Bone Changes due to Glucocorticoid Application in an Ovariectomized Animal Model for Fracture Treatment in Osteoporosis

In a pilot experiment comparing four different modalities for inducing osteoporosis in the sheep, a combination of ovariectomy, calcium/vitamin D-restricted diet and steroid administration was found to generate the highest decrease in bone mineral density (BMD). The aim of the present study was to quantify the outcome of this triple treatment in an animal model of osteoporosis in terms of alteration in bone mass, bone structure and bone mechanics. A total of 32 sheep were divided into two equal groups. Group 1 (age 3–5 years) was used as a normal control. Group 2 (age 7–9 years) was ovariectomized, fed a calcium/vitamin D-restricted diet and injected with methylprednisolone (MP) over 7 months (22 weeks MP solution, 6 weeks MP suspension). The BMD at the distal radius and tibia was determined preoperatively and at repeated intervals bilaterally using quantitative computed tomography. Steroid blood levels were determined 4 and 24 h after selected injections. BMD was measured at L3 and L4 after 7 months. Biopsies were taken from iliac crests, vertebral bodies and femoral heads, and bone structure parameters investigated by three-dimensional micro-CT. Compressive mechanical properties of cancellous bone were determined from biopsies of vertebral bodies and femoral heads. After 7 months of osteoporosis induction the BMD of cancellous bone decreased 36 ± 3% in the radius and 39 ± 4% in the tibia. Steroid blood levels 24 h after injection of MP suspension were significantly higher than after injection of MP solution. Changes in structural parameters of cancellous bone from the iliac crest, lumbar spine and femoral head in group 2 indicated osteoporosis-associated changes. In group 2 there was a significant reduction in BMD of the lumbar spine and a significant reduction in stiffness and failure load in compression testing of biopsies of lumbar vertebrae. In sheep, changes in the structural parameters of bone such as trabecular number and separation during osteoporosis induction are comparable to the human situation. The sheep model presented seems to meet the criteria for an osteoporosis model for fracture treatment with respect to mechanical and morphometric bone properties. Received: 4 May 2001 / Accepted: 6 December 2001     

Sheep model for fracture treatment in osteoporotic bone: a pilot study about different induction regimens

OBJECTIVE: Various regimens to induce osteoporosis in sheep were compared to establish a large animal model for further studies of fracture healing and fracture treatment in severe osteoporosis. DESIGN: Prospective, randomized animal study (six months' duration). PARTICIPANTS: Eight sheep (seven to nine years old) were divided into four treatment groups of two animals each. INTERVENTION: Group 1: Ovariectomy (OVX) + calcium/vitamin D-restricted diet (O + D); Group 2: Ovariectomy + daily injection of steroids (O + S); Group 3: Ovariectomy + daily injection of steroids + calcium/vitamin D-restricted diet (O + D + S); Group 4: Control, untreated. MAIN OUTCOME MEASUREMENTS: Preoperatively and every 2 months, the bone mineral density (BMD) was determined by quantitative computed tomography (QCT) bilaterally at the distal tibia. Bone structural parameters were determined from iliac crest biopsy specimens using micro-CT. In vitro torsional stiffness of tibia segments was measured. RESULTS: The control group showed a slight increase in BMD with time. The greatest decrease in BMD was seen in Group 3, with a decrease of 55 percent in cancellous bone and 7 percent in cortical bone. In the iliac crest biopsy specimens, trabecular number decreased 19 percent, trabecular thickness decreased 22 percent, and bone volume fraction decrased 37 percent during the 6 months. The torsional strength and stiffness of the tibia showed a difference of approximately 50 percent between Group 3 and the control group. CONCLUSIONS: The induction of severe osteoporosis in sheep is best possible by combined treatment with ovariectomy, calcium/vitamin D-restricted diet, and steroids. There is a good relationship between density, structural parameters, and mechanical properties of bone.     

Trabecular Bone Architecture in the Distal Radius Using Magnetic Resonance Imaging in Subjects with Fractures of the Proximal Femur

To determine whether magnetic resonance (MR)-derived measures of trabecular bone architecture in the distal radius are predictive for prevalent hip fractures, 20 subjects with hip fractures and 19 age-matched postmenopausal controls were studied. Bone mineral density (BMD) measures at the hip (dual-energy X-ray absorptiometry, DXA) and the distal radius (peripheral quantitative computed tomography, pQCT) were also obtained. We compared the MR-based structural measures derived in the radius with those in the calcaneus of the same patients. In the radius, images were acquired at an in-plane resolution of 156 μm and a slice thickness of 0.5 mm. Stereologic measures such as the apparent trabecular thickness (app. Tb.Th), fractional trabecular bone volume (app. BV/TV), trabecular spacing (app. Tb.Sp) and trabecular number (app. Tb.N) were derived from the images. Measures of app. Tb.Sp and app. Tb.N in the distal radius showed significant (p<0.05) differences between the two groups, as did hip BMD measures. However, radial trabecular BMD measures showed only a marginal difference (p= 0.05). Receiver operating curve analysis was used to determine the diagnostic efficacy of BMD, structural measures and a combination of the two. The area under the curve (AUC) for total hip BMD was 0.73, and for radial trabecular BMD was 0.69. AUC for most of the measures of trabecular bone structure at the distal radius was lower than for hip BMD measures; however, AUC for app. Tb.N at the radius was 0.69, comparable to trabecular BMD using pQCT. The AUC for combined BMD (hip) and structure measures was higher (0.87) when radius and calcaneus structure was included. Measures of trabecular architecture derived from MR images combined with BMD measures improve the discrimination between subjects with hip fractures and normal age-matched controls. Received: 22 December 1998 / Accepted: 12 February 1999     

Contact Quantitative Ultrasound: An Evaluation of Precision, Fracture Discrimination, Age-Related Bone Loss and Applicability of the WHO Criteria

The aim of this study was to assess a dry calcaneal quantitative ultrasound (QUS) device by examining: (i) short- and long-term precision; (ii) the ability of the ultrasound parameters to identify women with vertebral fractures; (iii) age- and menopause-related bone loss; (iv) applicability of the WHO criteria in scan interpretation. The study group consisted of 422 healthy women with no risk factors associated with osteoporosis (227 premenopausal and 195 postmenopausal) and 93 women with one or more vertebral fractures. All women had calcaneal QUS and bone mineral density (BMD) measurements of the lumbar spine and hip performed. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements in the heel were combined and expressed as estimated heel BMD. Short-term precision studies yielded coefficient of variations of 0.3% for SOS, 4% for BUA and 3.3% for estimated heel BMD. Standardized short-term precision values were approximately 0.2 SD. Long-term standardized precision errors ranged from 0.17 to 0.38 SD. All the QUS and BMD measurement parameters showed significant negative relationships with age in the postmenopausal group. Annual losses were 0.35 dB/MHz per year for BUA, 0.56 m/s per year for SOS and 0.002 g/cm² per year for estimated heel BMD. All the QUS and BMD parameters were able to discriminate between healthy postmenopausal women and women with vertebral fracture. Age-adjusted odds ratios for each SD decline in QUS measurements were 3.63, 5.25 and 4.79 for BUA, SOS and estimated heel BMD respectively. Corresponding odds ratios for BMD at the lumbar spine, femoral neck and total hip were 2.39, 2.51 and 2.95 respectively. When the QUS and BMD parameters were expressed as T-scores, estimated heel BMD showed the least age-related decline, while femoral neck BMD displayed the greatest decrease with age. The mean T-score and prevalence of osteoporosis (T<−2.5) for a Caucasian woman aged 60–65 years were −1.35 and 21% respectively for the lumbar spine compared with −0.59 and 2% for estimated heel BMD. In conclusion, this study revealed that contact ultrasound can detect age- and menopause-related influences on bone status and was able to discriminate between healthy individuals and women with vertebral fracture. However, the widely accepted threshold of a T-score of less than −2.5 for the definition of osteoporosis may need modifying for the interpretation of QUS scans. Received: 8 February 1999 / Accepted: 5 May 1999     

Risedronate Reduces the Risk of First Vertebral Fracture in Osteoporotic Women

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score =–3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg (n= 328) or placebo (n= 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P= 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P= 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P= 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause. Received: 12 September 2001 / Accepted: 11 December 2001     

Do Men and Women Fracture Bones at Similar Bone Densities?

When the World Health Organization (WHO) guidelines for the definition of osteoporosis in postmenopausal women were identified similar proposals were not developed for men as there was insufficient evidence about the relationship between bone density and fracture in men. We have therefore examined the relationship between bone density and vertebral fracture in men and women attending for assessment of possible osteoporosis. Two hundred and sixty-four women (age 64 [SD 10] years) and 37 men (age 55 [10] years) were studied. Bone density was measured in the lumbar spine and femoral neck by dual-energy X-ray absorptiometry and expressed both as bone mineral density (BMD; g/cm²) and as T-scores. In both sexes there was a sigmoid relationship between the cumulative frequency of vertebral fracture and bone density at both sites. There was a linear relationship between the log odds of fracture and bone mass for both sexes and both sites (r= 0.97–0.99; p<0.0001). The slope of these lines was significantly steeper for men than women. The BMD at which there was 50% risk of fracture was higher in men than women (0.908 vs 0.844 g/cm²). The difference between the slopes was similar when the bone mass was expressed as a T-score. However, the T-score associated with 50% prevalence of fracture was similar in the two sexes (F: −2.77 vs M: −2.60). We conclude that although there is a different relationship between bone density and fracture in the two sexes the current WHO definition of osteoporosis in postmenopausal women can be appropriately applied to men. Received: 24 February 1999 / Accepted: 12 July 1999     

Changes in Calcaneal Trabecular Bone Structure Assessed with High-Resolution MR Imaging in Patients with Kidney Transplantation

The purpose of this study was to use high-resolution magnetic resonance (HR-MR) imaging to analyze the trabecular bone structure of the calcaneus in patients before and after renal transplantation and to compare this technique with bone mineral density (BMD) in predicting therapy-induced bone loss and osteoporotic fracture status. HR-MR imaging (voxel size: 0.195×0.195×1 mm) was performed at 1.5 T with an axial and sagittal orientation in 48 patients after transplantation, 12 patients before renal transplantation and 20 healthy controls. Structure measures analogous to standard histomorphometry and fractal dimension were determined in these images. BMD measurements of the lumbar spine and the proximal femur were obtained in the healthy female controls and the patients. Vertebral and peripheral fracture status were determined in all patients. The structural measures app.BV/TV, Tb.Sp, Tb.Th and Tb.N showed significant differences between controls and patients (p<0.05) while fractal dimension showed no significant differences. Neither the structural measures nor BMD showed significant differences between patients before and after transplantation. Correlations between time after transplantation versus structural measures and BMD were not significant. Differences between fracture and nonfracture patients were significant for the structural measures app.BV/TV, Tb.Sp and Tb.N (axial images) as well as for app.Tb.Th (sagittal images) and spine BMD (p<0.05) but not for hip BMD. Using odds ratios the strongest discriminators between patients with and without fractures were app. BV/TV, app.Tb.Sp (axial images) and app.Tb.Th (sagittal images), even after adjustment for age and BMD. Using receiver operating characteristic analysis the highest diagnostic performance was found for a combination of BMD and structural measures. In conclusion, our results indicate that structural measures obtained from HR-MR images may be used to characterize fracture incidence in kidney transplant patients; the best results, however, are obtained using a combination of BMD and structural measures. Received: 25 October 2000 / Accepted: 1 August 2001     

Image-Based Assessment of Spinal Trabecular Bone Structure from High-Resolution CT Images

The goal of this study was to assess whether a high-resolution CT measure of trabecular bone structure can enhance the discrimination between subjects with or without a vertebral fracture and having overall low hip or spine bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). Sixty-one women with low BMD by DXA (T-score <–2.5 at hip or spine) were examined. Twenty women had sustained a vertebral fracture. Quantitative CT (QCT) BMD and high-resolution CT spinal scans were performed on a whole-body CT scanner. For the high-resolution images (0.31 mm pixel, 1.5 mm thick slice), trabecular bone was segmented from marrow using an adaptive threshold, region growth and skeletonization step. From the processed image we measured the apparent trabecular bone fraction (BV/TV), apparent trabecular thickness (I.Th) and apparent trabecular spacing (I.Sp). We also assessed the connectivity of the marrow space using region growing to derive a mean (H_A) and maximum (H_M) hole size. Despite the fact that the study population was preselected to have a low BMD by DXA, QCT BMD was highly associated with (p <0.005) with fracture status. All structural parameters were correlated (r ~ 0.64 to 0.79) with BMD with p <0.003 and showed significant differences between the fracture and non-fracture group. However, except for H_A, this difference did not remain significant after adjustment for BMD. When BMD and then H_A was entered into a paired linear regression model to predict fracture outcome, H_A contributed with p= 0.03 and BMD with p= 0.86. ROC analysis was applied and showed that H_A, BMD, I.Th and I.Sp discriminated the two groups with areas of 0.76, 0.75, 0.71 and 0.68, respectively. These findings suggest that an assessment of vertebral trabecular structure from high-resolution CT images is useful in discriminating subjects with vertebral fractures and potentially useful for predicting future fractures. Received: 10 October 1997 / Accepted: 4 December 1997     

Therapy of Established Postmenopausal Osteoporosis with Monofluorophosphate plus Calcium: Dose-Related Effects on Bone Density and Fracture Rate

Recent experience from different groups suggests that low fluoride doses resulting in moderate increases in bone mineral density (BMD) may be advantageous in terms of fracture-reducing potency. In a randomized prospective 3-year study we examined the therapeutic efficacy of different dosages of monofluorophosphate (MFP) plus calcium in comparison with calcium alone in 134 women with established postmenopausal osteoporosis (mean age 64.0 years, average vertebral fractures per patient 3.6). Group A received 1000 mg calcium/day and a low-dose intermittent MFP regimen (3 months on, 1 month off) corresponding to an average daily fluoride ion dose of 11.2 mg. Group B received 1000 mg calcium/day plus continuous MFP corresponding to 20 mg fluoride ions per day. Group C was treated with 1000 mg calcium alone throughout the study period. Bone density was measured with dual-energy X-ray absorptiometry at L2–4 and three proximal femur areas and with single photon absorptiometry at two radius sites. New vertebral fractures were identified from annual lateral radiographs of the spine. A significant reduction in subjective complaints as measured by a combined pain–mobility score (CPMS) was found in both fluoride groups in comparison with the calcium monotherapy group. Group A showed increases in BMD at all six measuring sites, reaching +12.6% at the spine after 3 years. In group B we found significant increases at the spine, Ward’s triangle and distal radius, but slight decreases at the femoral neck and radius shaft. For the spine the average change amounted to +19.5% after 3 years. In group C losses of BMD were observed at all six sites, with an average loss of 1.6% for the spine at the end of the study. The incidence of new vertebral fractures per 100 patient-years was 8.6, 17.0 and 31.6 in groups A, B and C, respectively. In conclusion, both calcium–MFP regimens resulted in significantly lower vertebral fracture rates than calcium monotherapy. However, the low intermittent MFP regimen, leading to a mean annual increase in spinal BMD of only 4.2%, showed a clear trend to greater effectiveness in reducing vertebral fracture than the higher fluoride dosage that was followed by an average spinal BMD increase of 6.5% per year. Furthermore the rate of fluoride-specific side effects (lower-extremity pain syndrome) was 50% lower in patients receiving the lower fluoride dosage. Received: 3 November 1997 / Accepted: 4 June 1998     

Effects of Alendronate on Bone Density in Men with Primary and Secondary Osteoporosis

Alendronate has been reported to increase bone mineral density (BMD) and reduce fracture risk in women with osteoporosis. As there are no proven safe and effective treatments available for men with osteoporosis, we compared the effects of alendronate (10 mg/day) on BMD, measured using dual-energy X-ray absorptiometry, in a 12-month prospective, controlled, open label study involving (i) men with primary (n= 23) or secondary osteoporosis (n= 18), (ii) postmenopausal women with primary (n= 18) or secondary (n= 21) osteoporosis, and (iii) 29 male and 14 female untreated controls matched by age, height and weight. The patients had one or more vertebral fractures and ranged in age from 34.6 to 85.1 years. BMD was detectably increased relative to baseline by 6 months, and increased by comparable amounts in males and females with primary or secondary osteoporosis. At 12 months, lumbar spine BMD was 5.4%± 1.1% to 7.0%± 2.2% higher in the treated groups compared with baseline and controls (p<0.05 to 0.0001). Trochanteric BMD increased by 2.6%± 1.5% and 3.7%± 1.7% in treated men with primary and secondary osteoporosis, respectively (p = 0.06 to 0.08), and by 3.9%± 1.3% in treated women with primary osteoporosis (p<0.01) after 12 months. No significant changes were detected at the femoral neck or Ward’s triangle. BMD remained unchanged in controls. We infer that alendronate has comparable incremental effects on BMD in men and women with primary and secondary osteoporosis within 12 months of treatment. The changes are in the order of 0.5 SD – effects associated with a clinically worthwhile reduction in fracture risk. The data provide room for optimism regarding the role of alendronate in the treatment of osteoporosis in men. Randomized, double-masked and placebo-controlled trials are needed to confirm these preliminary findings and demonstrate antifracture efficacy using vertebral and nonvertebral fracture rates as the primary endpoint. Received: 23 February 1999 / Accepted: 2 June 1999