New Imaging Modalities in Bone

The digital era has witnessed an exponential growth in bone imaging as new modalities and analytic techniques improve the potential for noninvasive study of bone anatomy, physiology, and pathophysiology. Bone imaging very much lends itself to input across medical and engineering disciplines. It is in part a reflection of this multidisciplinary input that developments in the field of bone imaging over the past 30 years have in some respects outshone those in many other fields of medicine. These developments have resulted in much deeper knowledge of bone macrostructure and microstructure in osteoporosis and a much better understanding of the subtle changes that occur with age, concurrent disease, and treatment. This new knowledge is already being translated into improved day-to day clinical care with better recognition, treatment, and monitoring of the osteoporotic process. As “the more you know, the more you know you don’t know” certainly holds true with osteoporosis and bone disease, there is little doubt that further advances in bone imaging and analytical techniques will continue to hold center stage in osteoporosis and related research

Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial.

ObjectiveTo evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA).MethodsThis was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.ResultsIn total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles.ConclusionsDenosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD

Phenotypic characterization of skeletal abnormalities of Osteopotentia mutant mice by micro-CT: a descriptive approach with emphasis on reconstruction techniques

PurposeThe novel protein osteopotentia (Opt) has recently been described as an essential regulator of postnatal osteoblast maturation and might possibly be responsible for some of the rarer types of osteogenesis imperfecta. Our aim was the evaluation of micro CT for the qualitative morphological assessment of skeletal abnormalities of Osteopotentia-mutant mice in comparison to radiography and histology.Materials and methodsFour homozygous mice with insertional mutations in the Opt gene and three wild-type controls were examined ex vivo using radiography and micro-CT. Two of the homozygous animals were evaluated histologically (trichrome reagent). For the micro-CT evaluation three-dimensional (3D) surface reconstructions and two-dimensional (2D) multiplanar reformations (MPRs) were applied.ResultsThe Opt-homozygous mice exhibited severe growth. The radiographic examinations showed osteopenia and fractures with hypertrophic callus formation and pseudarthroses of the forelimbs and ribs. Micro-CT confirmed these findings and was able to demonstrate additional fractures especially at smaller bones such as the metacarpals and phalanges. Additional characterization and superior delineation of cortices and fracture fragments was achieved by 2D MPRs. Histological correlation verified several of these imaging findings.ConclusionMicro-CT is able to screen Opt-mutant mice for osseous pathologies and furthermore characterize these anomalies. The modality seems superior to conventional radiography, but is not able to demonstrate cellular pathology. However, histology is destructive and more time- and material-consuming than micro-CT. Additional information may be gathered by 2D MPRs

Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial

OBJECTIVES: To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). METHODS: In this multicentre, randomised, placebo-controlled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months. RESULTS: Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo. CONCLUSIONS: Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction. TRIAL REGISTRATION NUMBER: JapicCTI-101263

MRI of bone marrow abnormalities in hematological malignancies

Magnetic resonance imaging (MRI) is essential for evaluating bone marrow. Bone marrow undergoes constant modification and its appearance on MRI changes in response. Knowledge of the types of changes and their origins is essential for analysis of MRI findings of bone marrow infiltration with hematological malignancies. This pictorial review describes the MRI pulse sequences used for imaging of bone marrow, and illustrates bone marrow changes due hematological malignancies, including changes following treatment

Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab

In the randomized, placebo-controlled FREEDOM study of women aged 60 to 90 years with postmenopausal osteoporosis, treatment with denosumab once every 6 months for 36 months significantly reduced hip and new vertebral fracture risk by 40% and 68%, respectively. To gain further insight into this efficacy, we performed a nonlinear finite element analysis (FEA) of hip and spine quantitative computed tomography (QCT) scans to estimate hip and spine strength in a subset of FREEDOM subjects (n=48 placebo; n=51 denosumab) at baseline, 12, 24, and 36 months. We found that, compared with baseline, the finite element estimates of hip strength increased from 12 months (5.3%; p<0.0001) and through 36 months (8.6%; p<0.0001) in the denosumab group. For the placebo group, hip strength did not change at 12 months and decreased at 36 months (-5.6%; p<0.0001). Similar changes were observed at the spine: strength increased by 18.2% at 36 months for the denosumab group (p<0.0001) and decreased by -4.2% for the placebo group (p=0.002). At 36 months, hip and spine strength increased for the denosumab group compared with the placebo group by 14.3% (p<0.0001) and 22.4% (p<0.0001), respectively. Further analysis of the finite element models indicated that strength associated with the trabecular bone was lost at the hip and spine in the placebo group, whereas strength associated with both the trabecular and cortical bone improved in the denosumab group. In conclusion, treatment with denosumab increased hip and spine strength as estimated by FEA of QCT scans compared with both baseline and placebo owing to positive treatment effects in both the trabecular and cortical bone compartments. These findings provide insight into the mechanism by which denosumab reduces fracture risk for postmenopausal women with osteoporosis

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy : a randomised, open-label, phase 3 trial

Background: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. Methods: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged >= 55 to <= 90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2.5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 mu g once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. Findings: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2.6% (95% CI 2.2 to 3.0) in the romosozumab group and -0.6% (-1.0 to -0.2) in the teriparatide group; difference 3.2% (95% CI 2.7 to 3.8; p<0.0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. Interpretation: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture