A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders.

Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.

Radiofrequency Echographic Multi Spectrometry (REMS) for the diagnosis of osteoporosis in a European multicenter clinical context.

BACKGROUND: Radiofrequency Echographic Multi Spectrometry (REMS) is a non-ionizing technology for the densitometric assessment of osteoporosis. It has already been validated in Italian women with respect to the current clinical reference technology, Dual-energy X-ray Absorptiometry (DXA). PURPOSE: Aim of the current study was to assess the diagnostic accuracy of REMS technology with respect to DXA in a wider European clinical context. METHODS: A total of 4307 female Caucasian patients aged between 30 and 90 years underwent DXA and REMS scans at femoral neck and/or lumbar spine (the site depending on the medical prescription). The acquired data underwent a rigorous quality check in order to exclude the erroneous DXA and REMS reports. The diagnostic agreement between the two technologies was assessed, also stratifying for patients' age groups. The ability to recognise previously fractured patients was also investigated. RESULTS: Overall, 4245 lumbar spine scans and 4271 femoral neck scans were performed. The ability to discriminate patients with and without osteoporosis by femoral neck investigation resulted in sensitivity and specificity of 90.4% and 95.5%, respectively. For lumbar spine scans, a sensitivity of 90.9% and a specificity of 95.1% were obtained. The areas under the curve (AUCs) of the Receiver Operating Characteristic (ROC) curve evaluating the ability to discriminate groups of patients with previous osteoporotic fracture using DXA and REMS T-score values were 0.631 and 0.683 (p < 0.0001), respectively, for femoral neck scans, whereas 0.603 and 0.640 (p = 0.0002), respectively, for lumbar spine scans. CONCLUSION: The diagnostic effectiveness of REMS technology at reference anatomical sites for the assessment of osteoporosis has been confirmed in a large series of female patients, spanning from younger and pre-menopausal to elderly women up to 90 years, in a multicenter European clinical context.

Microindentation: A New Technique for Bone Quality Assessment.

Fractures are the result of the application of a greater force on bone than its strength. Therefore, to understand fracture physiopathology, it is essential to know bone strength determinants. These include bone mineral density (BMD), bone spatial structure (bone geometry and microarchitecture) and bone mechanical and tissue properties. While BMD and bone spatial structure can be easily evaluated through imaging technology, assessment of bone tissue and mechanical properties is complex and typically requires invasive techniques that are not suitable in clinical practice. Microindentation is a relatively recently developed technique that directly measures bone tissue and mechanical properties in patients in a fast, safe, feasible and minimally invasive way. It appears to be particularly informative in diseases associated with an increased risk of fracture not explained by BMD values as occurs in X-linked hypophosphataemia (XLH). The aim of this article is to provide an overview on bone microindentation and its potential utility in the evaluation of patients with XLH.

Gynecologic and reproductive outcomes in fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: Autonomous ovarian activation with recurrent estrogen-producing cysts is a hallmark feature of the rare bone and endocrine disorder fibrous dysplasia/McCune-Albright syndrome. Precocious puberty in girls with McCune-Albright syndrome has been well-described, however long-term effects on gynecologic and reproductive function are unknown. Concerningly, case reports have described poor skeletal outcomes associated with pregnancy in women with fibrous dysplasia. METHODS: Thirty-nine women with fibrous dysplasia/McCune-Albright syndrome were evaluated as part of a natural history study. Clinical, radiographic, and biochemical data were reviewed. Women were contacted to obtain detailed menstrual and reproductive histories. RESULTS: Abnormal uterine bleeding affected 77% of women (30/39), and was associated with severe anemia requiring blood transfusion in 3 cases. Nine women underwent hysterectomy for management of bleeding, including 67% (6/9) at the unusually young age of less than age 35 years. Infertility affected 43% of women (9/21), including 2 women who developed primary ovarian insufficiency after undergoing surgical treatment of ovarian cysts. Of 25 spontaneous pregnancies in 14 women, 35% (8) were unplanned. Among the 14 pregnancies, pregnancy was associated with no change in bone pain in 7 subjects (53%), increased bone pain in 4 subjects (31%), and decreased bone pain in 2 subjects (15%). No additional skeletal complications were reported during pregnancies. CONCLUSIONS: Women with fibrous dysplasia/McCune-Albright syndrome report a high prevalence of gynecologic morbidity and reduced fertility. There is no clear association between pregnancy and poor skeletal outcomes in this population.

Sex ratio at birth is associated with first-trimester maternal thyrotropin in women receiving levothyroxine.

BACKGROUND: The sex ratio at birth (male out of total alive newborns) is historically established at 0.515 and is influenced by numerous factors. It is not known, however, whether it is influenced by maternal thyroid conditions. Our aim was to analyze its association with maternal thyroid autoimmunity and first-trimester thyrotropin (TSH). METHODS: We performed a retrospective cohort study at a tertiary care center. We studied 167 women who had received pregestational treatment with levothyroxine for hypothyroidism or differentiated thyroid carcinoma and gave birth to live infants. Women with secondary/tertiary hypothyroidism, pregestational diabetes mellitus, or multiple pregnancies were excluded. Autoimmunity was defined as present/absent, and mean first-trimester TSH was tested both as a quantitative variable and using six predefined categories. The outcome measure was sex ratio at birth. RESULTS: The sex ratio at birth was 0.485, not significantly different from expected. Maternal characteristics were similar in mothers of female and male newborns with the exception of mean first-trimester TSH, which was higher in pregnancies of female fetuses (3.27 vs. 2.52 mUI/L, p<0.025). Newborn sex differed across predefined TSH categories (p<0.021, with a sex ratio of 0.200 [95% confidence interval 0.00-0.402] for TSH ≥10 mUI/L). A multiple logistic regression analysis to predict newborn male sex confirmed maternal mean first-trimester TSH as the single predictor (odds ratio 0.900 [95% confidence interval 0.823-0.984], p<0.020). CONCLUSIONS: In women under pregestational treatment with levothyroxine, mean maternal first-trimester TSH is negatively associated with sex ratio at birth. This association has not been previously described.