Search

SUMMARY: Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline) are discussed. INTRODUCTION: Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) workshop was convened to discuss osteoporosis in men and to provide a report by a panel of experts (the authors). METHODS: A debate with an expert panel on preselected topics was conducted. RESULTS AND CONCLUSIONS: Although additional fracture data are needed to endorse the clinical care of osteoporosis in men, consensus views were reached on diagnostic criteria and intervention thresholds. Empirical data in men display similarities with data acquired in women, despite pathophysiological differences, which may not be clinically relevant. Men should receive treatment at a similar 10-year fracture probability as in women. The design of mixed studies may reduce the lag between comparable treatments for osteoporosis in women becoming available in men.

Objectives: Strontium ranelate 2 g/day has proven efficacy against vertebral and nonvertebral fracture over 5 years in postmenopausal osteoporosis, though many women require longer-term treatment. This article describes the efficacy, safety, and tolerability of this agent over 8 years. Methods: Postmenopausal osteoporotic women having participated in the 5-year efficacy trials SOTI and TROPOS were invited to enter a 3-year open-label extension study. The results presented here focus on patients who received strontium ranelate for 8 years. Results: At the extension baseline, the population treated for 8 years (n =879; 79.1 +/- 5.6 years) had femoral neck T-score of -2.61 +/- 0.71. The cumulative incidences of new vertebral and nonvertebral fractures (13.7% and 12.0%, respectively) over years 6 to 8 were non-statistically different from the cumulative incidences in the first 3 years of the original studies (11.5% and 9.6%). Lumbar spine, femoral neck, and total hip bone mineral density (BMD) increased throughout the 8-year period. Annual relative change in BMD was significant at every visit, except the 8-year visit for femoral neck and total hip BMD. Strontium ranelate was safe and well tolerated over 8 years. Conclusions: Long-term treatment with strontium ranelate 2 g/day in postmenopausal osteoporotic women leads to continued increases in BMD at all sites. The data also provide some evidence for a sustained antifracture efficacy. (C) 2009 Elsevier Inc. All rights reserved.

Although dietary fructans improve calcium absorption and bone mineral content (BMC) in rats, their effect on calcium bioavailability and bone density may vary with their degree of polymerization. Therefore, for a 3-month period, growing rats received either a control diet or a diet enriched with either oligofructose (OLF) or inulin. At sacrifice, body weight, lean body mass and appendicular bone length were similar in the 3 groups. Rats fed fructans had a similar increase in cecal wall weight (30%), but the relative increase in cecal levels of calbinding-9 K was 2 in the OLF group and 4 in the inulin group. Further, the significant decrease in serum levels of type I collagen C-telopeptide was greater in the inulin group (30%) than in the OLF group (16%). The increase in whole-body bone mineral content (BMC) as measured by DXA was greater in the inulin group than in the OLF group but DXA detected an increase in the BMC of excised femurs only in the inulin group. In contrast, pQCT conducted ex vivo detected a significant increase in the area and mineral density (BMD) of the cancellous bone of both the proximal tibia and vertebra in rats fed fructans and the effect of inulin was greater (P < 0.01) than that of OLF (P < 0.05). Further, inulin but not OLF significantly enhanced the BMD of the cortical bone in both appendicular and peripheral sites (P < 0.01) as well as the polar stress/strain index of femurs (P < 0.01). These observations suggest that, although both inulin and OLF both have a positive effect on BMD, the greatest effect of inulin is related to the higher capacity of this fructan to reduce bone resorption. The different anti-resorptive capacity of the 2 fructans might be related to their different impact on calcium absorption and bioavailability since the increase in cecal amounts of calbindin-9 K, a protein known to play an important role in calcium absorption, was greater in rat fed inulin than in rats fed OLF. Although cecal wall hyperplasia may be of concern, it remains to establish whether the positive effect of fructans observed on calcium absorption in humans is also associated with a positive effect on bone mass and/or mineral density.

This study directly compares peripheral quantitative computed tomography (pQCT) and histology for the assessment of 11 morphological parameters. Sixty-eight cylindrical cancellous bone samples were cored from the thoracic (T-9) thoracolumbar (T-12 or L-1), and lumbar (L-4) vertebral bodies of nine autopsy subjects (aged 44-88 years). Four transverse slices were acquired by pQCT from the bottom to the top of each cylinder. Slice thickness was 300 microm and pixel size was 70 x 70 microm. Thin sections (5 microm) were obtained at the same location in the samples, stained with Von Kossa, and photographed. Classical morphological parameters and strut analysis parameters were measured on all images (272 pQCT and 272 matched histological sections). Because of the partial volume effect and specific thresholding procedure, pQCT overestimated the absolute value of the bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) by a factor 2. The trabecular number (Tb.N), trabecular spacing (Tb.Sp), and total strut length (TSL) were correctly estimated. However, the direct correlation between pQCT and histology was excellent (r20.85, p0.001) for BV/TV, Tb.N, Tb.Sp, TSL, and star surface. For Tb.Th, number of nodes, and number of free ends, the correlation was also good (r(2)0.6, p0.001). Using a random regression model, we also explored the ability of these parameters to add structural information to the readily available BV/TV or apparent density. The model identified significant (p0.001) differences between subjects. For a given BV/TV, some patients had more trabeculae (Tb.N) that were thinner (Tb.Th) and more disconnected (higher free ends and star). This was observed for both histology and pQCT morphometrical data. Our analysis demonstrates the capacity of both histology and pQCT to detect subjects with specific structural patterns in vertebral cancellous bone.

Identifying patients at risk of developing an osteoporosis-related fracture will continue to be a challenge. The "gold standard" for osteoporosis diagnosis is bone densitometry. However, economic issues or availability of the technology may prevent its use under a mass screening scenario. A risk assessment instrument, the "simple calculated osteoporosis risk estimation" (SCORE), has been reported to appropriately identify women likely to have low (t scoreor = -2 SD) bone mineral density (BMD) and who should be referred for bone densitometry. The aim of our study is to evaluate the discriminatory performance of SCORE in a random sample of postmenopausal white women from Belgium. For this purpose, we gathered medical data on 4035 consecutive patients agedor = 45 years, either consulting spontaneously or referred for a BMD measurement to an outpatient osteoporosis center located at the University of Liège, Belgium. BMD measurements, using dual-energy X-ray absorptiometry (DXA) technology, were taken at the hip (total and neck) and lumbar spine (L2-4). At the recommended cutoff point of 6, SCORE had a sensitivity of 91.5% to detect low BMD at any of the measured sites, a specificity of 26.5%, a positive predictive value of 52.8%, and a negative predictive value of 77.7%. According to SCORE, 18% of the patients would not be recommended for densitometry. Among these, 10.9% were misclassified as they had osteoporosis (t scoreor = -2.5 SD) at one or more of the sites investigated. The negative predictive errors of SCORE, when failing to detect osteoporosis, were only 1% for the total hip, 3.2% for the femoral neck, and 8.8% for the lumbar spine. We conclude that, notwithstanding the high values of sensitivity, SCORE specificity is too low to be useful as a diagnostic tool for screening patients at high risk to later develop osteoporosis. Nevertheless, from a resource allocation perspective, this instrument can be used with relative confidence to exclude patients who do not need a BMD measurement, and would therefore provide an opportunity to realize substantial cost savings in comparison to a mass screening strategy.

In the spine, cancellous bone quality is usually assessed for the whole vertebral body in a transverse central slice. Correct identification and assessment of the weakest parts of the cancellous bone may lead to better prediction of fracture risk. The density and structural parameters were systematically investigated inside the thoracic (T-9), thoracolumbar (T12-L1), and lumbar (L-4) vertebral bodies of nine subjects. On both sides of the median sagittal plane, anterior and posterior 8.2 mm vertical cores were harvested in the thoracic vertebra. In the thoracolumbar and lumbar vertebrae, external samples were also cored. Peripheral quantitative computed tomographic (pQCT) density analysis of the 136 cores was performed at four different levels, from the lower to the upper endplate. The relatively thin slice thickness (300 microm) and small pixel size (70 microm x 70 microm) was considered sufficient to investigate the structural parameters on the four transverse slices and in the sagittal and coronal planes (total of 816 images). Using a constant threshold a binary image was generated and the morphometric data were extracted. The binary image was further skeletonized and classical strut analysis was performed. Cancellous bone density was 20% higher in the posterior cores than in the anterior and external cores. Moreover, clear vertical inhomogeneity was noted because the lowest half of the vertebral body presented lower density than the upper half (differences ranging from 25% to 15%). All structural parameters were strongly dependent on the location of the measurement. Structural differences between anterior, posterior, and external areas were mild and followed the density patterns. On the other hand, vertical inhomogeneity of the structural parameters was important. For example, in the thoracolumbar and lumbar vertebrae, the numbers of nodes or node-to-node struts were almost twofold higher in the inferior half than in the superior half (p < 0.01), whereas trabecular thickness and number of free-ends presented a center/close-to-endplate structural pattern, with central trabeculae being 15% thicker (p < 0.05) and presenting 30% fewer free-ends (p < 0.01) than the close-to-endplate ones. Variability of density and structural parameters was high and a substantial part of this variability could be explained by the place inside the vertebral body where the measurement was made. The weak part was not in the center of the body but in its upper half where the lower density did not seem to be compensated by a higher structural architecture. Further clinical investigation could enhance fracture prediction by tracking and focusing on the weakest part of the vertebral body.

We studied 265 men (mean age 56.4 years; range 18-83 years), among patients enrolled in two arms of a double-blind, 1-year study comparing the effects of zoledronic acid (ZOL) with risedronate (RIS) in patients either commencing (prednisolone 7.5 mg/day or equivalent) (prevention arm, n=88) or continuing glucocorticoid therapy (treatment arm, n=177).Patients received either a single ZOL 5 mg infusion or RIS 5 mg oral daily at randomization, along with calcium (1000 mg) and vitamin D (400-1200 IU). Primary endpoint: difference in percentage change from baseline in bone mineral density (BMD) at the lumbar spine (LS) at 12 months. Secondary endpoints: percentage changes in BMD at total hip (TH) and femoral neck (FN), relative changes in bone turnover markers (β-CTx and P1NP), and overall safety.In the treatment subpopulation, ZOL increased LS BMD by 4.7% vs. 3.3% for RIS and at TH the percentage changes were 1.8% vs. 0.2%, respectively. In the prevention subpopulation, bone loss was prevented by both treatments. At LS the percentage changes were 2.5% vs. -0.2% for ZOL vs. RIS and at TH the percentage changes were 1.1% vs. -0.4%, respectively. ZOL significantly increased lumbar spine BMD more than RIS at Month 12 in both the prevention population (p=0.0024) and the treatment subpopulation (p=0.0232) in men. In the treatment subpopulation, ZOL demonstrated a significantly greater reduction in serum β-CTx and P1NP relative to RIS at all time-points. In the prevention subpopulation, ZOL significantly reduced β-CTx at all time-points, and P1NP at Month 3 (p=0.0297) only. Both treatments were well tolerated in men, albeit with a higher incidence of influenza-like illness and pyrexia events post-infusion with ZOL.Once-yearly ZOL preserves or increases BMD within 1 year to a greater extent than daily RIS in men receiving glucocorticoid therapy.

INTRODUCTION: A variation in bone response to fluoride (F(-)) exposure has been attributed to genetic factors. Increasing fluoride doses (0 ppm, 25 ppm, 50 ppm, 100 ppm) for three inbred mouse strains with different susceptibilities to developing dental enamel fluorosis (A/J, a "susceptible" strain; SWR/J, an "intermediate" strain; 129P3/J, a "resistant" strain) had different effects on their cortical and trabecular bone mechanical properties. In this paper, the structural and material properties of the bone were evaluated to explain the previously observed changes in mechanical properties. MATERIALS AND METHODS: This study assessed the effect of increasing fluoride doses on the bone formation, microarchitecture, mineralization and microhardness of the A/J, SWR/J and 129P3/J mouse strains. Bone microarchitecture was quantified with microcomputed tomography and strut analysis. Bone formation was evaluated by static histomorphometry. Bone mineralization was quantified with backscattered electron (BSE) imaging and powder X-ray diffraction. Microhardness measurements were taken from the vertebral bodies (cortical and trabecular bones) and the cortex of the distal femur. RESULTS: Fluoride treatment had no significant effect on bone microarchitecture for any of the strains. All three strains demonstrated a significant increase in osteoid formation at the largest fluoride dose. Vertebral body trabecular bone BSE imaging revealed significantly decreased mineralization heterogeneity in the SWR/J strain at 50 ppm and 100 ppm F(-). The trabecular and cortical bone mineralization profiles showed a non-significant shift towards higher mineralization with increasing F(-) dose in the three strains. Powder X-ray diffraction showed significantly smaller crystals for the 129P3/J strain, and increased crystal width with increasing F(-) dose for all strains. There was no effect of F(-) on trabecular and cortical bone microhardness. CONCLUSION: Fluoride treatment had no significant effect on bone microarchitecture in these three strains. The increased osteoid formation and decreased mineralization heterogeneity support the theory that F(-) delays mineralization of new bone. The increasing crystal width with increasing F(-) dose confirms earlier results and correlates with most of the decreased mechanical properties. An increase in bone F(-) may affect the mineral-organic interfacial bonding and/or bone matrix proteins, interfering with bone crystal growth inhibition on the crystallite faces as well as bonding between the mineral and organic interface. The smaller bone crystallites of the 129P3/J (resistant) strain may indicate a stronger organic/inorganic interface, reducing crystallite growth rate and increasing interfacial mechanical strength.

Paget's disease of bone is characterized by a high bone turnover. Therefore, antiresorbing agents such as bisphosphonates are clearly indicated. However, as they accumulate in the pagetic lesions, they could produce some focal defects of bone mineralization. In a double-blind study, we have had the opportunity to compare the effects of tiludronate and of etidronate (both at a fixed dose of 400 mg/day orally) on the radiological changes of 12 patients suffering from Paget's disease of bone. After breaking the code, good agreement was observed between the radiological evaluations and the applied therapy: All positive bone balances were observed in the tiludronate group, except for three questionable densifications in the etidronate group, and the negative bone balances in the etidronate group. This confirms our previous experience with etidronate in Paget's disease when X-ray films of the lesions are followed sequentially during therapy.

Little is known regarding the mechanisms that govern the structural organization of cancellous bone. In this study, we compare the nature of the collagen in vertebral cancellous bone with the structural organization of its trabecular network. Cylindrical specimens of cancellous bone from vertebrae were obtained from nine autopsy subjects (ages 46-88). In each subject, eight pairs of corresponding samples were obtained from three levels in the spine and three areas within the vertebral body, leading to a total of 68 pairs of samples. The cylinders from one side were used for morphometry and the classical morphometrical parameters were obtained (BV/TV, bone volume fraction; Tb.Th, trabecular thickness; Tb.N, number; Tb.Sp, trabecular spacing) and strut analysis (TSL, total strut length; Nd, number of nodes; Fe, number of free-ends). The amount of osteoid bone was also quantified. The cylinders from the other side were powdered and used for collagen assessment, including the amount of collagen (% w/w), and its content in immature cross-links; such as hydroxylysinonorleucine (mol/mol of collagen) and dihydroxylysinornorleucine, as well as stable mature cross-links, such as hydroxylysylpyridinoline (HP), lysylpyridinoline (LP), and the pyrrole cross-links. A random regression model was used to explore the correlations. None of the biochemical parameters correlated with the BV/TV except the ratio between immature and mature cross-links (eta(2) = 0.34, p0.05). There was no relationship between the amount of osteoid bone and the cross-link profile. However, the concentration of pyrrole and HP cross-links in the bone samples correlated with the structural organization of its trabeculae, but in an opposite direction. Hence, the pyrrole/HP ratio was a good predictor of Tb.Th, Tb.N, Tb.Sp, and TSL (eta(2)0.65 and p0.01) as well as Fe and star marrow space (eta(2)0.45 and p0.05). The cylinders from subjects with high pyrrole or low HP in their bone collagen had a relatively thick and simple structure. Those with low pyrrole and high HP had relatively thin trabeculae that were more numerous and spread over a complex network. The relative concentrations of the pyrrole and pyridinoline cross-links appear to reflect the structural organization of the trabeculae.

Rank (receptor activator of nuclear factor-\kappaB), encoded by the TNFRSF11A gene, is one of the most important proteins in osteoclastogenesis and bone remodeling. Mutations in TNFRSF11A have been reported to cause Paget's disease of bone (PDB)-like diseases (i.e. familial expansile osteolysis, expansile skeletal hyperphosphatasia and early onset PDB) and an osteoclast-poor form of osteopetrosis. Yet, the role of the TNFRSF11A gene in classical PDB has not been investigated in detail. We have conducted an association study in 196 Belgian sporadic PDB patients (83 females and 112 males) and 212 controls (86 females and 126 males). Based on HapMap, 27 tagSNPs and 5 multimarker tests (MMTs) were selected in and around TNFRSF11A. In addition, we have included 1 non-synonymous SNP (H141Y) which is not present in HapMap. Genotyping was carried out by KASPar technique (KBioscience, UK), TaqMan assay and direct sequencing. Statistical analysis indicates that 13 SNPs and 2 MMTs are significantly associated (P-values between 0.037 and 3.17×10−4), the majority of them due to an association in the female subcohort. Six SNPs and 1 MMT withstand the Bonferroni correction (P

Any adverse events 105 (80.2) 88 (65.7) Any serious adverse events (including deaths) 26 (19.85) 28 (20.90) Deaths 3 (2.29) 1 (0.75) Discontinuation of follow-up because of adverse events 4 (3.05) 2 (1.49) Adverse events occurring in >5% of patients in either treatment group Pyrexia 15 (11.5) 6 (4.5) Influenza like illness 10 (7.6) 1 (0.7) Arthralgia 10 (7.6) 13 (9.7) Myalgia 8 (6.1) 5 (3.7) Asthenia 7 (5.3) 6 (4.5) Dyspepsia 7 (5.3) 6 (4.5) Back pain 4 (3.1) 9 (6.7) Rheumatoid arthritis 4 (3.1) 7 (5.2) Hypertension 4 (3.1) 8 (6.0)