Neurogenic Obesity and Skeletal Pathology in Spinal Cord Injury

Spinal cord injury (SCI) results in dramatic changes in body composition, with lean mass decreasing and fat mass increasing in specific regions that have important cardiometabolic implications. Accordingly, the recent Consortium for Spinal Cord Medicine (CSCM) released clinical practice guidelines for cardiometabolic disease (CMD) in SCI recommending the use of compartmental modeling of body composition to determine obesity in adults with SCI. This recommendation is guided by the fact that fat depots impact metabolic health differently, and in SCI adiposity increases around the viscera, skeletal muscle, and bone marrow. The contribution of skeletal muscle atrophy to decreased lean mass is self-evident, but the profound loss of bone is often less appreciated due to methodological considerations. General-population protocols for dual-energy x-ray absorptiometry (DXA) disregard assessment of the sites of greatest bone loss in SCI, but the International Society for Clinical Densitometry (ISCD) recently released an official position on the use of DXA to diagnose skeletal pathology in SCI. In this review, we discuss the recent guidelines regarding the evaluation and monitoring of obesity and bone loss in SCI. Then we consider the possible interactions of obesity and bone, including emerging evidence suggesting the possible influence of metabolic, autonomic, and endocrine function on bone health in SCI.

A case of bilateral “double/multiple crush” entrapment syndrome of the upper limbs in a violinist

Entrapment syndromes of the upper limb are common neuro-muscular-skeletal pathology in musician instrumentists. From this group of morbid entities, the most prevalent worldwide is carpal tunnel syndrome closely followed by the cubital tunnel syndrome and de Quervain stenosing tenosynovitis. Due to their distinctive etiopathogenic correlation with exposure to specific occupational factors linked to instrument interpretation and professional environment, these diseases raise a medical challenge and constitute a socioeconomic and professional burden with legal branchings and implications for individuals and society. These syndromes develop isolated or more often in various associations with each other in a clinical pattern that has been described under the model of “double crush” syndrome by Upton and McComas. From its inception in 1973 until the present time, this clinical model has been a point of interesting debate between various specialists worldwide. This model underlines an already lesioned neuron’s susceptibility and vulnerability for further neural damage at a different level from the initial lesion. The sophisticated clinical presentation of this “double or multiple crush” syndrome is due not only to overlapping symptomatology from each contributing neuro-muscular-skeletal pathology or lesional site but also to other local or systemic conditions such as trauma, diabetes, osteoarthritis, thyroid disease, obesity, etc. The occupational factors such as repetitive movements, strain and overload, vibrations, ergonomics, and others all contribute to the creation and progression of the morbid process. We cannot overstate the implications of understanding these complex relations and interdependencies between the factors mentioned above as they are essential not only for the diagnosis of these neuropathies but also for the treatment, rehabilitation, and occupational reinsertion of the patients. The studies support the fact that both lesional sites need to be medically addressed for an optimal outcome and resolution. We present the case of a female violinist with bilateral multiple neuro-muscular-skeletal pathologies of the upper limb treated previously invasively and conservatively over several years by various specialists without a satisfactory clinical resolution of the symptomatology or any professional and legal measures taken.

MEKK2 mediates aberrant ERK activation in neurofibromatosis type I

Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1fl/fl;Dmp1-Cre) and Mekk2−/− each displaying skeletal defects, Nf1fl/fl;Mekk2−/−;Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.

Osteoporosis: Current and Emerging Therapies Targeted to Immunological Checkpoints

: Osteoporosis is a skeletal pathology characterized by compromised bone strength leading to increased risk of fracture, mainly the spine and hip fractures. Osteoporosis affects more than 200 million people worldwide and because of the skeletal fractures it causes, represents a major cause of morbidity, disability and mortality in older people. Recently, the new discoveries of osteoimmunology have clarified many of the pathogenetic mechanisms of osteoporosis, helping to identify new immunological targets for its treatment opening the way for new and effective therapies with biological drugs. Currently, there are basically two monoclonal antibodies for osteoporosis therapy: denosumab and romosozumab. Here, we focus on the modern approach to the osteoporosis management and in particular, on current and developing biologic drugs targeted to new immunological checkpoints, in the landscape of osteoimmunology.

Spectrum of microarchitectural bone disease in inborn errors of metabolism: a cross-sectional, observational study

Background Patients diagnosed with inborn errors of metabolism (IBEM) often present with compromised bone health leading to low bone density, bone pain, fractures, and short stature. Dual-energy X-ray absorptiometry (DXA) is the current gold standard for clinical assessment of bone in the general population and has been adopted for monitoring bone density in IBEM patients. However, IBEM patients are at greater risk for scoliosis, short stature and often have orthopedic hardware at standard DXA scan sites, limiting its use in these patients. Furthermore, DXA is limited to measuring areal bone mineral density (BMD), and does not provide information on microarchitecture. Methods In this study, microarchitecture was investigated in IBEM patients (n = 101) using a new three-dimensional imaging technology high-resolution peripheral quantitative computed tomography (HR-pQCT) which scans at the distal radius and distal tibia. Volumetric BMD and bone microarchitecture were computed and compared amongst the different IBEMs. For IBEM patients over 16 years-old (n = 67), HR-pQCT reference data was available and Z-scores were calculated. Results Cortical bone density was significantly lower in IBEMs associated with decreased bone mass when compared to lysosomal storage disorders (LSD) with no primary skeletal pathology at both the radius and tibia. Cortical thickness was also significantly lower in these disorders when compared to LSD with no primary skeletal pathology at the radius. Cortical porosity was significantly greater in hypophosphatasia when compared to all other IBEM subtypes. Conclusion We demonstrated compromised bone microarchitecture in IBEMs where there is primary involvement of the skeleton, as well as IBEMs where skeletal complications are a secondary outcome. In conclusion, our findings suggest HR-pQCT may serve as a valuable tool to monitor skeletal disease in the IBEM population, and provides insight to the greatly varying bone phenotype for this cohort that can be used for clinical monitoring and the assessment of response to therapeutic interventions.