Ling Oei

We aimed to: (1) examine the relationship between glycemic control, BMD estimated from heel ultrasound (eBMD) and fracture risk in individuals with type 1 (T1D) and type 2 diabetes (T2D) and (2) perform a one-sample Mendelian randomization (MR) study to explore potential causal associations between glycemic control, eBMD, and fractures. This study comprised 452 131 individuals from the UK Biobank with glycated hemoglobin A1C (HbA_1c) and eBMD levels. At baseline, 4078 participants were diagnosed with T1D and 23 682 with T2D. HbA_1c was used to classify patients into “adequately-” (ACD; n = 17 078; HbA_1c < 7.0%/53 mmol/mol) and “inadequately-” (ICD; n = 10 682; HbA_1c ≥ 7.0%/53 mmol/mol) controlled diabetes. In individuals with T1D, a 1% unit (11 mmol/mol) increase in HbA_1c levels was associated with a 12% increase in fracture risk (HR: 1.12, 95% CI [1.05-1.19]). Fracture risk was highest in individuals with T1D and ICD (HR 2.84, 95%CI [2.53, 3.19]), followed by those with ACD (HR 2.26, 95%CI [1.91, 2.69]), as compared to subjects without diabetes. Evidence for a non-linear association between HbA_1c and fracture risk was observed (F-test ANOVA p-value = 0.002) in individuals with T2D, with risk being increased at both low and high levels of HbA_1c. Fracture risk between the T2D ACD and ICD groups was not significantly different (HR: 0.97, 95%CI [0.91-1.16]), despite increased BMD. In MR analyses genetically predicted higher HbA_1c levels were not significantly associated with fracture risk (causal risk ratio: 1.04, 95%CI [0.95-1.14]). We did observe evidence of a non-linear causal association with eBMD (quadratic test p-value = 0.0002), indicating U-shaped relationship between HbA_1c and eBMD. We obtained evidence that lower HbA_1c levels will reduce fracture risk in patients with T1D. In individuals with T2D, lowering HbA_1c levels can mitigate the risk of fractures up to a threshold, beyond which the risk may begin to rise again.

Introduction: Osteoporosis is a prevalent skeletal disease associated with increased fracture risk, morbidity, and mortality. Several meta-analyses have investigated the association between non-genetic, non-pharmacologic factors and osteoporosis risk. Purpose: We aimed to perform an umbrella review of the literature to systematically evaluate the available evidence. Methods: Meta-analyses of observational studies evaluating the association between non-genetic, non-pharmacologic factors and osteoporosis risk in mainly adult populations were identified by searching MEDLINE (via PubMed), Scopus and CENTRAL databases up to March 2022. The epidemiological validity and methodological quality of the evidence were graded based on commonly accepted criteria. Results: Twenty-nine meta-analysis publications were identified (41 individual meta-analyses, 33 risk factors, 242 primary study comparisons). Assessed risk factors included nutritional exposures, disease entities (gastrointestinal, endocrinological, dermatological, other systems), infections, biomarkers, and lifestyle characteristics. Of the 41 meta-analyses, 2 (5%) were graded as of high validity evidence to support the association with higher osteoporosis risk (hyponatremia, peptic ulcer), and 4 (10%) as of moderate validity (lower total dairy or fruit intake, Parkinson’s disease, higher urine cadmium). Of the 29 meta-analyses, 2 (7%) were judged as of high quality (fruit intake, atopic dermatitis). Most meta-analyses evaluated as of high/moderate validity or high quality included a few primary longitudinal studies. Conclusion: Despite the breadth of the meta-analytical literature on osteoporosis risk factors, only hyponatremia, peptic ulcer, lower total dairy or fruit intake, Parkinson’s disease, and higher urine cadmium were evaluated as of high/moderate validity. Identifying epidemiologically robust risk factors could help guide clinical practice and public health policy.

Worldwide, there are millions of people who have been diagnosed with osteoporosis, a bone disease that increases the risk of fracture due to low bone mineral density and deterioration of bone architecture. In the US alone, there are approximately ten million men and women diagnosed with osteoporosis and this number is still growing. Diagnosis is made by measuring bone mineral density. Medications used for the treatment of osteoporosis are bisphosphonates, denosumab, raloxifene, and teriparatide. Recently, romosozumab has been added as well. In recent years, a number of advances have been made in the field of diagnostic methods and the diverse treatment options for osteoporosis. Despite these advances and a growing incidence of osteoporosis, there is a large group being left undertreated or even untreated. This group of the under/untreated has been called the treatment gap. Concerns regarding rare side effects of the medications, such as osteonecrosis of the jaw, have been reported to be one of the many causes for the treatment gap. Also, this group seems not to be sufficiently informed of the major benefits of the treatment and the diversity in treatment options. Knowledge of these could be very helpful in improving compliance and hopefully reducing the gap. In this paper, we summarize recent evidence regarding the efficacy of the various treatment options, potential side effects, and the overall benefit of treatment.

Purpose of Review: The purpose of this review is to summarize the recently published evidence concerning vertebral fracture risk in individuals with diabetes mellitus. Recent Findings: Vertebral fracture risk is increased in individuals with T2DM. The presence of vertebral fractures in T2DM is associated with increased non-vertebral fracture risk and mortality. TBS could be helpful to estimate vertebral fracture risk in individuals with T2DM. An increased amount of bone marrow fat has been implicated in bone fragility in T2DM. Results from two recent studies show that both teriparatide and denosumab are effective in reducing vertebral fracture risk also in individuals with T2DM. Summary: Individuals with T2DM could benefit from systematic screening in the clinic for presence of vertebral fractures.

Summary We conducted a randomized placebo-controlled double-blinded clinical trial of MK-7 or placebo daily for 3 years in postmenopausal women with osteopenia. BMD decreased at all sites without differences between the MK-7 and placebo-treated women. Changes in bone turnover markers and microstructure were similar between the two groups. Introduction Vitamin K is a cofactor in the carboxylation of osteocalcin (OC) and carboxylated OC promotes mineralization of bone. Clinical studies suggest that vitamin K2 prevents bone loss. The aim of the study was to investigate the effect of vitamin K2 as an add-on to calcium and vitamin D supplementation on osteocalcin, bone mass, and microarchitecture in postmenopausal women. Methods We conducted a randomized placebo-controlled double-blinded clinical trial, including 142 postmenopausal women with osteopenia who received vitamin K2 (375 μg MK-7) or placebo daily for 3 years. Both groups received vitamin D3 (38 μg/day) and calcium (800 mg/day). We measured bone turnover markers in serum and bone mineral density and microarchitecture by DXA and HRpQCT. Results Undercarboxylated osteocalcin decreased in the MK-7-group (− 65.2 ± 23.5%) (mean ± SD) compared with the placebo group (− 0.03 ± 38.5%), p < 0.01 after 1 year. After 3 years, aBMD decreased at all sites without differences between the MK-7 and placebo-treated women (p > 0.09). aBMD decreased at the total hip by 1.5 ± 2.5% and 2.4 ± 2.7% in the MK-7 and the placebo groups, respectively, at the femoral neck by 1.5 ± 3.5% and 1.0 ± 5.0% in the MK-7 and the placebo groups, respectively, and at the lumbar spine by 1.8 ± 3.9% and 1.1 ± 3.1% in the MK-7 and the placebo groups, respectively. Changes in bone turnover markers were also similar between the two groups.We have previously reported improved microarchitecture with MK-7 after 1 year. However, changes in microstructure over 3 years were similar between the two groups, as assessed by both HRpQCT and DXA trabecular bone score. Conclusion Treatment with MK-7 375 μg daily as an add-on to calcium and vitamin D increased carboxylation of osteocalcin. However, treatment of postmenopausal women with osteopenia for 3 years did not affect biochemical markers of bone turnover, bone mineral density, or bone microarchitecture. Trial registration The study was registered at Clinicaltrial.gov:NCT01922804.

Genetic susceptibility, together with old age, female sex, and low bone mineral density (BMD) are amongst the strongest determinants of fracture risk. Tmost recent large-scale genome-wide association study (GWAS) meta-analysis has yielded fifteen loci. This review focuses on the advances in the research of genetic determinants of fracture risk. We first discuss the genetic architecture of fracture risk, touching upon different methods and overall findings. We then discuss in a second paragraph the most recent advances in the field and focus on the genetics of fracture risk and also of other endophenotypes closely related to fracture risk such as bone mineral density (BMD). Application of state-of-the-art methodology such as Mendelian randzation in fracture GWAS are reviewed. The final part of this review touches upon potential future directions in genetic research of osteoporotic fractures.

Background: An increasing amount of biomedical data is becoming available, and methods are needed to tackle these “big data”. Methods: We performed a systematic evaluation of 138 environmental and behavioral factors in relation to bone mineral density (BMD) in the National Health and Nutrition Examination Survey (NHANES). Dual energy X-ray absorptiometry (DXA) scans were available for total body, head, pelvis and lumbar spine for 27,259 participants from NHANES surveys 1999–2000 (A), 2001–2002 (B), 2003–2004 (C) and 2005–2006 (D). A discovery Environment-Wide Association Study (EWAS) was performed on cohorts B and D, and replication was sought in cohorts A and C. Results: Higher serum levels of a-tocopherol (per S.D. β=−0.25% for lumbar spine) and of g-tocopherol (β=−0.54% for total body), forms of vitamin E, were associated with decreased BMD. In contrast, retinol serum levels were related to higher BMD (per S.D. β=+0.21% for total body). Serum lead levels had a negative relationship to BMD of the lumbar spine (per S.D. β=−0.43%) and head (per S.D. β=−0.87%). Higher levels of physical activity were associated with higher BMD (total body: per MET +1.2%). Being a current or past smoker was associated with decreased BMD of the total body, pelvis and head. Conclusion: In conclusion, our study demonstrates consistently that several behavioral traits and fat-soluble vitamins may have detrimental effects on BMD, while reinforcing the benefit of physical activity for skeletal health.