The Effects of Osteoporotic and Non-osteoporotic Medications on Fracture Risk and Bone Mineral Density
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ABSTRACT: Supplementary Information
The online version contains supplementary material available at 10.1007/s40265-021-01625-8.
SUBMITTER: van der Burgh A
PROVIDER: S-EPMC8578161 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ?2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)<P<5.9 × 10(-4)) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.
| S-EPMC3390364 | biostudies-literature
Project description:To identify susceptibility genes for osteoporosis, we conducted an integrative analysis that combined epigenomic elements and previous genome-wide association studies (GWASs) data, followed by validation at population and functional levels, which could identify common regulatory elements and predict new susceptibility genes that are biologically meaningful to osteoporosis. By this approach, we found a set of distinct epigenomic elements significantly enriched or depleted in the promoters of osteoporosis-associated genes, including 4 transcription factor binding sites, 27 histone marks, and 21 chromatin states segmentation types. Using these epigenomic marks, we performed reverse prediction analysis to prioritize the discovery of new candidate genes. Functional enrichment analysis of all the prioritized genes revealed several key osteoporosis related pathways, including Wnt signaling. Genes with high priority were further subjected to validation using available GWASs datasets. Three genes were significantly associated with spine bone mineral density, including BDNF, PDE4D, and SATB2, which all closely related to bone metabolism. The most significant gene BDNF was also associated with osteoporotic fractures. RNA interference revealed that BDNF knockdown can suppress osteoblast differentiation. Our results demonstrated that epigenomic data could be used to indicate common epigenomic marks to discover additional loci with biological functions for osteoporosis.
| S-EPMC4964617 | biostudies-literature
Project description:ImportanceScreening for osteoporosis with bone mineral density (BMD) is recommended for older adults. It is unclear whether repeating a BMD screening test improves fracture risk assessment.ObjectivesTo determine whether changes in BMD after 4 years provide additional information on fracture risk beyond baseline BMD and to quantify the change in fracture risk classification after a second BMD measure.Design, setting, and participantsPopulation-based cohort study involving 310 men and 492 women from the Framingham Osteoporosis Study with 2 measures of femoral neck BMD taken from 1987 through 1999.Main outcomes and measuresRisk of hip or major osteoporotic fracture through 2009 or 12 years following the second BMD measure.ResultsMean age was 74.8 years. The mean (SD) BMD change was -0.6% per year (1.8%). Throughout a median follow-up of 9.6 years, 76 participants experienced an incident hip fracture and 113 participants experienced a major osteoporotic fracture. Annual percent BMD change per SD decrease was associated with risk of hip fracture (hazard ratio [HR], 1.43 [95% CI, 1.16 to 1.78]) and major osteoporotic fracture (HR, 1.21 [95% CI, 1.01 to 1.45]) after adjusting for baseline BMD. At 10 years' follow-up, 1 SD decrease in annual percent BMD change compared with the mean BMD change was associated with 3.9 excess hip fractures per 100 persons. In receiver operating characteristic (ROC) curve analyses, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance. The area under the curve (AUC) was 0.71 (95% CI, 0.65 to 0.78) for the baseline BMD model compared with 0.68 (95% CI, 0.62 to 0.75) for the BMD percent change model. Moreover, the addition of BMD change to a model with baseline BMD did not meaningfully improve performance (AUC, 0.72 [95% CI, 0.66 to 0.79]). Using the net reclassification index, a second BMD measure increased the proportion of participants reclassified as high risk of hip fracture by 3.9% (95% CI, -2.2% to 9.9%), whereas it decreased the proportion classified as low risk by -2.2% (95% CI, -4.5% to 0.1%).Conclusions and relevanceIn untreated men and women of mean age 75 years, a second BMD measure after 4 years did not meaningfully improve the prediction of hip or major osteoporotic fracture. Repeating a BMD measure within 4 years to improve fracture risk stratification may not be necessary in adults this age untreated for osteoporosis.
| S-EPMC3903386 | biostudies-literature
Project description:Candidate osteoporosis gene variants were examined for associations with fracture risk and bone mineral density (BMD). A total of 9,704 white women were recruited at four U.S. clinical centers and enrolled into the Study of Osteoporotic Fractures, a longitudinal cohort study. Genotyping of 31 polymorphisms from 18 candidate osteoporosis genes was performed in 6,752 women. Incident radiographic fractures were identified at the third and eighth examinations compared with the baseline examination. BMD was measured at the total hip by dual-energy X-ray absorptiometry. Analyses were adjusted for age, clinic site, and self-reported ethnicity. During a mean follow-up of 14.5 years, a total of 849 hip, 658 vertebral, and 2,496 nonhip/nonvertebral fractures occurred in 6,752 women. Women carrying the ALOX15_G48924T T/T genotype had a higher rate of hip fracture (hazard ratio [HR] = 1.33;95% confidence interval [95% CI] = 1.00-1.77) compared with the G/G genotype. Compared with those carrying the PRL_T228C T/T genotype, women with either the C/C (HR = 0.80; 95% CI = 0.67-0.95) or C/T (HR = 0.81; 95% CI = 0.68-0.97) genotype had a lower rate of nonvertebral/nonhip fractures. Women carrying the BMP2_A125611G G/G genotype had a higher rate of vertebral fracture (odds ratio [OR] = 1.51; 95% CI = 1.03-2.23) compared with the A/A genotype. Women with the ESR1_C1335G G/G genotype had a higher rate of vertebral fracture (OR = 1.64; 95% CI = 1.07-2.50) compared with the C/C genotype. Compared with those with the MMP2_C595T C/C genotype, women with the C/T (OR = 0.79; 95% CI = 0.65-0.96) or T/T (OR = 0.44; 95% CI = 0.27-0.72) genotype had a lower rate of vertebral fracture. In conclusion, polymorphisms in several candidate genes were associated with hip, vertebral, and nonhip/nonvertebral fractures but not with total hip BMD in this large population based cohort study.
| S-EPMC2699257 | biostudies-literature
Project description:We performed a systematic review on the effect of drug holidays (discontinuation) on bone mineral density (BMD) and fracture risk. Bisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3-5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.IntroductionWe performed a systematic review and meta-analysis on the effect of drug holidays (discontinuation) on BMD and fracture risk.MethodsWe searched PubMed, Embase, and Cochrane Library databases to locate controlled clinical trials and cohort studies evaluating the effect of drug holidays/discontinuation versus osteoporosis treatment continuation. We performed random-effects meta-analyses of hazard ratios of hip and any clinical osteoporotic fracture for individuals who discontinued bisphosphonates compared to persistent users.ResultsThirteen records reporting results from eight different studies met inclusion criteria. The FLEX study found a reduced clinical vertebral fracture risk with 10 years of alendronate therapy compared to 5 (RR 0.45, 95% CI 0.24-0.85), and the HORIZON extension studies found a reduced risk of morphometric vertebral fracture with 6 years of zoledronic acid therapy compared to 3 (OR = 0.51, 95% CI 0.26-0.95); subgroup analyses showed that women with low hip BMD T-scores after the initial treatment period benefitted from continued treatment in terms of reduced vertebral fracture risk. Meta-analysis of adjusted hazard ratios of hip and any clinical osteoporotic fracture for women who discontinued bisphosphonates revealed no significant differences in the risk of hip fracture (summary estimate of HR 1.09, 95% CI 0.87-1.37) or any clinical fracture (summary estimate of HR 1.13, 95% CI 0.75-1.70) compared to persistent users.ConclusionsBisphosphonate discontinuation may be considered for women who do not have low hip BMD after 3 to 5 years of initial treatment, while women who have low hip BMD may benefit from treatment continuation.
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Project description:Osteoporosis and Parkinson's disease (PD) are two important age-related diseases, which have an influence on pain, physical activity, disability, and mortality. The aim of this research was to study the parameters of bone mineral density (BMD), frequency, and 10-year probability of osteoporotic fractures (OFs) in females with Parkinson's disease (PD). We have examined 113 postmenopausal women aged 50-74 years old which were divided into 2 groups (I, control group (CG), n?=?53 and II, subjects with PD, n?=?60). Bone mineral density of lumbar spine, femoral neck, distal radius, and total body were measured, and quantity and localization of vertebral deformities were performed by the vertebral fracture assessment (VFA). Ten-year probability of OFs was assessed by Ukrainian version of FRAX®. It was established that BMD of lumbar spine, femoral neck, distal radius, and total body in PD women was reliably lower compared to CG. The frequency of OFs in PD subjects was higher compared to CG (51.7 and 11.3%, respectively) with prevalence of vertebral fractures (VFs) in women with PD (52.6% among all fractures). 47.4% of the females had combined VFs: 74.2% of VFs were in thoracic part of the spine and 73.7% were wedge ones. Ten-year probability of major OFs and hip fracture were higher in PD women compared to CG with and without BMD measurements. Inclusion of PD in the FRAX calculation increased the requirement of antiosteoporotic treatment from 5 to 28% (without additional examination) and increased the need of additional BMD measurement from 50 to 68%. Anterior/posterior vertebral height ratios (Th8-Th11) measured by VFA in PD females without confirmed vertebral deformities were lower compared to indices of CG. In conclusion, women with PD have lower BMD indices, higher rate of osteoporosis, and risk of future low-energy fractures that should be taken into account in the assessment of their osteoporosis risk and clinical management.
| S-EPMC7132579 | biostudies-literature
Project description:In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD.IntroductionHypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce.MethodsRetrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history.ResultsAnalysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was - 0.1 (SD 1.9), and mean total hip T-Score was - 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20%) patients (p < 0.001) with 21 of them having biallelic mutations.ConclusionBMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis.Trial registration numberGerman register for clinical studies (DRKS00014022) DATE OF REGISTRATION: 02/10/2018 - retrospectively registered.
| S-EPMC7838076 | biostudies-literature
Project description:With aging, poor bone mineral density (BMD) and accelerated decrease in BMD are strong risk factors for fracture. Reports of the associations of dietary protein intake with bone strength are inconsistent, possibly owing to differences in protein sources and amino acid (AA) composition. We examined the associations of serum AA with 4-year hip BMD loss and subsequent fracture risk within 10 years in older community-dwelling adults, and further addressed whether lifestyle, dietary protein intake and its source, and body composition would affect the associations. In 1424 men and 1573 women (mean age 72 years), using binary logistic regression, higher serum valine, leucine, isoleucine and tryptophan concentrations were associated (or approaching a borderline significance in case of the last three ones) with less hip BMD decline (defined as BMD loss ? 2.8 times the precision error of the BMD measurement at femoral neck) in 4 years later, with the OR (95%CI) /SD of AA increase, ranging from 0.83 (0.75, 0.91) to 0.92 (0.87, 0.98) after multiple adjustments for baseline age, gender, BMI, BMD, estimated glomerular filtration rate (eGFR), dietary protein intake (animal- and plant-derived protein intakes), calcium intake, established lifestyles (physical activity level, smoking and alcohol drinking status), osteoporosis medications, and changes of body fat and lean muscle mass. Higher serum total homocysteine (tHcy) concentration was independently associated with BMD decline 4 years later (OR (95%CI) /SD of 1.16 (1.05, 1.27)). Using multivariate Cox regression, higher serum tryptophan concentration potentially predicted low risk of incident major osteoporotic fractures (MOFs) (HR/SD (95%CI)=0.86 (0.75, 0.98)) after multiple adjustments. Higher serum tHcy was associated with MOFs (HR/SD (95%CI)=1.29 (1.12, 1.50)) risk after multiple adjustments in men. These findings suggest that a specific AA profile correlates with greater BMD and lower subsequent fracture risk, independent of diet and lifestyle factors.
| S-EPMC6925590 | biostudies-literature
Project description:Introduction: Chronic pancreatitis (CP) can lead to malnutrition, an established risk factor for low bone mineral density (BMD) and fractures. This study aims to determine the prevalence of low BMD, assess fracture incidence and explore risk factors for fractures in patients with CP. Patients and methods: We performed a retrospective analysis of all patients treated for CP at Karolinska University Hospital between January 1999 and December 2020. Electronic medical records were retrieved to assess demographic, laboratory and clinical data. Patients subjected to dual-energy X-ray absorptiometry (DXA) were categorised as either low BMD or normal BMD. We investigated whether the rate of fractures, defined by chart review, differed between these groups using Cox regression, adjusting the model for age, sex and body mass index (BMI). Additional within-group survival analysis was conducted to identify potential risk factors. Results: DXA was performed in 23% of patients with definite CP. Some 118 patients were included in the final analysis. Low BMD was present in 63 (53.4%) patients. Mean age at CP diagnosis in the total cohort was 53.1 years and was significantly lower in patients with normal BMD than in patients with low BMD (45.5 vs. 59.8, p < 0.001). Significant differences were observed in smoking status and disease aetiology, i.e., a higher proportion of patients with low BMD were current or former smokers, with nicotine or alcohol being a more common cause of CP (p < 0.05). Total follow-up time was 898 person-years. Fractures were found in 33 (28.0%) patients: in 5 of 55 patients (16.7%) with normal DXA and in 28 of 63 patients (44.4%) with low BMD (adjusted hazard ratio = 3.4, 95% confidence interval (CI) = 1.2-9.6). Patients with at least 3 months of consecutive pancreatic enzyme replacement therapy (PERT) or vitamin D treatment had a longer median time to fracture after CP diagnosis. Conclusion: DXA was only performed in 23% of patients with definite CP in this study, indicating a low adherence to current European guidelines. A low BMD was found in 53.4% of patients with CP, and 44% of the patients with a low BMD experienced a fracture during follow-up. Moreover, the fracture rate in patients with low BMD increased compared to those with normal BMD.
| S-EPMC8308495 | biostudies-literature
Project description:BackgroundWe investigated the prevalence of and the factors associated with a high risk of osteoporotic fractures in Korean patients with ankylosing spondylitis (AS).MethodsThis was a multicenter, retrospective study including 219 AS patients from five university hospitals; the control group was selected by matching age and sex with those of the AS patients. The fracture risk was evaluated based on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry and the fracture risk assessment tool (FRAX) with/without BMD.ResultsThe mean age of the patients was 47.6 years, and 144 (65.8%) patients were men. According to the WHO criteria and FRAX with/without BMD, the candidates for pharmacological treatment were 44 (20.1%), 20 (13.2%), and 23 (15.1%) patients, respectively, significantly more than those in the healthy control group. Among them, the proportion of patients receiving osteoporosis treatment was 39.1-75%. In logistic regression analysis, menopause was an independent factor for the high risk of fracture according to the WHO criteria and FRAX with/without BMD. C-reactive protein level (odds ratio (OR) 3.8 and OR 6) and glucocorticoid use (OR 1.5 and OR 1.7) were associated with a high risk of osteoporotic fracture based on FRAX without BMD and osteoporosis diagnosed according to the WHO criteria.ConclusionsOur study suggests that both FRAX and WHO criteria may be complementary for treatment decisions to reduce osteoporotic fractures in patients with AS.
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