Advances and Unmet Needs in the Therapeutics of Bone Fragility

The prevalence of fragility fractures increases as longevity increases the proportion of the elderly in the community. Until recently, the majority of studies have targeted women with osteoporosis defined as a bone mineral density (BMD) T score of < −2.5 SD, despite evidence that the population burden of fractures arises from women with osteopenia. Antiresorptive agents reduce vertebral and hip fracture risk by ~50 percent during 3 years but efficacy against non-vertebral fractures, 80% of all fractures in the community, is reported in few studies, and of those, the risk reduction is only 20–30%. Recent advances in the use of antiresorptives and anabolic agents has addressed some of these unmet needs. Zoledronic acid is now reported to reduce vertebral and non-vertebral fractures rates in women with osteopenia. Studies using teriparatide demonstrate better vertebral and clinical (symptomatic vertebral and non-vertebral) antifracture efficacy than risedronate. Abaloparatide, a peptide sharing amino acid sequences with teriparatide, reduces vertebral and non-vertebral fractures. Romosozumab, a monoclonal antibody suppressing sclerostin, reduces vertebral and non-vertebral fractures within a year of starting treatment, and does so more greatly than alendronate. Some recent studies signal undesirable effects of therapy but provide essential cautionary insights into long term management. Cessation of denosumab is associated with a rapid increase in bone remodeling and the uncommon but clinically important observation of increased multiple vertebral fractures suggesting the need to start alternative anti-resorptive therapy around the time of stopping denosumab. Antiresorptives like bisphosphonates and denosumab suppress remodeling but not completely. Antifracture efficacy may be limited, in part, as a consequence of continued unsuppressed remodeling, particularly in cortical bone. Bisphosphonates may not distribute in deeper cortical bone, so unbalanced intracortical remodeling continues to cause microstructural deterioration. In addition, suppressed remodeling may compromise the material composition by increasing matrix mineral density and glycosylation of collagen. As antiresorptive agents do not restore microstructural deterioration existing at the time of starting treatment, under some circumstances, anabolic therapy may be more appropriate first line treatment. Combining antiresorptive and anabolic therapy is an alternative but whether anti-fracture efficacy is greater than that achieved by either treatment alone is not known

Construction of the Femoral Neck During Growth Determines its Strength in Old Age

Study of the design of the FN in vivo in 697 women and in vitro in 200 cross-sections of different sizes and shapes along each of 13 FN specimens revealed that strength in old age was largely achieved during growth by differences in the distribution rather than the amount of bone material in a given FN cross-section from individual to individual. Introduction: We studied the design of the femoral neck (FN) to gain insight into the structural basis of FN strength in adulthood and FN fragility in old age. Materials and Methods: Studies in vivo were performed using densitometry in 697 women and in vitro using high-resolution μCT and direct measurements in 13 pairs of postmortem specimens. Results: The contradictory needs of strength for loading yet lightness for mobility were met by varying FN size, shape, spatial distribution, and proportions of its trabecular and cortical bone in a cross-section, not its mass. Wider and narrower FNs were constructed with similar amounts of bone material. Wider FNs were relatively lighter: a 1 SD higher FN volume had a 0.67 (95% CI, 0.61-0.72) SD lower volumetric BMD (vBMD). A 1 SD increment in height was achieved by increasing FN volume by 0.32 (95% CI, 0.25-0.39) SD with only 0.15 (95% CI, 0.08-0.22) SD more bone, so taller individuals had a relatively lighter FN (vBMD was 0.13 [95% CI, 0.05-0.20 SD] SD lower). Greater periosteal apposition constructing a wider FN was offset by even greater endocortical resorption so that the same net amount of bone was distributed as a thinner cortex further from the neutral axis, increasing resistance to bending and lowering vBMD. This was recapitulated at each point along the FN; varying absolute and relative degrees of periosteal apposition and endocortical resorption focally used the same amount of material to fashion an elliptical FN of mainly cortical bone near the femoral shaft to offset bending but a more circular FN of proportionally more trabecular and less cortical bone to accommodate compressive loads adjacent to the pelvis. This structural heterogeneity was largely achieved by adaptive modeling and remodeling during growth-most of the variance in FN volume, BMC, and vBMD was growth related. Conclusions: Altering structural design while minimizing mass achieves FN strength and lightness. Bone fragility may be the result of failure to adapt bone's architecture to loading, not just low bone mass

Method and system for image analysis

A computer-implemented method for analyzing a sample comprising a first material and a second material of generally different densities and having a junction therebetween. The method comprises: defining automatically a plurality of regions of interest within an image of the sample, each of said regions of interest having a width of one or more voxels or pixels; determining respective density, intensity or attenuation profiles within the regions of interest; determining a location of said junction including defining a first reference point within one of said first and second materials and employing the first reference point as current reference point, and (i) determining a closest point to said current reference point that is on said respective profile and in the other of said first and second materials to that of the current reference point; (ii) locating a greatest difference in values of the respective profile between an adjacent peak and trough in a segment of the respective profile between said current reference point and said closest point; and (iii) locating a point of inflexion in said segment

Adding marrow adiposity and cortical porosity to femoral neck areal bone mineral density improves the discrimination of women with nonvertebral fractures from controls

Advancing age is accompanied by a reduction in bone formation and remodeling imbalance, which produces microstructural deterioration. This may be partly caused by a diversion of mesenchymal cells towards adipocytes rather than osteoblast lineage cells. We hypothesized that microstructural deterioration would be associated with an increased marrow adiposity, and each of these traits would be independently associated with nonvertebral fractures and improve discrimination of women with fractures from controls over that achieved by femoral neck (FN) areal bone mineral density (aBMD) alone. The marrow adiposity and bone microstructure were quantified from HR‐pQCT images of the distal tibia and distal radius in 77 women aged 40 to 70 years with a recent nonvertebral fracture and 226 controls in Melbourne, Australia. Marrow fat measurement from HR‐pQCT images was validated using direct histologic measurement as the gold standard, at the distal radius of 15 sheep, with an agreement (R2 = 0.86, p < 0.0001). Each SD higher distal tibia marrow adiposity was associated with 0.33 SD higher cortical porosity, and 0.60 SD fewer, 0.24 SD thinner, and 0.72 SD more‐separated trabeculae (all p < 0.05). Adjusted for age and FN aBMD, odds ratios (ORs) (95% CI) for fracture per SD higher marrow adiposity and cortical porosity were OR, 3.39 (95% CI, 2.14 to 5.38) and OR, 1.79 (95% CI, 1.14 to 2.80), respectively. Discrimination of women with fracture from controls improved when cortical porosity was added to FN aBMD and age (area under the receiver‐operating characteristic curve [AUC] 0.778 versus 0.751, p = 0.006) or marrow adiposity was added to FN aBMD and age (AUC 0.825 versus 0.751, p = 0.002). The model including FN aBMD, age, cortical porosity, trabecular thickness, and marrow adiposity had an AUC = 0.888. Results were similar for the distal radius. Whether marrow adiposity and cortical porosity indices improve the identification of women at risk for fractures requires validation in prospective studies. © 2019 American Society for Bone and Mineral Research

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood

Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 × 10−4; Australia: P = 3.7 × 10−4). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 × 10−11). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 × 10−5). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth

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 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