Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders

Context Many different inherited and acquired conditions can result in premature bone fragility / low bone mass disorders (LBMD). Objective We aimed at elucidating the impact of genetic testing on differential diagnosis of adult LBMD and at defining clinical criteria for predicting monogenic forms. Methods Four clinical centers broadly recruited a cohort of 394 unrelated adult women before menopause and men younger than 55 years with a bone mineral density (BMD) Z-score 2), and a high normal BMI. In contrast, mutation frequencies did not correlate with age, prevalent vertebral fractures, BMD, or biochemical parameters. In individuals without monogenic disease-causing rare variants, common variants predisposing for low BMD, e.g. in LRP5, were overrepresented. Conclusion The overlapping spectra of monogenic adult LBMD can be easily disentangled by genetic testing and the proposed clinical criteria can help to maximize the diagnostic yield

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA

High prevalence and undertreatment of osteoporosis in elderly patients undergoing total hip arthroplasty

We detected a high prevalence of low bone mineral density assessed by DXA in 268 elderly patients with end-stage osteoarthritis scheduled for total hip arthroplasty (18% osteoporosis, 41% osteopenia). Therefore, and due to the identified concomitant undertreatment, routine DXA measurements should be considered in elderly patients prior to surgery.!##!Introduction!#!Bone quality represents a decisive factor for osseointegration, durability, and complications of an implanted prosthesis. Although the risk of osteoporosis increases with age and the assessment of bone mineral density (BMD) prior to total hip arthroplasty (THA) is recommended in elderly patients, a systematic, unbiased analysis of such patients is not available in the literature.!##!Methods!#!In this retrospective study, we examined 268 elderly patients (age ≥70 years) who underwent dual-energy X-ray absorptiometry (DXA) within 3 months prior to primary THA. Demographics, medical history, radiographic OA grade, and stem fixation method (i.e., cemented or cementless) were obtained.!##!Results!#!In total, 153 (57%) cemented and 115 (43%) cementless stem fixations during THA were performed. Forty-nine patients (18%) were diagnosed with osteoporosis (T-score ≤-2.5), 110 patients (41%) with osteopenia (T-score ≤-1.0), and 109 patients (41%) with normal BMD (T-score >-1.0). Importantly, 36/49 patients (73%) with osteoporosis were not diagnosed before, resulting in a relevant undertreatment. Female sex and low body mass index (BMI) were the main factors negatively influencing the bone mineral density (BMD).!##!Conclusions!#!Due to a high incidence of undiagnosed and untreated osteoporosis in elderly patients with potential effects on the success of osseointegration as well as other clinical outcomes, DXA measurements should be included in the clinical routine for these patients prior to THA

Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2

Pregnancy was found to be a skeletal risk factor promoting the initial onset of previously unrecognized monogenic bone disorders, thus explaining a proportion of cases with pregnancy-associated osteoporosis. Therapeutic measures should focus in particular on the normalization of the disturbed calcium homeostasis in order to enable the partial skeletal recovery

Characterization of hearing-impairment in Generalized Arterial Calcification of Infancy (GACI)

Abstract Background and importance Hearing loss (HL) has been sporadically described, but not well characterized, in Generalized Arterial Calcification of Infancy (GACI), a rare disease in which pathological calcification typically presents in infancy. Objectives This study aims to describe the clinical audiologic and otologic features and potential etiology of hearing impairment in GACI and gain pathophysiological insight from a murine model of GACI. Design Cross-sectional cohort study of individuals with GACI. Murine ossicle micromorphology of the ENPP1 asj/asj mutant compared to wild-type. Setting Clinical research hospital; basic science laboratory. Participants Nineteen individuals with GACI who met clinical, biochemical, and genetic criteria for diagnosis. Main outcomes and measures Clinical, biochemical, and radiologic features associated with hearing status. Results Pure-tone thresholds could be established in 15 (n = 30 ears) of the 19 patients who underwent audiological assessments. The prevalence of HL was 50% (15/30) of ears, with conductive HL in 80% and sensorineural HL in 20%. In terms of patients with HL (n = 8), seven patients had bilateral HL and one patient had unilateral HL. Degree of HL was mild to moderate for 87% of the 15 ears with hearing loss. Of those patients with sufficient pure-tone and middle ear function data, 80% (8/10) had audiometric configurations suggestive of ossicular chain dysfunction (OCD). Recurrent episodes of otitis media (ROM) requiring pressure-equalizing tube placement were common. In patients who underwent cranial CT, 54.5% (6/11) had auricular calcification. Quantitative backscattered electron imaging (qBEI) of murine ossicles supports an OCD component of auditory dysfunction in GACI, suggesting loss of ossicular osteocytes without initiation of bone remodeling. Conclusions and relevance Hearing loss is common in GACI; it is most often conductive, and mild to moderate in severity. The etiology of HL is likely multifactorial, involving dysfunction of the ossicular chain and/or recurrent otitis media. Clinically, this study highlights the importance of early audiologic and otologic evaluation in persons with GACI. Novel findings of high rates of OCD and ROM may inform management, and in cases of unclear HL etiology, dedicated temporal bone imaging should be considered