Piet Geusens

Genetic determinants of bone mineral content at the spine and radius: A twin study

The possible role of genetic and/or environmental factors in determining bone mass has been investigated in 30 pairs of twins (16 monozygotic and 14 dizygotic) divided in two age groups (below and above 25 years of age). Bone mineral content was evaluated by single- and dual photon absorptiometry at the distol third of the radius for peripheral cortical bone and in the lumbar spine for the axial bone. The within pair variance has been used as an index of genetic influence. A significant (p less than 0.01) genetic determinant was found for the bone mass of the radius in adults and for the spinal bone mass in the age group younger than 25 years. The heritability index h2 was 0.75 for cortical BMC and 0.88 for axial BMC. Such a genetic determinant could not conclusively be demonstrated in adult twins for the spine and in youngsters for the cortical bone, suggesting that environmental factors may play a more dominant role in growth of cortical bone during adolescence and diminution of axial bone during adult life.

Age-Related (Type II) Femoral Neck Osteoporosis in Men: Biochemical Evidence for Both Hypovitaminosis D– and Androgen Deficiency–Induced Bone Resorption

The problem of osteoporosis in men has recently been recognized as an important public health issue. To test the hypothesis that endocrine deficiency–mediated alterations in bone metabolism might contribute to osteoporotic fracture risk in elderly men, serum levels of 25‐hydroxycholecalciferol (25(OH)D), 1,25‐dihydroxycholecalciferol (1,25(OH)2D), intact parathyroid hormone (PTH), testosterone, and estradiol were measured in 40 males (mean age 73 years) who were consecutively recruited within 18 h following a fracture of the proximal femur, and in an equal number of community‐living older men (mean age 72 years) who served as controls. In addition, circulating osteocalcin and urinary excretion of (deoxy)pyridinoline were determined as markers of bone formation and resorption, respectively. No differences were observed between the mean serum concentrations of osteocalcin and estradiol. Serum levels of 25(OH)D, 1,25(OH)2D, and testosterone, however, were decreased in hip fracture patients. When correcting for differences in vitamin D binding protein, differences in 1,25(OH)2D did not persist, whereas serum 25(OH)D was still significantly lower in patients than in controls (6.1 ± 4.3 vs. 7.6 ± 2.8, p = 0.01). Similarly, a highly significant deficit was observed in the free testosterone index, calculated from total testosterone and the level of sex hormone binding globulin (2.6 ± 1.3 vs. 8.2 ± 2.9, p < 0.001). Serum PTH and urinary pyridinium cross‐links, however, were markedly increased in the fracture group. Moreover, in fracture patients, free 25(OH)D and free testosterone were both significant and mutually independent negative predictors of (deoxy)pyridinoline excretion. Although limited by its cross‐sectional design, the present study suggests that both hypovitaminosis D and androgen deficiency may predispose to bone resorption in elderly men and in turn to remodeling imbalance and fracture risk.

Aging of the thoracic spine: Distinction between wedging in osteoarthritis and fracture in osteoporosis—A cross-sectional and longitudinal study

Thoracic kyphosis is clinically associated with osteoporosis as well as with osteoarthritis. Because misinterpretation of thoracic spine deformities on X-rays may lead to overdiagnosis of vertebral fracture, we studied morphological changes of the thoracic spine in a cross-sectional (n = 89) and longitudinal study (n = 38) in 30 women with established osteoporosis (OP), in 31 women with spinal osteoarthritis (OA), and in 28 normal women. Vertebral deformation was assessed on lateral roentgenograms of the thoracic spine from T-4-T-12. The anterior, middle, and posterior heights were measured using six points corresponding to the four corners of the vertebral body excluding osteophytes and the midpoints of the endplates. For the thoracic T-6-T-9 region, the mean anterior/posterior height ratio was 7.7% in the controls, 13% in osteoarthritis, and 21% in osteoporosis. For the mid-height/posterior height ratio the respective values were 13%, 12%, and 22%. The osteoporosis group differed significantly from the control and osteoarthritis group in anterior and in midheight reduction. The yearly mean anterior height reduction in the osteoarthritis group was 0.7% compared with 1.5% in the osteoporosis group. The mean yearly midheight reduction was, respectively, 0.5% versus 2.9%. The differences between the groups were significant. We conclude that vertebral deformity, in particular wedging, of the thoracic spine is not exclusively characteristic for osteoporosis and that certain vertebral deformities develop by mechanisms other than fracture. Osteoporotic fracture of the thoracic spine is characterized by an exaggerated reduction of the midheight to posterior height in addition to reduction of the anterior to posterior height.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-linear increase in vertebral density induced by a synthetic steroid (Org OD 14) in women with established osteoporosis

The results of a 2-year placebo-controlled study in 38 female patients with osteoporosis are presented. This study was conducted to evaluate the efficacy of a daily oral dose of 2.5 mg Org OD 14 ((7 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) in the treatment of established osteoporosis. Org OD 14 is a steroid which shows combined weak oestrogenic, androgenic and progestational activity. A total of 31 patients completed a 12-month study period (17 placebo, 14 Org OD 14) and 25 of these went on to complete the full 24-months (15 placebo, 10 Org OD 14). A significant increase in bone mineral density as measured by dual photon absorptiometry was recorded in the lumbar spine in the Org OD 14-treated patients at 8, 16 and 24 months. The gain in bone mass after 8 months averaged 4% (P less than 0.01) and after 24 months 8% (P less than 0.001). In the control group, a bone loss rate of 2% per year was recorded in the lumbar spine. No significant changes in bone density in the forearm as assessed by single photon absorptiometry were found in either group. The increase in spinal bone density in the Org OD 14 group was non-linear and followed an S-shaped upward pattern. Org OD 14, while inducing no appreciable endometrial stimulation, was found to be a bone-active compound with anti-resorbing as well as anabolic activity. Org OD 14 warrants consideration not only for the long-term prevention of bone loss but also for curative treatment of post-menopausal osteoporosis.

Mechanical properties, bone mineral content, and bone composition (collagen, osteocalcin, IGF-I) of the rat femur: Influence of ovariectomy and nandrolone decanoate (anabolic steroid) treatment

SummaryNandrolone decanoate (ND) is an anabolic steroid with a positive effect on bone mass in osteoporotic patients. The mechanism of action, (i.e., reduction of bone resorption and/or Stimulation of bone formation), the ultimate effect on mechanical properties, and the most effective dosage are not yet clear. To address these issues, dose-related effects of the long-term effect of ND on Serum and bone biochemistry, bone mineral content, and bone mechanical properties in ovariectomized (OVX) rats (12 weeks old at the Start of the experiment) were Studied for 6 months. The results were compared with those obtained in agematched, intact, and OVX rats. OVX caused in the femur a significant increase in net periosteal bone formation and net endosteal bone resorption of bone collagen content and torsional strength, and of Serum alkaline phosphatase, osteocalcin, and insulin-like growth factor-I (IGF-I) levels, whereas cortical bone density and calcium/creatinine and phosphorus/creatinine in 24-hour urine were Significantly reduced.Treatment of OVX rats with 1 mg ND/14 days resulted in a Significant increase in periosteal bone formation, femur length, cortical and trabecular bone mineral content and density, torsion stiffness and Strength, and bone IGF-I content, and a decrease in Serum osteocalcin, urinary calcium/creatinine levels, and bone collagen content compared with OVX controls. The higher ND dosage of 2.5 mg/14 days did not improve the results. ND treatment did not reverse all changes induced by OVX to the level of the intact controls.These results indicate that ND acts as an antiresorptive drug and as a bone formation Stimulating drug. Furthermore, the increased bone mass and bone mineral density is associated with improved bone Strength and stiffness and the presence of an increased amount of IGF-I. IGF-I is a growth factor considered to play a role in the maintenance of normal skeletal balance by a paracrine or autocrine mechanism.

Physical and histomorphological characteristics of iliac crest bone differ according to the grade of osteoarthritis at the hand

The amount of cortical and trabecular bone was studied in 32 iliac crest necropsy specimens from women 60-75 years of age and examined according to the grade of osteoarthritis. Three different methods to evaluate bone mass were used: dual photon absorptiometry, physical assessment according to Archimedes principle, and histomorphometry. Patients were divided into groups--with or without osteoarthritis--according to the presence of osteoarthritis on hand x rays. A significantly increased amount of cortical and trabecular bone mass was found in those who had osteoarthritis at the hands. Percent pure/crude bone volume and trabecular width were found to be increased with osteoarthritic grade, indicating that primary osteoarthritis is probably part of a generalized bone disease.

The Aged Male Rat as a Model for Human Osteoporosis: Evaluation by Nondestructive Measurements and Biomechanical Testing

SummaryEffects of androgen deficiency and androgen replacement on bone density, as measured with dual-energy X-ray absorptiometry (DXA) and single photon absorptiometry (SPA), cortical ratio (cortical thickness/outside bone diameter x 100), and biomechanical properties were evaluated in 14-month-old (1 month after orchiectomy (orch) or sham-operation) and in 17-month-old (4 months after orch or sham) male rats. Whole femoral bone mineral content (BMC) and density (BMD) measured with DXA were not significantly decreased 1 month after orch. Whole femoral BMC and BMD were 10% and 8% lower in 4 months after orch (P < 0.01 andP < 0.001, respectively). This decrease was prevented by testosterone replacement. There was an excellent correlation (R = 0.99) between whole femoral BMC and femoral ash weight. Selective scanning of cortical and cancellous sites of the femur showed that both cancellous and cortical BMC and BMD were significantly decreased 4 months after orch. SPA of the right tibia confirmed a 7% decrease in cancellous BMC and BMD 4 months after orch (preventable by testosterone) but not in cortical BMD and BMC. Femoral cortical ratio decreased with age (47 ± 2 in 14-month-old and 40 ± 2 in 17-month-old sham rats versus 63 ± 1 in 6-month-old male rats) due to a continuously enlarging femoral shaft. Androgen deficiency resulted in an even greater decrease of the cortical ratio 4 months after orch (36 ± 2 in 17-month-old orch rats) that was again prevented by testosterone (47 ± 3). These changes in femoral cortical, cancellous density, and cortical ratio did not affect biomechanical properties of the femur as evaluated by torsion testing. The lack of an effect on bone biomechanics was most likely due to the protection afforded by an increased femoral shaft diameter. We conclude that 4 months after orch, aged male orch rats had a lower femoral cortical and cancellous density and a lower cortical ratio without decrease of biomechanical properties of the femoral shaft. Testosterone replacement was effective not only in preventing the decrease of cancellous and cortical density but also in preventing the age-related thinning of the femoral cortex.

Timing and quantification of bone loss in cardiac transplant recipients

To evaluate osteopenic bone disease in heart transplant patients, we prospectively measured bone mineral density (BMD) in 33 consecutive male recipients before hospital discharge and 1 year later, using dual photon absorptiometry. At hospital discharge BMD measurement at the lumbar spine was only 90% of that expected in healthy age- and sex-matched controls (P=0.005). One year later BMD had further decreased by 8.5% at the lumbar spine and by 10.4% at the femoral neck (P=0.0001). Five patients suffered vertebral compression fractures during the 1st post-operative year. Our results indicate that osteopenia of the lumbar spine is already present at the time of hospital discharge after transplantation and that further bone loss occurs at a considerable rate during the 1st postoperative year at the lumbar spine and at the femoral neck.

Dual X-ray absorptiometry—cross-calibration and normative reference ranges for the spine: Results of a European Community Concerted Action

Bone density measurements by dual X-ray absorptiometry (DXA) of the spine can now be made precisely, but there is no uniformity in reporting results and in presenting reference data. A European Union Concerted Action therefore devised a uniform procedure for cross-calibrating and standardizing instruments, using the European spine phantom (ESP) prototype. This phantom differs in a number of respects from the final version of the ESP. Eighteen centers in nine countries obtained 1619 records (1035 women) from Caucasian subjects, aged 20-80 years, drawn from normal populations. The DXA machines used were made by the Hologic, Lunar, and Norland companies. Highly statistically significant differences were evident between populations, both in apparent rates of bone loss with age and in the spread of values about the age-adjusted means. There were small residual differences in the results obtained with the three machine brands which could have been due to the relatively large between-center population differences we observed. The alternative or additional explanation that they were attributable, in part, to the design differences between the ESP prototype and the definitive ESP, which became available after this study was completed, was shown to be a valid possibility. Results from postmenopausal women reported in relation to the years that have elapsed since menopause showed reduced population variance when compared with conventional reporting in relation to age. After cross-calibration, the center with the highest age-adjusted normal density value averaged 23% more than the center with the lowest. It is therefore crucially important to select appropriate reference data in clinical and epidemiological studies.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation between resonant frequencies and torsional stiffness of long bones in vitro. Validation of a simple beam model.

The results of vibration analysis experiments and impact torsion tests performed on excised animal long bones were used to validate a simple beam model for the prediction of torsional stiffness from resonant frequencies. Resonant frequency data on two mutually perpendicular bending vibration modes of 142 excised long bones were evaluated. Torsional stiffness of the same bones had been determined by an impact torsion test. Using a simple beam model, a theoretical relation between resonant frequencies and torsional stiffness was derived. If total bone mass and bone length are known, the formula thus derived allows one to calculate torsional stiffness from resonant frequencies. Linear regression analysis shows a strong correlation between the measured and the calculated torsional stiffness for sheep femora (r2 = 0.63, n = 24), dog femora (r2 = 0.94, n = 34), dog tibiae (r2 = 0.79, n = 18) and monkey radii (r2 = 0.77, n = 66). It was found that this linear relation was valid not within one bone type alone. Linear regression analysis on the combined data of all bones demonstrated that all bones obeyed the same global linear relation between measured and the calculated torsional stiffness (r2 = 0.98, n = 142). This implies that one and the same beam model is valid for the different bone types investigated. The calculation of stiffness from resonant frequencies, however, requires total bone mass, m, and length to be known. In view of in vivo applications, the feasibility of using total bone mineral content (TBMC) as a measure for m was investigated.(ABSTRACT TRUNCATED AT 250 WORDS)