to assess ecological differences between communities. During a 1-year period of observation a total of 3629 men and women over the age of 50 years were identified with hip fracture from a catchment of 3 million. In all communities the fracture rate increased exponentially with age. There were large and significant differences between centres in the doubling time for hip fracture risk with age and in crude and age-standardized rates. Greater than 4-fold and 13-fold differences in age-standardized risk were found amongst men and women respectively. The lowest rates were observed from Turkey and the highest from Seville, Crete and Porto. Fractures were significantly more frequent among women than men with the exception of three rural Turkish centres. Indeed, in rural Turkey the normal female/male ratio was reserved. Variations in incidence between regions were greater than the differences within centres between sexes, and there was a close and significant correlation between incidence rates for men and those for women in the regions studied. Excess female morbidity increased progressively from the age of 50 years but attained a plateau after the age of 80 years, suggesting a finite duration of the effect of the menopause. The retrospective questionnaire completed by 80% of cases suggested that differences in incidence between the communities studied could not be explained by differences in gonadal status in women. In both men and women cross-cultural associations were found with factors related to age or socioeconomic prosperity, the majority of which disappeared after adjustment for age. We conclude that there are marked and sizeable differences in the incidence rates of hip fracture throughout Southern Europe. The reasons for these differences are not known but affect both men and women, and are likely to be related to lifestyle or genetic factors rather than to differences in endocrine status.

Assessment of the strength of proximal femur in vitro : Relationship to femoral bone mineral density and femoral geometry

Femoral neck axis length, neck width, and neck-shaft angle were measured on radiographs of right proximal femora from 64 cadavers (28 female, 36 male). Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DXA) for various regions of interest, and quantitative computed tomography (QCT) was used to determine BMD and bone areas for cortical and trabecular bone at the trochanter and femoral neck. The strength of the femur was determined by a mechanical test simulating a fall on the greater trochanter, and the fracture type (cervical or trochanteric) was subsequently determined from radiographs. Twenty-six cervical fractures and 38 trochanteric fractures were observed, with no significant sex difference in the distribution of fracture types. Femoral strength was significantly elevated in males compared to females. DXA trochanteric BMD was more strongly (p < 0.05) correlated with femoral strength (r2 = 0.88) than were any of the other DXA BMD measurements (r2 = 0.59-0.76). In multiple regression models, a combination of different DXA BMD measurements produced only a small increase (1%) in the explained variability of femoral strength. Of the QCT measurements, trochanteric cortical area yielded the optimal correlation with femoral strength (r2 = 0.83). Weak, but significant, correlations were observed between femoral strength and cortical BMD at trochanteric (r2 = 0.28) and neck regions (r2 = 0.07). In multiple regression models, combining QCT parameters yielded, at best, an r2 of 0.87. Of the geometrical parameters, both neck axis length and neck width were significantly correlated with femoral strength (r2 = 0.24, 0.22, respectively), but no significant correlation was found between strength and the neck-shaft angle. Combining DXA trochanteric BMD with femoral neck width resulted in only a small increase in the explained variability (1%) compared to trochanteric BMD alone. The results demonstrated that DXA and QCT had a similar ability to predict femoral strength in vitro. Trochanteric BMD was the best DXA parameter, and cortical area (not cortical BMD) was the optimal QCT parameter. Geometric measurements of the proximal femur were only weakly correlated with the mechanical strength, and combinations of DXA, QCT, and geometric parameters resulted in only small increases in predictive power compared to the use of a single explanatory variable alone.

Determinants of incident vertebral fracture in men and women: results from the European Prospective Osteoporosis Study (EPOS)

Abstract The aim of this analysis was to determine the influence of lifestyle, anthropometric and reproductive factors on the subsequent risk of incident vertebral fracture in men and women aged 50–79 years. Subjects were recruited from population registers from 28 centers across Europe. At baseline, they completed an interviewer-administered questionnaire and had lateral thoraco-lumbar spine radiographs performed. Repeat spinal radiographs were performed a mean of 3.8 years later. Incident vertebral fractures were defined morphometrically and also qualitatively by an experienced radiologist. Poisson regression was used to determine the influence of the baseline risk factor variables on the occurrence of incident vertebral fracture. A total of 3173 men (mean age 63.1 years) and 3402 women (mean age 62.2 years) contributed data to the analysis. In total there were 193 incident morphometric and 224 qualitative fractures. In women, an age at menarche 16 years or older was associated with an increased risk of vertebral fracture (RR=1.80; 95%CI 1.24, 2.63), whilst use of hormonal replacement was protective (RR=0.58; 95%CI 0.34, 0.99). None of the lifestyle factors studied including smoking, alcohol intake, physical activity or milk consumption showed any consistent associations with incident vertebral fracture. In men and women, increasing body weight and body mass index were associated with a reduced risk of vertebral fracture though, apart from body mass index in men, the confidence intervals embraced unity. For most variables the strengths of the associations observed were similar using the qualitative and morphometric approaches to fracture definition. In conclusion our data suggest that modification of other lifestyle risk factors is unlikely to have a major impact on the population occurrence of vertebral fractures. The important biological mechanisms underlying vertebral fracture risk need to be explored using new investigational strategies.

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.

Osteoarthritis and osteoporosis: Clinical and research evidence of inverse relationship

The etiology of osteoporosis (OP) and osteoarthritis (OA) is multifactorial: both constitutional and environmental factors, ranging from genetic susceptibility, endocrine and metabolic status, to mechanical and traumatic injury, are thought to be involved. When interpreting research data, one must bear in mind that pathophysiologic factors, especially in disorders associated with aging, must be regarded as either primary or secondary. Therefore, findings in end-stage pathology are not necessarily the evidence or explanation of the primary cause or event in the diseased tissue. Both aspects of research are important for potentially curative or preventive measures. These considerations, in the case of our topic — the inverse relationship of OP and OA — are of particular importance. Although the inverse relationship between two frequent diseases associated with aging, OA and OP, has been observed and studied for more than 30 years, the topic remains controversial for some and stimulating for many. The anthropometric differences of patients suffering from OA compared with OP are well established. OA cases have stronger body build and are more obese. There is overwhelming evidence that OA cases have increased BMD or BMC at all sites. This increased BMD is related to high peak bone mass, as shown in mother-daughter and twin studies. With aging, the bone loss in OA is lower, except when measured near an affected joint (hand, hip, knee). The lower degree of bone loss with aging is explained by lower bone turnover as measured by bone resorption-formation parameters. OA cases not only have higher apparent and real bone density, but also wider geometrical measures of the skeleton, diameters of long bones and trabeculae, both contributing positively to better strength and fewer fragility fractures. Not only is bone quantity in OA different but also bone quality, compared with controls and OP cases, with increased content of growth factors such as IGF and TGFβ, factors required for bone repair. Furthermore, in vitro studies of osteoblasts recruited from OA bone have different differentiation patterns and phenotypes. These general bone characteristics of OA bone may explain the inverse relationship OA-OP and why OA cases have fewer fragility fractures. The role of bone, in particular subchondral bone, in the pathophysiology, initiation and progression of OA is not fully elucidated and is still controversial. In 1970, it was hypothesized that an increased number of microfractures lead to an increase in subchondral bone stiffness, which impairs its ability to act as a shock absorber, so that cartilage suffers more. Although subchondral bone is slightly hypomineralized because of local increased turnover, the increase in trabecular number and volume compensates for this, resulting in a stiffer structure. There is also some experimental evidence that osteoblasts themselves release factors such as metalloproteinases directly or indirectly from the matrix, which predispose cartilage to deterioration. Instead, the osteoblast regenerative capacity of bone in OP is compromised compared with OA, as suggested by early cell adhesion differences. The proposition that drugs which suppress bone turnover in OP, such as bisphosphonates, may be beneficial for OA is speculative. Although bone turnover in the subchondral region of established OA is increased, the general bone turnover is reduced. Further reduction of bone turnover, however, may lead to overmineralized (aged) osteons and loss of bone quality, resulting in increased fragility.

The European Spine Phantom: a tool for standardization and quality control in spinal bone mineral measurements by DXA and QCT

The lack of standardization in bone mineral measurements of the lumbar spine and other skeletal sites is generally recognized as an important and unresolved issue. We report and discuss efforts at standardization and cross-calibration of DXA and QCT equipment. We have designed and tested a geometrically defined, semi-anthropomorphic phantom, the European Spine Phantom (ESP). It contains a spine insert consisting of three vertebrae of increasing bone mineral densities and thicknesses of cortical structures; the respective parameters are given in tabular form for the final phantom design. Results for cross-calibration with the ESP compare well with patient results. Measurements on the first 30 phantoms confirmed that the ESP can be manufactured with a variation of about 1%. We conclude that the ESP is suitable for daily quality assurance, cross-calibration of instruments and universal standardization. The ESP was used to establish standardized BMD (sBMD) units for DXA equipment going into effect in late 1995. Its acceptance by manufacturers as a calibration standard for DXA and QCT measurements appears imminent.