Vitamin D in pituitary driven osteopathies.

The evidence that pituitary hormones may bypass peripheral endocrine glands to exert remarkable effects on the skeleton is gaining ground. Both hormonal excess and deficit may determine impairment in bone structure, and they commonly result in bone loss in patients affected by pituitary and neuroendocrine disorders. Vertebral fractures are the most common skeletal alterations and may occur independently of bone mass. Use of vitamin D (VD) supplementation is still debated in this setting. This review will focus on the interactions between different metabolites of VD and pituitary hormones, and the effects of VD supplementation on bone metabolism in patients with pituitary diseases.

Bone health and skeletal fragility in second- and third-line medical therapies for acromegaly: preliminary results from a pilot single center experience.

INTRODUCTION: Skeletal fragility is a clinically relevant and not-reversible complication of acromegaly, involving around 30-40% of patients since the disease diagnosis. Few studies have investigated the effects on skeletal health of medical therapies for acromegaly. In this retrospective longitudinal monocentre study, we investigated the outcome of skeletal fragility in patients treated with Pasireotide Lar in combination with Pegvisomant (Pasi-Lar + Peg-V), also comparing those observed in patients treated with conventional therapies. RESULTS: We included 6 patients treated with Pasi-Lar + Peg-V, 5 patients treated with Peg-V in monotherapy (m-Peg-V), 16 patients treated with Peg-V plus first-generation somatostatin receptor ligands (fg-SRLs + Peg-V), 9 patients treated with Pasi-Lar. None of the patients treated with Pasi-Lar + Peg-V experienced worsening of spine and femoral bone mineral density (BMD) and incident vertebral fractures (i-VFs). Eight patients experienced i-VFs. The frequency of i-VFs was significantly lower in patients treated with the Pasi-Lar + Peg-V (0/8; 0%), as compared to those observed in m-Peg-V treated patients (4/8; 50%, p = 0.02). The frequency of i-VFs was slightly but not significantly higher in Pasi-Lar treated patients (1/8; 12.5% p = 0.6) and in fg-SRLs + Peg-V treated patients (3/8; 37.5% p = 0.364), concerning those treated with Pasi-Lar + Peg-V (0/8; 0%). I-VFs occurred more frequently in patients with higher GH levels at acromegaly diagnosis (p < 0.001), and in patients who experienced a BMD worsening (p = 0.005). CONCLUSION: Our preliminary data suggested that in conventional and multi-drug resistant acromegaly, the combination therapy Pasi-Lar + Peg-V may prevent the worsening of BMD and the occurrence of i-VFs. Prospective and translational studies should further validate these results and ascertain underlying physiopathology mechanisms.

Use of noninvasive imaging to identify causes of skeletal fragility in adults with diabetes: a review.

Diabetes, a disease marked by consistent high blood glucose levels, is associated with various complications such as neuropathy, nephropathy, retinopathy, and cardiovascular disease. Notably, skeletal fragility has emerged as a significant complication in both type 1 (T1D) and type 2 (T2D) diabetic patients. This review examines noninvasive imaging studies that evaluate skeletal outcomes in adults with T1D and T2D, emphasizing distinct skeletal phenotypes linked with each condition and pinpointing gaps in understanding bone health in diabetes. Although traditional DXA-BMD does not fully capture the increased fracture risk in diabetes, recent techniques such as quantitative computed tomography, peripheral quantitative computed tomography, high-resolution quantitative computed tomography, and MRI provide insights into 3D bone density, microstructure, and strength. Notably, existing studies present heterogeneous results possibly due to variations in design, outcome measures, and potential misclassification between T1D and T2D. Thus, the true nature of diabetic skeletal fragility is yet to be fully understood. As T1D and T2D are diverse conditions with heterogeneous subtypes, future research should delve deeper into skeletal fragility by diabetic phenotypes and focus on longitudinal studies in larger, diverse cohorts to elucidate the complex influence of T1D and T2D on bone health and fracture outcomes.

Skeletal Fragility in Adult People Living With Type 1 Diabetes.

Advances in the management of people with type 1 diabetes (T1D) led to longer life expectancy, but with it an aging population with age-associated conditions. While macrovascular and microvascular complications are widely recognized, bone fragility has received considerably less attention, although fractures lead to high morbidity and mortality. Hip fracture risk is up to sixfold higher in T1D than in nondiabetic controls and significantly higher than in type 2 diabetes. Hip fractures occur at a younger age, and the consequences are worse. The risk of nonvertebral fractures is also significantly increased. Altered bone quality is a major underlying mechanism. Areal BMD measured by DXA underestimates fracture risk. BMD testing is recommended in T1D patients with poor glycemic control and/or microvascular complications. Trabecular bone score is mildly reduced, and its ability to predict fractures in T1D is unknown. Bone turnover markers, particularly procollagen type 1 N-terminal propeptide, are suppressed and do not predict fracture risk in T1D. T1D-related risk factors for fractures include disease onset at age <20 years, longer disease duration, HbA1c ≥8%, hypoglycemic episodes and microvascular complications. Data regarding the efficacy of therapeutic interventions to prevent or treat skeletal fragility in T1D is scant. Adequate calcium and vitamin D intake and fall prevention are recommended. Antiosteoporosis therapies are recommended in T1D patients with previous hip or vertebral fragility fracture, more than 1 other fragility fracture, BMD T-score < -2.5 at the femoral neck or spine, and increased FRAX score. Fracture risk assessment needs to be part of the management of people with T1D.

Vascular deficits contributing to skeletal fragility in type 1 diabetes.

Over 1 million Americans are currently living with T1D and improvements in diabetes management have increased the number of adults with T1D living into later decades of life. This growing population of older adults with diabetes is more susceptible to aging comorbidities, including both vascular disease and osteoporosis. Indeed, adults with T1D have a 2- to 3- fold higher risk of any fracture and up to 7-fold higher risk of hip fracture compared to those without diabetes. Recently, diabetes-related vascular deficits have emerged as potential risks factors for impaired bone blood flow and poor bone health and it has been hypothesized that there is a direct pathophysiologic link between vascular disease and skeletal outcomes in T1D. Indeed, microvascular disease (MVD), one of the most serious consequences of diabetes, has been linked to worse bone microarchitecture in older adults with T1D compared to their counterparts without MVD. The association between the presence of microvascular complications and compromised bone microarchitecture indicates the potential direct deleterious effect of vascular compromise, leading to abnormal skeletal blood flow, altered bone remodeling, and deficits in bone structure. In addition, vascular diabetic complications are characterized by increased vascular calcification, decreased arterial distensibility, and vascular remodeling with increased arterial stiffness and thickness of the vessel walls. These extensive alterations in vascular structure lead to impaired myogenic control and reduced nitric-oxide mediated vasodilation, compromising regulation of blood flow across almost all vascular beds and significantly restricting skeletal muscle blood flow seen in those with T1D. Vascular deficits in T1D may very well extend to bone, compromising skeletal blood flow control, and resulting in reduced blood flow to bone, thus negatively impacting bone health. Indeed, several animal and ex vivo human studies report that diabetes induces microvascular damage within bone are strongly correlated with diabetes disease severity and duration. In this review article, we will discuss the contribution of diabetes-induced vascular deficits to bone density, bone microarchitecture, and bone blood flow regulation, and review the potential contribution of vascular disease to skeletal fragility in T1D.

Genetic and Gene Expression Resources for Osteoporosis and Bone Biology Research.

PURPOSE OF REVIEW: The integration of data from multiple genomic assays from humans and non-human model organisms is an effective approach to identify genes involved in skeletal fragility and fracture risk due to osteoporosis and other conditions. This review summarizes genome-wide genetic variation and gene expression data resources relevant to the discovery of genes contributing to skeletal fragility and fracture risk. RECENT FINDINGS: Genome-wide association studies (GWAS) of osteoporosis-related traits are summarized, in addition to gene expression in bone tissues in humans and non-human organisms, with a focus on rodent models related to skeletal fragility and fracture risk. Gene discovery approaches using these genomic data resources are described. We also describe the Musculoskeletal Knowledge Portal (MSKKP) that integrates much of the available genomic data relevant to fracture risk. The available genomic resources provide a wealth of knowledge and can be analyzed to identify genes related to fracture risk. Genomic resources that would fill particular scientific gaps are discussed.

Vitamin D and Chronic Kidney Disease Association with Mineral and Bone Disorder: An Appraisal of Tangled Guidelines.

Chronic kidney disease (CKD) is a highly prevalent condition worldwide in which the kidneys lose many abilities, such as the regulation of vitamin D (VD) metabolism. Moreover, people with CKD are at a higher risk of multifactorial VD deficiency, which has been extensively associated with poor outcomes, including bone disease, cardiovascular disease, and higher mortality. Evidence is abundant in terms of the association of negative outcomes with low levels of VD, but recent studies have lowered previous high expectations regarding the beneficial effects of VD supplementation in the general population. Although controversies still exist, the diagnosis and treatment of VD have not been excluded from nephrology guidelines, and much data still supports VD supplementation in CKD patients. In this narrative review, we briefly summarize evolving controversies and useful clinical approaches, underscoring that the adverse effects of VD derivatives must be balanced against the need for effective prevention of progressive and severe secondary hyperparathyroidism. Guidelines vary, but there seems to be general agreement that VD deficiency should be avoided in CKD patients, and it is likely that one should not wait until severe SHPT is present before cautiously starting VD derivatives. Furthermore, it is emphasized that the goal should not be the complete normalization of parathyroid hormone (PTH) levels. New developments may help us to better define optimal VD and PTH at different CKD stages, but large trials are still needed to confirm that VD and precise control of these and other CKD-MBD biomarkers are unequivocally related to improved hard outcomes in this population.

Diabetes and osteoporosis - Treating two entities: A challenge or cause for concern?

People with T1D and T2D have an increased risk of fractures than the general population, posing several significant pathophysiologic, diagnostic, and therapeutic challenges. The pathophysiology is still not fully elucidated, but it is considered a combination of increased skeletal fragility and falls. Diagnostics issues exist, as regular and even newer scan methods underestimate the true incidence of osteoporosis and thus the fracture risk. Therefore, co-managing diabetes and osteoporosis by using top-line strategies is essential to preserve bone health and minimize the risk of falls. The therapeutic focus should start with lifestyle implementation and physical exercise interventions to reduce diabetic complications, strengthen bones, and improve postural control strategies. In addition, osteoporosis should be treated according to current guidelines by including bisphosphonates and antidiabetic drugs that support bone health. Finally, potentially modifiable risk factors for falls should be managed.

Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience.

INTRODUCTION: Acromegaly is a chronic disease with systemic complications. Disease onset is insidious and consequently typically burdened by diagnostic delay. A longer diagnostic delay induces more frequently cardiovascular, respiratory, metabolic, neuropsychiatric and musculoskeletal comorbidities. No data are available on the effect of diagnostic delay on skeletal fragility. We aimed to evaluate the effect of diagnostic delay on the frequency of incident and prevalent of vertebral fractures (i-VFs and p-VFs) in a large cohort of acromegaly patients. PATIENTS AND METHODS: A longitudinal, retrospective and multicenter study was conducted on 172 acromegaly patients. RESULTS: Median diagnostic delay and duration of follow-up were respectively 10 years (IQR: 6) and 10 years (IQR: 8). P-VFs were observed in 18.6% and i-VFs occurred in 34.3% of patients. The median estimated diagnostic delay was longer in patients with i-VFs (median: 11 years, IQR: 3), in comparison to those without i-VFs (median: 8 years, IQR: 7; p = 0.02). Age at acromegaly diagnosis and at last follow-up were higher in patients with i-VFs, with respect to those without i-VFs. The age at acromegaly diagnosis was positively associated with the diagnostic delay (p < 0.001, r = 0.216). A longer history of active acromegaly was associated with a high frequency of i-VFs (p = 0.03). The logistic regression confirmed that patients with a diagnostic delay > 10 years had 1.5-folds increased risk of developing i-VFs (OR: 1.5; 95%CI: 1.1-2; p = 0.017). CONCLUSION: Our data showed that the diagnostic delay in acromegaly has a significant impact on VF risk, further supporting the clinical relevance of an early acromegaly diagnosis.

Determinants of skeletal fragility in acromegaly: a systematic review and meta-analysis.

PURPOSE: Vertebral fractures (VFs) are a potential complication in acromegaly. However, the etiology of this skeletal fragility is unknown. This review aimed to evaluate the effect of acromegaly on VFs, bone turnover, areal bone mineral density (aBMD), and bone quality/microarchitecture. The effect of disease activity and gonadal status in these determinants of skeletal fragility was also evaluated. METHODS: Articles published in English until September 6, 2020 on PubMed and Embase that reported at least one determinant of skeletal fragility in acromegalic patients, were included. Odds ratio (OR) to evaluate the risk of VFs and the standardized mean difference (SMD) to evaluate bone turnover, aBMD and bone quality/microarchitecture were calculated. RESULTS: Fifty-eight studies met eligibility criteria, assembling a total of 2412 acromegalic patients. Of these, 49 studies were included in the meta-analysis. Acromegalic patients, when compared to non-acromegalic patients, had higher risk of VFs [OR 7.00; 95% confidence interval (CI) 2.80-17.52; p < 0.0001], higher bone formation (SMD 1.14; 95% CI 0.69-1.59; p < 0.00001), higher bone resorption (SMD 0.60; 95% CI 0.09-1.10; p = 0.02) and higher aBMD at the femoral neck (SMD 0.36; 95% CI 0.15-0.57; p = 0.0009). No significant differences were found regarding aBMD at lumbar spine. Considering the results of the different techniques evaluating bone quality/microarchitecture, the main reported alterations were a decrease in trabecular bone thickness and density, and an increase in trabecular separation. The presence of active disease and/or hypogonadism were associated with worst results. CONCLUSION: Patients with acromegaly are at increased risk of VFs, mainly because of deterioration in bone microarchitecture.

Bone Mineral Density Post a Spinal Cord Injury: A Review of the Current Literature Guidelines.

BACKGROUND: Spinal cord injury (SCI) causes rapid osteoporosis below the level of injury in a multi-factorial manner. This literature review focused on the early diagnosis of low bone mass (LBM) in SCI patients and aimed to summarize all the available recent data on the diagnosis and treatment of osteoporosis in this unique patient population.  Materials and Methods: Advanced literature research was conducted in the online PubMed database using the keywords 'bone mineral density, 'spinal cord injury, 'skeletal fragility', and 'osteoporotic fractures'. Out of the initial 430 articles, duplicates were removed and the remaining studies were assessed for eligibility. Two reviewers independently extracted data from each study and assessed variable reporting of outcome data. The exclusion criteria were: studies not measuring bone mineral density (BMD), studies comparing SCI to other diseases, animal studies, molecular studies, studies including children, and studies not written in English. The 83 remaining papers were divided into studies focusing on treatment and studies investigating LBM in SCI. Following this step, studies with small patient samples set at 20 patients with SCI for the treatment group and 30 patients for the diagnosis of the LBM group, were also excluded. RESULTS: In the remaining 32 studies, 18 focused on the diagnosis of LBM in SCI and 14 focused on the various treatment options to address this phenomenon. Most of these studies (n=13) used the dual-energy X-ray absorptiometry (DXA) method to evaluate bone mass while five studies preferred quantitative computed tomography (QCT) measurements and one evaluated LBM using calcaneal qualitative ultrasound. In the treatment group of studies, seven papers administered medication to address LBM and four clinical protocols used physiotherapy methods to reduce bone loss post-SCI while three studies combined medical treatment with physiotherapy. CONCLUSION: The unawareness of the unique mechanism through which bone is rapidly lost in the first months post-SCI led to initial scientific confusion. In this review, we summarize information to increase physicians' awareness of the dangers of 'silent' osteoporosis progression post-SCI. We have also provided information on the best timing to evaluate bone loss as well as treatment options that could prevent fragility fractures in this population.

Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome.

PURPOSE: Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS: Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS: bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION: TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.

Deletion of Coagulation Factor IX Compromises Bone Mass and Strength: Murine Model of Hemophilia B (Christmas Disease).

Osteopenia and osteoporosis have increasingly become a recognized morbidity in those persons with hemophilia (PwH) receiving inadequate prophylactic clotting factor replacement. Animal models can control or eliminate genetic and environmental factors and allow for invasive testing not clinically permissible. Here, we describe the skeletal phenotype of juvenile and adult male mice with a genetically engineered deficiency in coagulation factor IX (FIX KO). Although the somatic growth of FIX KO mice matched that of their wild-type (WT) littermates at 10 and 20 weeks of age, the FIX KO mice displayed reduced bone mineral density (BMD), reduced cortical and cancellous bone mass, and diminished whole bone fracture resistance. These findings coupled with parallel observations in a murine model of hemophilia A (FVIII deficiency) point to an effector downstream of the coagulation cascade that is necessary for normal skeletal development. Further study of potential mechanisms underlying the bone disease observed in rare clotting factor deficiency syndromes may lead to new diagnostic and therapeutic insights for metabolic bone diseases in general.

Type 2 diabetes and bone fragility- An under-recognized association.

BACKGROUND AND AIMS: Diabetes and osteoporosis are common chronic disorders with growing prevalence in the aging population. Skeletal fragility secondary to diabetes increases the risk of fractures and is underestimated by currently available diagnostic tools like fracture risk assessment (FRAX) and dual-energy X-ray absorptiometry (DXA). In this narrative review we describe the relationship and pathophysiology of skeletal fragility and fractures in Type 2 diabetes (T2DM), effect of glucose lowering medications on bone metabolism and the approach to diagnosing and managing osteoporosis and bone fragility in people with diabetes (PWD). METHODS: A literature search was conducted on PubMed for articles in English that focused on T2DM and osteoporosis or bone/skeletal fragility. Articles considered to be of direct clinical relevance to physicians practicing diabetes were included. RESULTS: T2DM is associated with skeletal fragility secondary to compromised bone remodeling and bone turnover. Long duration, poor glycemic control, presence of chronic complications, impaired muscle function, and anti-diabetic medications like thiazolidinediones (TZD) are risk factors for fractures among PWD. Conventional diagnostic tools like DXA and FRAX tool underestimate fracture risk in diabetes. Presence of diabetes does not alter response to anti-osteoporotic treatment in post-menopausal women. CONCLUSION: Estimation of fragility fracture risk should be included in standard of care for T2DM along with screening for traditional complications. Physicians should proactively screen for and manage osteoporosis in people with diabetes. It is important to consider effects on bone health when selecting glucose lowering agents in people at risk for fragility fractures.

Glomerular filtration rate is associated with trabecular bone score in patients with type 2 diabetes mellitus.

AIMS: The present study aimed to evaluate the trabecular and cortical bone components using Trabecular Bone Score (TBS) and its association with estimated-Glomerular Filtration Rate (e-GFR) in T2DM patients. METHODS: An assessment both of bone mineral density (BMD) and vertebral bone microarchitecture was performed in all patients using TBS iNsight® software version 3.0.2.0. Furthermore, the total population was divided into two groups based on the value of the eGFR (eGFR < o > at 60 ml/min/1.73 m2). RESULTS: TBS value was lower in patients with low e-GFR than that in patients with higher e-GFR (1.246 ± 0.125 vs 1.337 ± 0.115, respectively, p = 0.013 adjusted by gender and age) while there was no difference in total BMD value between two groups. In the multivariate model taking into account several possible confounders, such as age, gender, duration of diabetes, BMI, LDL cholesterol, serum calcium and HbA1c, the correlation between e-GFR and TBS remained significant (p: 0.046). CONCLUSIONS: In individuals with T2DM and reduced kidney function, TBS provides information independent of BMD, age and gender. TBS may be a useful additional tool to predict fracture risk in this unique population.

Hyperglycemia impairs osteoblast cell migration and chemotaxis due to a decrease in mitochondrial biogenesis.

Diabetes is associated with an increase in skeletal fragility and risk of fracture. However, the underlying mechanism for the same is not well understood. Specifically, the results from osteoblast cell culture studies are ambiguous due to contradicting reports. The use of supraphysiological concentrations in these studies, unachievable in vivo, might be the reason for the same. Therefore, here, we studied the effect of physiologically relevant levels of high glucose during diabetes (11.1 mM) on MC3T3-E1 osteoblast cell functions. The results showed that high glucose exposure to osteoblast cells increases their differentiation and mineralization without any effect on the proliferation. However, high glucose decreases their migratory potential and chemotaxis with a decrease in the associated cell signaling. Notably, this decrease in cell migration in high glucose conditions was accompanied by aberrant localization of Dynamin 2 in osteoblast cells. Besides, high glucose also caused a shift in mitochondrial dynamics towards the appearance of more fused and lesser fragmented mitochondria, with a concomitant decrease in the expression of DRP1, suggesting decreased mitochondrial biogenesis. In conclusion, here we are reporting for the first time that hyperglycemia causes a reduction in osteoblast cell migration and chemotaxis. This decrease might lead to an inefficient movement of osteoblasts to the erosion site resulting in uneven mineralization and skeletal fragility found in type 2 diabetes patients, in spite of having normal bone mineral density (BMD).

FGF23-related hypophosphatemia in patients with low bone mineral density and fragility fractures: challenges in diagnosis and management.

PURPOSE: Hypophosphatemia (HP) can be observed in patients evaluated for skeletal fragility. We investigated prevalence of HP among outpatients referred for low bone density or fragility fractures, HP-associated clinical and biochemical features and outcomes of recommended diagnostic algorithm in our cohort. METHODS: Chronic HP (phosphate ≤ 2.7 mg/dL over 6 months or longer) was retrospectively investigated among 2319 patients. In renal wasting-related HP, intact FGF23 was assessed; non-suppressed FGF23 prompted the performance of 68Ga-DOTATOC PET/CT in the suspicion of tumor-induced steomalacia (TIO). RESULTS: Renal wasting-related HP (median 2.2, range 1.6-2.6 mg/dL) was observed in 19 patients (0.82%). FGF23 levels were suppressed in two patients diagnosed with renal tubular disease, increased in one and within normal range in most patients. X-linked hypophosphatemic rickets was diagnosed in one woman. In the remaining 16 patients, highly prevalent fragility fractures (50%) and severely reduced bone mineral density were detected, though diagnostic criteria for osteomalacia were not fulfilled. 68Ga-PET was performed in nine patients and was positive in four. While intact FGF23 levels alone failed to differentiate PET's outcomes (positive: FGF23 median 70.5 pg/mL; negative: 52 pg/mL, P = 0.462), the coexistence of multiple biochemical and radiologic alterations performed better in prediction of PET's positivity. CONCLUSION: Mild, apparently unexplained HP is observed in 0.82% of patients with low bone density or fragility fractures. In asymptomatic patients with isolated mild hypophosphatemia, the probability of finding an underlying tumor disease is very low, and utility of extensive and expensive diagnostic workup should be carefully considered in this setting.

The Effect of Type 2 Diabetes on Bone Biomechanics.

PURPOSE OF REVIEW: There is ample evidence that patients with type 2 diabetes (T2D) have increased risk of fracture even though they have normal or high bone mineral density. As a result, poor bone quality is suggested to contribute to skeletal fragility in this population. Thus, our goal was to conduct a comprehensive literature review to understand how bone quality components are altered in T2D and their effects on bone biomechanics and fracture risk. RECENT FINDINGS: T2D does affect bone quality via alterations in bone microarchitecture, organic matrix, and cellular behavior. Further, studies indicate that bone biomechanical properties are generally deteriorated in T2D, but there are few reports in patients. Additional work is needed to better understand molecular and cellular mechanisms that contribute to skeletal fragility in T2D. This knowledge can contribute to the development of improved diagnostic tools and drug targets to for improved quality of life for those with T2D.

A novel mutation in COL1A2 leads to osteogenesis imperfecta/Ehlers-Danlos overlap syndrome with brachydactyly.

Osteogenesis imperfecta (OI) is mainly characterized by bone fragility and Ehlers-Danlos syndrome (EDS) by connective tissue defects. Mutations in COL1A1 or COL1A2 can lead to both syndromes. OI/EDS overlap syndrome is mostly caused by helical mutations near the amino-proteinase cleavage site of type I procollagen. In this study, we identified a Thai patient having OI type III, EDS, brachydactyly, and dentinogenesis imperfecta. His dentition showed delayed eruption, early exfoliation, and severe malocclusion. For the first time, ultrastructural analysis of the tooth affected with OI/EDS showed that the tooth had enamel inversion, bone-like dentin, loss of dentinal tubules, and reduction in hardness and elasticity, suggesting severe developmental disturbance. These severe dental defects have never been reported in OI or EDS. Exome sequencing identified a novel de novo heterozygous glycine substitution, c.3296G > A, p.Gly1099Glu, in exon 49 of COL1A2. Three patients with mutations in the exon 49 of COL1A2 were previously reported to have OI with brachydactyly and intracranial hemorrhage. Notably, two of these three patients did not show hyperextensible joints and hypermobile skin, while our patient at the age of 5 years had not developed intracranial hemorrhage. Here, we demonstrate that the novel glycine substitution in the carboxyl region of alpha2(I) collagen triple helix leads to OI/EDS with brachydactyly and severe tooth defects, expanding the genotypic and phenotypic spectra of OI/EDS overlap syndrome.

Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility.

Obesity is associated with increased risk for fragility fractures. However, the cellular mechanisms are unknown. Using a translational approach combining RNA sequencing and cellular analyses, we investigated bone marrow stromal stem cells (BM-MSCs) of 54 men divided into lean, overweight, and obese groups on the basis of BMI. Compared with BM-MSCs obtained from lean, obese BM-MSCs exhibited a shift of molecular phenotype toward committed adipocytic progenitors and increased expression of metabolic genes involved in glycolytic and oxidoreductase activity. Interestingly, compared with paired samples of peripheral adipose tissue-derived stromal cells (AT-MSCs), insulin signaling of obese BM-MSCs was enhanced and accompanied by increased abundance of insulin receptor positive (IR+) and leptin receptor positive (LEPR+) cells in BM-MSC cultures. Their hyper-activated metabolic state was accompanied by an accelerated senescence phenotype. Our data provide a plausible explanation for the bone fragility in obesity caused by enhanced insulin signaling leading to accelerated metabolic senescence of BM-MSCs.